A systems perspective on rare diseases: integrating human phenotype ontology with the Anukta framework of Ayurveda

A systems perspective on rare diseases: integrating human phenotype ontology with the Anukta framework of Ayurveda | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article A systems perspective on rare diseases: integrating human phenotype ontology with the Anukta framework of Ayurveda Deepika Jangir, Aditi Joshi, Saketh Ram Thrigulla, Abhimanyu Kumar, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6639616/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Rare diseases pose significant diagnostic and management challenges. In Ayurveda, these conditions are not explicitly mentioned (referred as Anukta Vyadhi) and are interpreted using foundational principles of Dosha imbalance with a systems perspective. This study examines the potential of the Anukta Vyadhi framework to deconvolute rare diseases. Human Phenotype Ontology (HPO), comprising 10,610 phenotypic terms across 12,678 rare diseases, was used to create a unifying vocabulary for mapping with Ayurvedic classifications. 140 Nanatamja Vikara (NV) based phenotypic descriptions that map to imbalance of specific Dosha Vata (80 nV), Pitta (40 nP) and Kapha (20 nK) curated from classical Ayurveda texts were mapped to HPO phenotypes. An extensive exercise was undertaken to preserve the meaning and context of Sanskrit descriptions while mapping HPO phenotypes and applying the structured principles of the Anukta Vyadhi framework. Rare diseases were re-annotated with nV, nP, and nK-labeled phenotypes and reinterpreted through this lens. The framework was further applied to three exemplary rare diseases—Steinert Myotonic Dystrophy (108 HPO terms), Syndromic Diarrhea (52 HPO terms), and Alstrom Syndrome (117 HPO terms)—to demonstrate its utility. Of the total NVs (140), 92% (128) mapped to 199 HPO IDs which corresponded to 7,200 rare diseases. Among these, 66% were uniquely enriched in nV associated phenotypes, followed by nP (6.5%) and nK (3.3%). Approximately 18% of diseases exhibited dual NV involvement, while 5% had contributions from all three Dosha. Seizures, short stature, and ptosis were predominant features of nV; gastroesophageal reflux, fever, and abnormal skin blistering of nP; and obesity, lethargy, and pallor were dominant of nK. Detailed case interpretations revealed that Steinert Myotonic Dystrophy (SMD) was primarily associated with Vata and secondarily with Kapha, Syndromic Diarrhea (SD) with Vata-Pitta involvement, and Alstrom Syndrome (ALMS) with contributions from all three doshas.This Anukta Vyadhi framework provides an innovative approach for interpreting rare diseases through foundational principles of Dosha . Integration of this framework with HPO provides (a) an assistive tool for rare disease diagnostics in Ayurveda clinics and (b) opens avenues of redefining rare diseases from systems perspective and (c) palliative management through complementary therapies. Integrative & Complementary Medicine Rare diseases Human Phenotype Ontology Anukta Vyadhi Nanatamja Vikara personalized medicine Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Background Rare diseases, collectively affecting 3.5–5.9% of the population, present a significant challenge to modern healthcare due to their low prevalence, complex etiology, and limited treatment options ( 1 ). Despite advancements in genomics and precision medicine, the average time to diagnose a rare disease remains 7–10 years, often leading to delayed or missed interventions ( 2 , 3 ). These conditions are frequently degenerative, significantly impacting the quality of life and placing a heavy financial burden on affected individuals and healthcare systems ( 4 ). As a result, many patients seek alternative and complementary approaches, including Ayurveda’s holistic disease management, which offers a personalized and systemic perspective on health and disease progression ( 5 , 6 ). In an Ayurveda setting, patients often present with rare diseases described from a modern medicine perspective, which focuses on specific organs, but Ayurveda looks at disease from a systems perspective, seeing organs as places where the imbalances manifest ( 7 – 9 ). For an Ayurveda practitioner, to diagnose and evolve the most appropriate therapeutic approach, these clinical phenotypes must be de-convolved in Ayurveda perspective. One of the key barriers is the absence of a shared interoperable language that unifies the core principles of both medical systems. Disease perturbation in Ayurveda is primarily assessed through examination of imbalance of three physiological entities “Tri- dosha ” that govern the kinetic ( Vata ), metabolic ( Pitta ), and structural ( Kapha ) axes of the entire system ( 10 – 12 ) (Supplementary note). Depending on the proportions of the three Dosha the diseases “ Vikriti ” are described ( 11 ) The diseases have been categorized into two distinct groups: endogenous diseases ( Nija Vyadhi ) and exogenous diseases ( Agantuja Vyadhi ) where the former is further classified into Nanatamja Vikara (NV) and Samanyaja Vikara (SV) depending on the involvement of single or multiple Dosha respectively. NV forms the first foundational principle towards understanding diseases with 80 types of Vata , 40 types of Pitta , and 20 types of Kapha NV herein as nV ,nP and nK are described depending on the dash imbalance involved ( 10 , 13 – 15 ) (Supplementary note). For example, pain, inflammation and obesogenic phenotype, regardless of its location in the body or general conditions, are each categorized under broad phenotypic groups nV, nP and nK respectively. In contemporary practices of Ayurveda, Dosha imbalances form the initial point of inquiry to understand the diseases. Research spanning over two decades has provided evidence of molecular correlates of Dosha and has led to the development of an Ayurgenomics framework to bridge the ontologies at the molecular level ( 12 ). Unlike conventional medicine, Ayurveda describes disease states in a dynamic, system-based manner, and several conditions recognized today are not explicitly named in ancient texts. Ayurveda addresses unlisted or newly emerging diseases under an Anukta Vyadhi (unexplained or unsaid diseases) framework, where classical scholars emphasized the importance of understanding diseases based on their phenotypic attributes rather than their nomenclature ( 16 ). It is explicitly stated that as the number of rare diseases is innumerable ( 10 , 15 , 16 ) with hundreds of phenotypes and clinically heterogeneous, it becomes a challenge to comprehend and map every disease with classical textual descriptions (Supplementary note). This framework offers an opportunity to apply foundational principles to novel diseases through abductive reasoning (Atidesha Tantrayukti) where analogy and similarity enables systemic understanding beyond direct textual descriptions ( 17 , 18 ). It aims to elucidate the root cause of the disease by linking its manifestation to Dosha imbalance using a three-pronged approach (Trividha Bodhya Sangraha) - involved Dosha (Vikara Prakrtiti) , location of disease in body (Adhisthana) and primary causes of disease (Samutthana) ( 10 ). We hypothesized that Ayurveda’s systems understanding from Dosha perspective when integrated with the standardized phenotypic vocabulary such as the Human Phenotype Ontology provide a novel framework for understanding heterogeneity seen in rare diseases ( 16 ). This study attempts to build a framework to bridge ontologies of two contrasting systems of medicine from the first principles of Anukta i.e. Dosha that define NV and SV ( 10 , 13 – 15 ) (Supplementary note). We explored the utility of Human Phenotype Ontology (HPO) that provides a standardized vocabulary through unifying human phenotype codes (HP ID’s) for describing 10610 phenotypic abnormalities in over 12,678 rare diseases, to address this objective ( 9 ). HPO’s interoperable interface has been integrated into electronic health records (EHRs) in many bio banks and has been adopted for 10 different languages ( 17 ). It has been used extensively for phenotype-driven differential diagnostics, genomic analysis, and translational research ( 18 , 19 ). By extensively curating Ayurvedic NV and SV annotating them to corresponding HPO phenotypic descriptors, and synthesizing this information through the Anukta framework, we demonstrate how this approach: (a) enhances the understanding of rare diseases through the systems perspective of Ayurveda; (b) reveals Dosha -specific signatures underlying clinical heterogeneity; and (c) lays the groundwork for developing an interoperable ontological framework for seamless dialogue in integrative medicine settings. Methods 1. Literature mining for comprehensive understanding of Nanatmaja Vikara Ayurveda literature is primarily descriptive and qualitative, whereas Human Phenotype Ontology (HPO) relies on quantitative, measurable phenotypes. To overcome the divide, a comprehensive mining of Ayurveda literature with respect to basic principles of Ayurveda for 80 nV, 40 nP and 20 nK Vikara was carried out for understanding and diagnosis of diseases (Supplementary note). This included curating information with respect to Dosha (basic humor), Dhatu (Body tissues), Mala (waste product), Srotas (microchannels), Trisutra (Cause, symptoms, treatment), Aavarana (obstruction of/by Vata ), Anukta (Unsaid/ undescribed), Trividh Bodhya Sangraha (triads of disease) etc. Charaka Samhita along with authoritative commentaries such as Ayurvedadipika by Chakrapani were referenced to ensure authenticity and appropriateness ( https://niimh.nic.in/ebooks/ecaraka/?mod=read ). Contemporary medical interpretations and terminologies were also used for better comprehension and interpretation and mapping to modern terminologies 2. Annotation to HPO from Dosha perspective Diseases in Ayurveda are broadly classified into NV if caused by a single Dosha imbalance and SV when two or more Dosha are involved. We utilized the HPO version released in October 2022, which included 12,678 diseases and 10,610 non-redundant phenotypic features for annotation ( 9 ). The following exercise was done: 2.1 Mapping of HPO phenotypes to perspective In an earlier exercise, a team of Ayurveda doctors manually correlated each of the HPO terms with one of the three Dosha (Vata, Pitta , or Kapha) based on the foundational principles of Ayurveda described in ancient texts ( 9 ). This annotation encompasses the entire disease spectrum, from onset to progression and prognosis. Each Dosha carries distinct attributes, and its imbalance manifests through characteristic symptoms across multiple organ systems. For instance, Vata imbalance is marked by dryness, which presents in various forms such as dry skin (HP: 0000958), dry mouth (HP: 0000217), vaginal dryness (HP: 0031088), dry cough (HP: 0031246) and many others. In contrast, Pitta imbalance is often associated with increased heat and inflammation, manifesting as bleeding tendencies (HP: 0000421), hemorrhage (HP: 0040242) and burning sensations (HP: 6000420). Meanwhile, Kapha imbalance tends to result in stagnation and heaviness, leading to symptoms such as anorexia (HP: 0002039), excessive salivation (HP: 0003781), and lethargy (HP: 0001254). Also, phenotypic attributes related to sweat, stool, urine etc. and Dosha involvement in symptoms from different tissues like lymph, blood, muscle, adipose, bones, marrow, reproductive tissue, skin, nervous were also considered. By mapping these phenotypic expressions to Dosha imbalances, we create a structured framework that integrates Ayurveda and modern clinical description, through unifying phenotype ontologies. (Supplementary table S1) 2.2 Mapping of Nanatamja Vikara to HPO IDs There are some fundamental differences present between Ayurveda and modern medicine for defining diseases. This was taken into consideration during annotation of all NV to HPO interface. For instance- brittle nails ( Nakhbheda ), in Ayurveda is considered a disorder associated with the Vata Dosha (nV), while HPO classifies it as a phenotypic abnormality of nails (HPO ID: HP:0001808) related to 28 different diseases. Excessive thirst (Polydipsia, Trishna-adhikya ) is a Pitta related disorder (nP), whereas HPO lists it as a symptom (HPO ID: HP: 0001959) found in over 62 diseases. Excessive sleepiness ( Nidra adhikya) is categorized as a Kapha related disorder (nK) in Ayurveda HPO (HPO ID: HP: 0100786) associated with 28 diseases. There were few NV feature annotations not found in HPO. (Supplementary table S2) 3. Co-occurrence Network of Nanatamja Vikara Chord diagrams were generated in R using phenotype–disease association data. The input included all mapped NV —Vata, Pitta , and Kapha —along with their corresponding diseases sourced from the Human Phenotype Ontology (HPO). Co-occurrence was calculated based on the number of diseases shared between two or more phenotypes. 4. Interpretation of rare diseases in Ayurveda setting with HPO integrated Anukta framework 4.1 Case Selection Three rare diseases—Steinert Myotonic Dystrophy (SMD, ORPHA:273), Syndromic Diarrhea (SD, ORPHA:84064), and Alstrom Syndrome (ALMS, ORPHA:64)—were selected for analysis from an Ayurveda perspective based on their multisystem involvement and availability of well-annotated phenotypic data in the Human Phenotype Ontology (HPO) and published literature. These disorders exhibit contrasting phenotypic profiles, are clinically heterogeneous, and contain many HPO terms, making them suitable for demonstrating the application of the Anukta Vyadhi framework. For each of three diseases, phenotypic features were extracted from the HPO database and further supplemented with clinical information from comprehensive peer-reviewed sources ( 20 – 22 ). 4.2 Ayurveda Mapping via the Anukta Vyadhi Framework Phenotypes were mapped onto Ayurveda categories using the Anukta Vyadhi framework, which considers Trividha Bodhya Sangraha including Dosha involvement ( Vikara Prakriti) , site of disease ( Adhisthana) , and observable clinical manifestations ( Samutthana) . Specifically, phenotypes were assigned to one of the NV categories— Vata (nV), Pitta (nP), or Kapha (nK)—based on Ayurveda physiological principles and classical interpretations, supported by expert consensus from Ayurveda scholars and clinicians. A two-tiered annotation strategy was employed: NV Mapping: Selected HPO terms that showed a direct conceptual alignment with Nanatmaja categories were annotated accordingly. SV Mapping: Remaining HPO terms were classified under the broader Dosha categories ( Vata, Pitta, Kapha ) based on previously conducted mapping exercises and Ayurveda reasoning. The distribution of Dosha annotations including counts of nV, nP, nK, and V, P, K categories are visualized using bar plots to identify dominant patterns (Fig. 5). These Dosha patterns were then correlated with classical Ayurveda descriptions of disease progression, pathophysiology, and system-level dysfunctions. In addition, Ayurveda textual descriptors were mapped onto clinical phenotypes using interpretative methods grounded in Ayurveda epistemology. This ensured the semantic integrity of Sanskrit terms and avoided superficial or literal translation mismatches. Each disease was then re-contextualized within an Ayurveda clinical framework by identifying: Dosha progression over time, Disease classification (e.g., Sahaja Vyadhi , Adibala Pravritta Vyadhi ), Possible categorization under Yapya Roga (manageable but not curable). The resulting synthesis was used to generate disease-specific Ayurveda profiles and to propose potential therapeutic and palliative strategies based on Ayurveda principles. Results and Discussion HPO descriptors for bridging Ayurveda and modern clinical phenotypes The annotation of NV with modern medical phenotype database through literature mining posed multiple challenges. The principles of Ayurveda are more qualitative, holistic, and non-linear while modern medicine follows a quantitative, pathology-based approach. During the annotation the direct correlations were quite difficult. Another concern was the ambiguous and cryptic nature of Sanskrit terms depending on context and lack of direct equivalents terminology for Ayurveda concepts like cold body temperature ( Sheeta Agnita ), burning sensation ( Osha ) and many more (Supplementary table S2). Ayurveda knowledge varies across different schools and relies on empirical wisdom, which often lacks large-scale clinical validation in the form of modern parameters. To overcome such challenges, we first explored the feasibility of utilizing the Anukta Vyadhi framework and NV with modern medical terminologies for understanding rare diseases as a first milestone. In an earlier study, through a comprehensive and systematic approach, a total of 10,610 phenotypes spanning 12,678 rare diseases were examined and manually annotated based on their clinical characteristics in alignment with the attributes of Vata, Pitta , and Kapha Dosha , as described in classical Ayurveda literature ( 9 ). Remarkably, all HPO phenotypes could be mapped to one or more Dosha , highlighting the universal applicability of the Tridosha framework in capturing phenotypic diversity. This supports the possibility of convergence of traditional Ayurveda classifications with modern clinical phenotyping through a unifying language ( 9 ). In addition to this, 140 NV terms — representing Dosha specific disease manifestations in Ayurveda — were mapped to the most appropriate corresponding HPO phenotypes. Of these, nearly 92% of the NV terms apart from few (2 nV, 6 nP and 4 nK) could be successfully mapped to at least one HPO phenotype and a few of them were map able to multiple terms. (Table 1) Table 1 Count of Nanatamja Vikara Mapping to HPO Phenotypes and Rare Diseases nV nP nK Total No. of NV Features 80 40 20 140 No. of NV Mapped to HPO Phenotypes 78 34 16 128 No. of HPO Phenotypes Mapped to NV 134 42 23 199 Over 56% (7200) of all rare diseases were found to have at least one phenotypic feature corresponding to NV. The prevalence of NV features showed distinct differences depending on the Dosha imbalance. Analysis of the mapping revealed that Vata -associated disorders were the most prevalent (4786) among rare diseases, followed by those of Pitta (465) and Kapha dominance (240). However, the disease associated with combination of Vata with Pitta (858) or Kapha (419) were more likely. This resonates with Ayurveda descriptions, wherein Vata , regarded as the most dominant Dosha , affects multiple systems and is prone to early imbalances ( 23 ). Pitta and Kapha are significantly lower in the number of diseases they uniquely impact. In 5% of the diseases all the three NVs are present (Fig. 1). Further, the Dosha pattern observed in SV (general diseases) was found to be consistent with the fundamental axes defined by NV characteristics. Even for diseases lacking a direct mapping to NV, the predominance of Dosha features within their HPO phenotypic profiles allowed their classification within the Ayurveda Tridosha framework( 9 ). Topographical Presentation and Systemic Manifestations of Nanatamja Vikara The ordering of nV phenotypes seems much arranged as it first describes the phenotypes from the toe to upward towards the head following the body's natural axis. These also reflect progressive manifestation of Vata related disorders that primarily impacts the musculo-skeletal, neurological as well as psychological functions encompassing a wide spectrum of phenotypes. For instance: Musculoskeletal: pain ( Padshool, Gud Arti) , stiffness ( Urustambh, Trikgraha ), muscle wasting ( Pindiko udvestan ), deformities (Vatakhuddata ). Neurological: weakness ( Akshivyudas ), sensory loss ( Padsuptata ), seizures ( Aakshepaka ), paralysis ( Ardita ). Autonomic: bowel irregularities ( Vidbheda ), abnormal respiration ( Vaksh uprodha ), tachycardia/bradycardia ( Hritdrava, Hritmoha ) Cranial Sensory: hearing loss ( Badhirya ), anosmia ( Ghran nasha ), tinnitus ( Ashabdashravana ). Cognitive & Psychological: depression ( Vishada ), insomnia ( Aswapana ), drowsiness ( Jarimbha ), syncope ( Tama ). Unlike Vata , Pitta NV mainly impacts physiological functions linked to impaired inflammation, metabolism, and blood-related conditions. The phenotypes described have manifestations in skin, mucosa, and sensory tissues. For instance: Thermoregulatory: fever ( Ushmadhikya ), burning sensations ( Osha ). Digestive and hepatic: reflux ( Amlak ), biliary dysfunction ( Kamla ), halitosis ( putimukhata ). Blood and Immune: purpura ( Rakta kotha ), abnormal bleeding ( Rakta pitta ), jaundice ( Haritata ). Dermatological: skin lesions ( Rakta visphota ), ulcers ( Angavadarana ), flushing ( Daha ) hyperhidrosis ( Atiswedasch ). Oral and Upper Respiratory: stomatitis ( Aasyapaka ), pharyngitis ( Galapaka ). Ocular: conjunctival icterus ( Nilika ). Kapha disorders predominantly reflect hypo-functionality — a slowing down of physiological activities, accumulation of fluids, decreased metabolism, and cooling of body systems. This is in sharp contrast to the hyperactivity and inflammatory profile of Pitta and the degenerative/mobility spectrum of Vata . The phenotypes of these also manifest in various systems. For instance: Neurological: lethargy ( Alasyam ), excessive sleep ( Nidradhikyam ) Gastrointestinal: poor appetite ( Tripti ), dyspepsia ( Apakti ). Cardiovascular and Metabolic: obesity ( Atisthulata ), atherosclerosis ( Dhamani pratichaya ), pericardial effusion ( Hridya upalepa ). Respiratory and Mucosal: excessive salivation ( Mukhshrava ), abnormal sputum ( Shleshm udeernam ), laryngeal edema ( Kanth upalepa ). Cold Disorders: coldness (Balasaka9), hypothermia ( Staimitya ). Skin and Immunological: urticarial ( Udard ), pallor ( Sweta avabhasata ). Co-occurrence Network of Nanatamja Vikara In all the groups of NVs there were several features that emerged as the most reported in the context of rare disease associations while others were relatively less frequent (Fig. 2–4) as described below: 1. Vata Nanatamja Vikara Within the subset of 80 nV features, seizure or involuntary movement ( Aakshepaka), short as well as severely short stature ( Vamantva) , and abdominal distension ( Udavarta) were the most frequently co-occurring phenotypes. The co-occurrence was associated with 2426, 1921, 837 rare diseases respectively. Conversely, features like stiff ankle ( Gulphagraha ), proximal limb muscle stiffness ( Urusaada ), and parageusia ( Kashayasyata ) were reported only in single diseases. Also, multiple NVs were reported in many rare diseases (Fig. 2). 2. Pitta Nanatamja Vikara Among the 40 nP features, hot flashes ( Daha) , skin blistering, pustules, vesicles ( Raktavisphota ), eczema ( Twakawadaran ) emerged as the most mapped phenotypes, associated with 431, 216, 191 rare diseases respectively. On the other hand, phenotypes like parageusia ( Tiktasyata ) and balanitis, penile freckling ( Medhrapaka ), and abnormal liver physiology ( Kamala ) associated with single rare diseases (Fig. 3). 3. Kapha Nanatamja Vikara Within the 20 nK features, Early satiety ( Tripti ), lethargy ( Alasyam ), obesity ( Atisthulata ) was the most frequently reported, associated with 163, 189, 340, rare diseases respectively. In contrast, features like abnormal sputum ( Shleshmodirnam ), laryngeal edema ( Kanthuplaepha ), and dyspepsia ( Apakti ) were the least frequently reported (Fig. 4). Application of Anukta Framework in Interpretation of three Rare Diseases Case Study 1 : Dosha Based Interpretation of Steinert Myotonic Dystrophy (SMD) (ORPHA: 273) 1.1 Overview of the disease based on synthesis from HPO Steinert Myotonic Dystrophy (SMD) is a multisystem muscle disorder characterized by myotonia, progressive muscle weakness, cardiac conduction abnormalities, cataracts, endocrine dysfunction, sleep disorders, and baldness. Among the 108 documented HPO phenotypes (Supplementary table S3), the most frequently observed includes: Neuromuscular Abnormalities: Facial muscle weakness, masticatory muscle abnormality, distal muscle weakness, myotonia with warm-up phenomenon, foot dorsiflexor weakness. Cardiac and Endocrine Manifestations: Prolonged QRS complex, conduction abnormalities, atrial fibrillation. Neurological and Behavioral Symptoms: Personality impairment, cognitive decline, hypersomnia, abnormal REM sleep, atypical behavior, sleep apnea, excessive daytime somnolence. Motor and Sensory Dysfunction: Poor fine motor coordination, gait disturbance. Pain and Fatigue: Myalgia, fatigue. 1.2 Dosha Annotation of SMD Phenotypes Annotation of SMD-associated phenotypes through the Anukta Vyadhi framework reveal predominant involvement of nV (six) followed by nK (two) and no nP. The features of Nanatmaja along with the HPO terms are given in table 2. Table 2 Associated Nanatamja (nV,nP,nK) features with SMD, SD and ALMS in HPO Disease Name NV HPO ID HPO Term SMD Atipralapa (nV) HP:0000712 Emotional lability Vishada (nV) HP:0000716 Depression Vidbheda (nV) HP:0002014 Diarrhea Padbhransa (nV) HP:0009027 Foot dorsiflexor weakness Anavasthita Chitta (nV) HP:0031466 Impairment in personality Vata Khuddata (nV) HP:0001762 Talipes equinovarus Nidradhikyam (nK) HP:0001262 Excessive daytime somnolence SD Rukshata (nV) HP:0000958 Dry skin Vamantva (nV) HP:0004322 Short stature Jiva Dan (nP) HP:0025085 Bloody diarrhea Antrdaha (nP) HP:0005263 Gastritis Shweta Avabhasata (nK) HP:0007513 Generalized hypopigmentation ALMS Vamantva (nV) HP:0004322 Short stature Amlak (nP) HP:0002020 Gastroesophageal reflux Atitriptisch (nP) HP:0002591 Polyphagia Kamla (nP) HP:0031865 Abnormal liver physiology Atisthulata (nK) HP:0001513 Obesity Remaining of phenotypes mapped to V (94), P ( 24 ) and K ( 25 ) (Fig. 5). This clearly demonstrates Vata predominance in SMD, both at the phenotype and NV levels, with lesser involvement of Kapha and minimal association with Pitta . The Dosha distribution pattern, visualized in the accompanying histogram (Fig. 5), underscores the central role of Vata vitiation in SMD's clinical manifestation. 1.3 Utilization of Anukta Framework in the Perspective of SMD SMD is a rare disorder caused by mutations in the DMPK gene. It acts as a non-receptor serine/threonine protein kinase which is necessary for the maintenance of skeletal muscle structure and function ( 24 ). According to Ayurveda, this would also belong to the class of congenital ( Sahaja Vyadhi ) and hereditary disorder ( Adibala Pravritta Vyadhi) ( 25 ); ( Beeja Bhaga Avyava Dusti ) which is not curable but manageable ( Yapya Roga ) ( 10 ) (Supplementary note). Using the Anukta Vyadhi principle in conjunction with the detailed SMD description ( 20 ), the following insights from Ayurveda perspective can be threaded (Table 3). Table 3 Clinical presentation of SMD with associated key symptoms and Ayurveda overview Clinical Presentation Age at Onset Key Symptoms Ayurvedic Overview Congenital DM1 Intrauterine Polyhydramnios, fetal weakness, hypotonia, delayed milestones, cerebral atrophy V/K – Severe Vata derangement (Vyana, Prana); Kapha impairs growth Childhood Onset DM1 Early Childhood Facial weakness, myotonia, psychosocial issues V – Delayed cognition due to Kapha (Gurutva) & Vata (Chala Guna) Classical Adult Onset Adult Muscle weakness, ptosis, facial wasting V – Vyana Vata degeneration Myotonia Adult Handgrip, percussion, eye closure myotonia V – Vyana Vata in neuromuscular conduction Ocular Adult Posterior subcapsular cataracts V – Timira ; Vata NV Cardiac Adult Arrhythmias, conduction defects, cardiomyopathy V – Prana/Vyana Vata affecting Pranavaha Srotas CNS Adult Cognitive issues, apneas, personality disorders V – Manovaha Srotas affected Gastrointestinal Adult Constipation, diarrhea, IBS, aspiration pneumonia V + P – Apana Vata with Pitta affecting metabolism Endocrinopathy Adult Thyroid, gonadal disturbances, infertility V + K – Vata affects signaling; Kapha impacts glands Skin Adult Balding, cysts, tumors P + V + K – Inflammation (P), cysts (K), hair loss (V, P) Respiratory Adult Diaphragm myotonia, aspiration pneumonia V – Udana/Prana Vata disturbance Psychiatry Adult Anxiety, depression V – Rajo Guna and Vata predominance Pregnancy Adult Spontaneous abortion, prolonged labor V + P – Apana Vata and Rakta/Pitta imbalance Neuropathology Adult Limbic issues, apathy V – Manovaha Srotas derangement 1.4 Nanatamja Vikara based in HPO vis-a-vis with Dosha based data interpretation The above mapping shows concordance between Ayurveda NV and SMD phenotypes from HPO and clinical summary from ( 20 ): Atipralapa (irrelevant talkativeness) aligns with emotional lability (HP: 0000712), reflecting Vata in psychiatric/CNS manifestations. Vidbheda corresponds to diarrhea (HP: 0002014), linked to Vata disturbance. Padbhransa maps to foot dorsiflexor weakness (HP: 0009027), showing Vata dysfunction. Vishada (depression) and Anavasthita Chitta (unstable mind) match depression and personality impairment, pointing to Vata imbalance in Manovaha Srotas . Vata Khuddata (deformity) aligns with talipes equinovarus (HP: 0001762), another Vata related anomaly. Nidradhikyam corresponds to Excessive Somnolence (HP: 0001262), indicative of Kapha vitiation. This analysis demonstrates the explanatory power of Ayurveda Dosha theory, especially Vata derangement, in SMD's multisystem involvement. 1.5 Inference of SMD in Ayurveda clinical setting The documented phenotypes and progression of SMD clearly show Vata Dosha predominance, with secondary roles for Kapha and Pitta . This is supported by both quantitative phenotype mapping and alignment with Ayurveda principles. Features involving the musculoskeletal and nervous systems, pain, and degeneration strongly resonate with classical signs of Vata vitiation. These findings are consistent with ( 20 ), validating the Anukta framework's application. Given the Ayurveda understanding that Vata aggravation increases with age and disease progression, early regulation of Vata — beginning in childhood — could offer therapeutic advantage. Addressing associated Pitta and Kapha imbalances may help delay progression and mitigate complications. Thus, a holistic Ayurvedic approach may offer valuable palliative strategies for improving function, delaying degeneration, and enhancing the quality of life in SMD. Moreover, the implicated gene DMPK has a role in cardiac conduction, ion homeostasis and muscle contraction, and all the functions map able to the reported activity of Vata Dosha which governs the kinetic components in a system. Case Study 2 : Dosha Based Understanding of Syndromic Diarrhea (ORPHA:84064) 2.1 Overview of the disease based on synthesis from HPO Syndromic Diarrhea (SD) is a severe congenital enteropathy characterized by intractable diarrhea in the first month of life, leading to failure to thrive. It is commonly associated with facial dysmorphism, hair abnormalities, immune disorders, and intrauterine growth restriction. Among the 52 documented phenotypic features of SD (Supplementary table S4), the most frequently observed include: Gastrointestinal Manifestations: Intractable diarrhea, failure to thrive Immune and Metabolic Dysfunction: Immunodeficiency, hepatomegaly, cirrhosis Dermatological and Structural Features: Abnormal skin, café-au-lait spots, woolly hair, abnormal facial shape Developmental Abnormalities: Intrauterine growth restriction 2.2 Dosha Annotation of SD Phenotypes Annotation of SD-associated phenotypes through the Anukta Vyadhi framework revealed involvement of nV (two) followed by nP (two) and nK (one) features. Table 2 lists the Nanatamja features along with the HPO terms. The remaining phenotypes mapped to V (43), P ( 16 ) and K ( 7 ) (Fig. 5). The dual-layered annotation clearly demonstrates the dominance of Vata and Pitta Dosha in SD’s clinical expression, with minimal Kapha involvement. The Dosha distribution, illustrated in (Fig. 5), underscores the central role of Vata-Pitta vitiation in SD pathophysiology. 2.3 Utilization of Anukta Framework in the Perspective of SD Syndromic Diarrhea (SD), is caused by mutations in the SKIC2 and SKIC3 genes, a multi-protein complex that assists the RNA-degrading exosome during the mRNA decay and quality-control pathways( 21 ). As in SD, Ayurveda would also classify this as a congenital hereditary disorder which is not curable but can be managed (Supplementary note). Using the Anukta Vyadhi principle in conjunction with the detailed description from ( 21 ), the following insights from Ayurveda perspective can be threaded as mentioned in Table 4. Table 4 Clinical presentation of SD with associated key symptoms and Ayurveda overview Clinical Presentation Age at Onset Key Symptoms & Dosha Association Ayurveda Overview Chronic diarrhea Infancy Feeding issues, colitis, gastritis V + P – Udana, Samana Vata and Pachaka Pitta derangement Hair abnormalities Childhood Brittle, woolly, unmanageable hair V + P – Vyana Vata, Bhrajaka Pitta derangement; Ruksha Guna of Vata Facial dysmorphism Childhood Wide forehead, coarse features V – Vata derangement Immune defect Childhood Low immunoglobulins, low lymphocytes V + P – Ranjaka Pitta and Vyana Vata derangement IUGR Intrauterine Low birth weight, preterm birth V – Vata vitiation Liver disease Childhood Cirrhosis, hepatomegaly, hepatoblastoma P – Pachaka Pitta and Samana Vata imbalance Skin abnormalities Childhood Café-au-lait spots, xerosis P – Bhrajaka Pitta; with Vata’s Ruksha Guna Cardiac abnormalities Childhood Tetralogy of Fallot, septal defects V – Vyana Vata derangement Platelet abnormality Childhood Increased platelet size P + V – Ranjaka Pitta and Vyana Vata involvement 2.4 Nanatamja Vikara based in HPO vis-a-vis with Dosha based data interpretation The above mapping shows concordance between Ayurveda NV and SD phenotypes from HPO and clinical summary from( 21 ). Mapping NV with HPO terms and clinical features shows clear Ayurveda parallels: Rukshata (dryness), a Vata NV, maps to dry skin (HP: 0000958), correlating with xerosis and rubbery skin in SD. Vamantva (short stature), also a Vata NV, aligns with short stature (HP: 0004322), linked to IUGR and growth retardation. Jiva Dan (bloody diarrhea), a Pitta NV, maps to bloody diarrhea (HP: 0025085), reflecting colitis and chronic digestive issues. Antrdaha (internal burning), a Pitta Vikara , corresponds to gastritis (HP: 0005263), commonly reported in SD. Shweta Avabhasata (hypopigmentation), a Kapha NV, maps to generalized hypopigmentation (HP: 0007513), associated with skin anomalies. This integrative mapping underscores Ayurveda’s potential in rare disease phenotyping by linking traditional observations to modern clinical taxonomies. 2.5 Inference of SD in Ayurveda clinical settin g A detailed analysis of clinical phenotypes and disease trajectory in Syndromic Diarrhea (SD) indicates predominant Vata and Pitta Dosha involvement, with lesser Kapha contribution. This Dosha pattern is supported by both phenotype annotation and NV mapping. Within the HPO framework, SD features — particularly gastrointestinal dysfunction, metabolic disturbances, skin anomalies, and IUGR — align with classical symptoms of Vata-Pitta vitiation. These findings are consistent with the clinical descriptions provided by( 21 ), reinforcing the Ayurveda interpretation. In Ayurveda, Vata often amplifies Pitta derangement. Hence, early intervention should focus on regulating both Vata and Pitta , while supportive strategies aimed at Kapha stabilization may help slow disease progression and improve patient outcomes. A holistic Ayurveda approach to SD may thus offer valuable palliative care, enhance functional capacity, mitigate complications, and improve quality of life. Case Study 3 : Dosha Based Understanding of Alstrom Syndrome (ORPHA: 64) 3.1 Overview of the disease based on synthesis from HPO Alstrom Syndrome (ALMS) is a rare multi-systemic disorder characterized by cone-rod dystrophy, progressive hearing loss, obesity, insulin resistance, type 2 diabetes mellitus, dilated cardiomyopathy (DCM), and progressive hepatic and renal dysfunction. Among the 117 documented phenotypic features of AS (Supplementary table S5), the most frequently observed includes: Developmental and Growth Abnormalities: Short stature, obesity Sensory and Neurological Manifestations: Otitis media, progressive sensorineural hearing loss, visual loss, retinal dystrophy, blindness Metabolic and Endocrine Dysfunction: Insulin resistance, hypertriglyceridemia, type 2 diabetes mellitus Cardiac and Systemic Complications: Dilated cardiomyopathy, progressive hepatic and renal dysfunction 3.2 Dosha Annotation of ALMS Phenotypes Annotation of ALMS-associated phenotypes through the Anukta Vyadhi framework reveal involvement of nV (one) followed by nP (three) and nK (one). The features of Nanatmaja features along with the HPO terms are given in Table 2. The remaining phenotypes mapped to V (83), P (43) and to K ( 21 ) (Fig. 5). This annotation underscores the multi-systemic nature of ALMS, with all three Dosha involved in the disease's expression. Pitta -related NV are most frequent, followed by those associated with Vata and Kapha . 3.3 Utilization of Anukta Framework in the Perspective of ALMS Alstrom Syndrome, caused by mutations in the ALMS1 gene. The encoded protein functions in microtubule organization, particularly in the formation and maintenance of cilia. According to Ayurveda this could also be classified as a congenital hereditary disorder that is manageable but not curable (Supplementary note). Using data from( 22 ), and applying the Anukta Vyadhi principle, the disease expression is interpreted through Dosha specific characteristics (Table 5). Table 5 Clinical presentation of ALMS with associated key symptoms and Ayurveda overview Clinical Presentation Age at Onset Key Symptoms Ayurveda overview Visual impairment < 6 months Retinal dystrophy, photophobia, strabismus Aalochaka Pitta with Vata disturbance Deafness Early childhood Sensorineural hearing loss Chala Guna of Vata disturbance Cardiovascular disease Infant to adult Cardiomyopathy, obesity, pulmonary issues Margavarodhjanya Vyana Vata with Avabodhaka Kapiha vitiation Endocrine/metabolic issues After puberty Hypothyroidism, short stature, scoliosis Asthivaha Srotas vitiation with Kapha disturbance Male hypogonadism After puberty Testicular atrophy, erectile dysfunction Shukravaha Srotodusti due to Vata Female hyperandrogenism After puberty Hirsutism, PCOS, obesity, hyperinsulinemia Kapha vitiation with Apana Vata Childhood obesity Early childhood Hyperphagia, obesity Atisthulya; Kapha NV Diabetes and dyslipidemia Early childhood T2DM, pancreatitis, hypertriglyceridemia Tridosha involvement Fatty liver disease Early childhood Cirrhosis, liver fibrosis, insulin resistance Pachaka Pitta with Samana Vata Respiratory issues Early childhood Otitis, pneumonia, fibrosis Inflammatory pathology; Pranavaha Srotas vitiation Renal/urological complications Mid-childhood–adulthood Renal failure, hypertension, uricemia Tridosha vitiation; Mutravaha Srotas Dysuria Late teens Urinary incontinence, pain Apana Vata disturbance Gastrointestinal dysfunction Childhood GERD, nausea, volvulus Pachaka Pitta with Vata vitiation Neurodevelopmental issues Early childhood Autism, seizures, sleep issues Vyana Vata with Pitta ; Manovaha Srotas involvement Psychosocial symptoms Adolescence Anxiety, depression, learning difficulties Manovaha Srotas vitiation; Vishada (nV) 3.4 Nanatamja Vikara based on HPO vis-a-vis with Dosha based data interpretation Mapping NV to HPO terms and clinical features reported by( 22 ) reveals strong correlations: Vamantva (short stature), a Vata NV, corresponds to short stature (HP: 0004322), aligning with developmental delay. Amlak (acid reflux) and Atitriptisch (polyphagia), both Pitta NV, correspond to gastroesophageal reflux (HP: 0002020) and polyphagia (HP: 0002591), seen in metabolic and GI dysfunctions. Kamala (abnormal liver physiology), a Pitta NV, maps to abnormal liver physiology (HP: 0031865), present in hepatic disorders and systemic complications. Atisthulata (obesity), a Kapha NV, maps to obesity (HP: 0001513), characteristic of early ALMS presentation. This mapping demonstrates the translational value of Ayurveda Dosha theory in explaining the phenotypic complexity of ALMS. 3.5 Inference of ALMS in Ayurveda clinical setting A comprehensive evaluation of ALMS through both HPO and Ayurvedic lenses reveals a sequential manifestation of Dosha , beginning with Kapha predominance in early childhood ( Balavastha ), followed by Pitta and Vata aggravation with disease progression. Phenotypes involving vision, metabolism, endocrine functions, neurological development, and hepatic/renal systems reflect Tridosha involvement and corroborates with ciliary dysfunction causing systemic manifestation( 9 ). The predominance of Pitta NV aligns with the systemic inflammatory and metabolic dysfunctions documented in ALMS. These findings underscore the utility of the Anukta Vyadhi framework in interpreting rare genetic disorders like ALMS. Early Ayurveda intervention focusing on Kapha regulation, followed by targeted strategies for managing Vata and Pitta aggravation, may offer a holistic approach for palliative care, functional support, and enhanced quality of life in affected individuals. Comparative Summary of Dosha Profiles Across all three diseases, distinct Dosha signatures were observed (Table 6). Table 6 Dosha count in SMD, SD and ALMS: Disease Dominant Dosha NV Count (nV/nP/nK) Total Dosha -Linked Phenotypes (V/P/K) SMD Vata-Kapha 6 / 0 / 2 94 / 24 / 25 SD Vata-Pitta 2 / 2 / 1 43 / 16 / 7 ALMS Tridoshaja 1 / 3 / 1 83 / 43 / 21 This integrative annotation revealed disease-specific Ayurveda pathophysiological patterns. The mapping not only demonstrated semantic compatibility between Ayurveda and contemporary phenotyping but also provided insights into Dosha progression and systemic involvement. The Anukta Vyadhi framework thus offers a valuable lens for interpreting complex, heterogeneous phenotypes in rare diseases and guiding personalized, Dosha oriented clinical strategies. Conclusion The innovative Dosha centric Anukta Vyadhi framework proposed here provides a deeper systems-level model for understanding the complexity of multi-systemic rare diseases. It not only enhances explanatory power but also opens new avenues for integrative phenotyping and context-specific complementary therapeutic strategies aimed at improving the quality of life for individuals affected by rare diseases. Importantly, the Anukta framework has been developed based on Human Phenotype Ontology (HPO) annotations of rare diseases. However, given that modern medicine predominantly adopts an organ-centric approach, many phenotypic manifestations described in Ayurveda may not be catalogued within existing databases. This underscores the need for a reassessment strategy that systematically captures Ayurveda phenotypic attributes, particularly through the lens of NV, in rare disease clinics. This might also reduce the time to diagnosis of rare diseases. Such an approach could open new possibilities for holistic management and palliative care of rare disease patients. Furthermore, the integration of curated rare disease datasets with Ayurveda-based phenotyping, supported by artificial intelligence and large language models, could significantly augment the future of integrative medicine. Coupled with Ayurgenomics, this could also enable novel drug repurposing strategies guided by Dosha based endophenotypes, offering a transformative pathway for rare disease therapeutics. Declarations Ethics approval and consent to participate No ethical approval and consent was required. Clinical trial number Not applicable Consent for publication Consent from all authors taken. Availability of data and materials The data is provided within the manuscript and Supplementary files. Competing interests The authors declare no competing interests. Funding Authors receive financial support from MoA (Ministry of Ayush) Authors' contributions MM designed the study. DJ, SRT, and AK contributed to the Ayurveda interpretation. DJ curated HPO terms and conducted Ayurveda mining. DJ, AJ, and MM performed the data analysis and prepared the figures. DJ, AJ, and MM wrote the manuscript. Acknowledgements MM and DJ would like to thank Dr. Ravi Pratap Singh for valuable discussion. Authors acknowledge financial support from MOA (Ministry Of AYUSH) for Center of Excellence “AyurTech” (S/MOA/MTM/AA/20210105), IIT Jodhpur. Authors acknowledge IIT Jodhpur for infrastructure support. References Nguengang Wakap S, Lambert DM, Olry A, Rodwell C, Gueydan C, Lanneau V et al (2020) Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. Eur J Hum Genet 28(2):165–173 Pavisich K, Jones H, Baynam G (2024) The diagnostic odyssey for children living with a rare disease – Caregiver and patient perspectives: A narrative review with recommendations. Rare 2:100022 Bauskis A, Strange C, Molster C, Fisher C (2022) The diagnostic odyssey: insights from parents of children living with an undiagnosed condition. Orphanet J Rare Dis. ;17(1) Austin CP, Cutillo CM, Lau LPL, Jonker AH, Rath A, Julkowska D et al (2018) Future of Rare Diseases Research 2017–2027: An IRDiRC Perspective. Clin Transl Sci 11:21–27 Costa-Font J, Sato A (2024) Cultural persistence and the ‘herbal medicine paradox’: Evidence from European data. J Health Psychol. Feb 1 Astin JA Why Patients Use Alternative Medicine Results of a National Study [Internet]. Available from: http://jama.jamanetwork.com/ Pogue RE, Cavalcanti DP, Shanker S, Andrade RV, Aguiar LR, de Carvalho JL et al (2018) Rare genetic diseases: update on diagnosis, treatment and online resources. Drug Discovery Today 23:187–195 Loscalzo J, Barabasi AL (2011) Systems biology and the future of medicine. Wiley Interdiscip Rev Syst Biol Med 3(6):619–627 Joshi A, Jangir D, Sharma A, Anand T, Verma H, Yadav M et al (2024) Ayurveda based phenotype annotation integrated with Expectation Maximization algorithm reveal six biological clusters of rare diseases: potential in resolving ciliopathies [Internet]. Available from: http://biorxiv.org/lookup/doi/10.1101/2024.09.13.612844 Vrat Sharma P Jaikrishnadas Ayurveda Series Caraka-Samhita Seminar . CHAUKHAMBHA ORIENTALIA Prasher B, Gibson G, Mukerji M (2016) Genomic insights into ayurvedic and western approaches to personalized medicine. J Genet 95(1):209–228 Mukerji M (2023) Ayurgenomics-based frameworks in precision and integrative medicine: Translational opportunities. Camb Prisms: Precision Med. ;1 Kumari H, Cs P (2023) Concept of NV in Ayurveda. IJBPAS [Internet]. ;12(2):950–4. Available from: https://doi.org/10.31032/IJBPAS/2023/12.2.6893 Kumari H, Pandey CS Perspectives of Understanding Vataja NV. Available from: https://doi.org/10.46607/iamj2410052022 B PS (2020) Maharoga Adhyaya. In: K AC, R S, D YS, B G (eds) Charak Samhita New Edition. Charak Samhita Research, Training and Skill Development Centre (CSRTSDC), pp 22–22 K AC, R S, D YS, B G (eds) (2020) Trishothiya Adhyaya. Charak Samhita New Edition. Charak Samhita Research, Training and Skill Development Centre (CSRTSDC), pp 20–20 The Library of the University of California Los Angeles [Internet] Available from: http://www.arcliive.org/details/englislitranslati03susr Susruta-Samhita Kalpasthana and Uttaratantra Gargano MA, Matentzoglu N, Coleman B, Addo-Lartey EB, Anagnostopoulos AV, Anderton J et al (2024) The Human Phenotype Ontology in 2024: phenotypes around the world. Nucleic Acids Res 52(D1):D1333–D1346 Son JH, Xie G, Yuan C, Ena L, Li Z, Goldstein A et al (2018) Deep Phenotyping on Electronic Health Records Facilitates Genetic Diagnosis by Clinical Exomes. Am J Hum Genet 103(1):58–73 Smedley D, Robinson PN (2015) Phenotype-driven strategies for exome prioritization of human Mendelian disease genes. Genome Med. ;7(1) Díaz-Santiago E, Moya-García AA, Pérez-García J, Yahyaoui R, Orengo C, Pazos F et al (2024) Better understanding the phenotypic effects of drugs through shared targets in genetic disease networks. Front Pharmacol. ;15 Turner C, Hilton-Jones D (2010) The myotonic dystrophies: Diagnosis and management. J Neurol Neurosurg Psychiatry 81:358–367 Fabre A, Martinez-Vinson C, Goulet O, Badens C (2013) Syndromic diarrhea/Tricho-hepato-enteric syndrome. Orphanet J Rare Dis. ;8 Tahani N, Maffei P, Dollfus H, Paisey R, Valverde D, Milan G et al (2020) Consensus clinical management guidelines for Alström syndrome. Orphanet J Rare Dis. ;15(1) Swetha BM, Kulkarni M, Hullur Y (2024) A review on Janusandhigata Vata. J Ayurveda Integr Med Sci 9(2):258–262 Safran M, Dalah I, Alexander J, Rosen N, Iny Stein T, Shmoish M et al (2010) GeneCards Version 3: the human gene integrator. Database (Oxford) . ;2010 Sharma SPV Susruta-Samhita: Text with English Translation, Dalhana’s Commentary along with Critical Notes Additional Declarations The authors declare no competing interests. Supplementary Files SupplementarynoteAnukta.docx Supplementary Note Anukta SupplementaryTablesNanatmaj12.xlsx supplementary Table Anukta Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6639616","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":458751086,"identity":"beab229e-c83c-47bb-a954-f7d556f6614c","order_by":0,"name":"Deepika Jangir","email":"","orcid":"","institution":"Center of Excellence - Ayurtech, School of Artificial Intelligence and Data Science, IIT Jodhpur, Rajasthan, 342037, India","correspondingAuthor":false,"prefix":"","firstName":"Deepika","middleName":"","lastName":"Jangir","suffix":""},{"id":458751087,"identity":"c31341cd-5eda-4e78-996f-82ee31ff231a","order_by":1,"name":"Aditi Joshi","email":"","orcid":"","institution":"Center of Excellence - Ayurtech, School of Artificial Intelligence and Data Science, IIT Jodhpur, Rajasthan, 342037, India","correspondingAuthor":false,"prefix":"","firstName":"Aditi","middleName":"","lastName":"Joshi","suffix":""},{"id":458751088,"identity":"e12dc6ed-bddf-4912-96d1-b0d81fd5d9a6","order_by":2,"name":"Saketh Ram Thrigulla","email":"","orcid":"","institution":"CCRAS-National Institute of Indian Medical Heritage, Hyderabad, India","correspondingAuthor":false,"prefix":"","firstName":"Saketh","middleName":"Ram","lastName":"Thrigulla","suffix":""},{"id":458751089,"identity":"de79bf70-9e67-42a9-a620-99dd5e9e14f3","order_by":3,"name":"Abhimanyu Kumar","email":"","orcid":"","institution":"Center of Excellence - Ayurtech, School of Artificial Intelligence and Data Science, IIT Jodhpur, Rajasthan, 342037, India","correspondingAuthor":false,"prefix":"","firstName":"Abhimanyu","middleName":"","lastName":"Kumar","suffix":""},{"id":458751090,"identity":"8685d172-249c-4c34-a450-8b781467afbe","order_by":4,"name":"Mitali Mukerji","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAuUlEQVRIiWNgGAWjYDACZiB+YGDDw8bAkADi8xChBagnwSCNh42NaC0gaxIYDjMwsBHrLt12/oMfEgrOy/DJNzxg+FHDIGNOSIvZYWZmiQSD22CHMfYcY+CxbCCshQGuhYG3gYHH4AARtvxIMDgHseUvkVrYgLYcAGthJtYWM4sEg2SgloSEwzLHJIjQcv7g4xsf/tjZyzefSXz4psbGnqAWJMCTAFQsQbx6IGAnwfhRMApGwSgYUQAACkkzqh+KOJ4AAAAASUVORK5CYII=","orcid":"","institution":"Department of Bioscience and Bioengineering, IIT Jodhpur, Rajasthan, 342037, India","correspondingAuthor":true,"prefix":"","firstName":"Mitali","middleName":"","lastName":"Mukerji","suffix":""}],"badges":[],"createdAt":"2025-05-11 12:45:53","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-6639616/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6639616/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":83293095,"identity":"734b9d16-8726-4bda-8749-99b435adbf2e","added_by":"auto","created_at":"2025-05-22 13:22:54","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":75680,"visible":true,"origin":"","legend":"\u003cp\u003eDistribution of diseases associated with NV - \u003cem\u003eVata \u003c/em\u003e(nV), \u003cem\u003ePitta \u003c/em\u003e(nP), and \u003cem\u003eKapha \u003c/em\u003e(nK). This Venn diagram illustrates the overlap and specificity of disease associations across the three \u003cem\u003eDoshas\u003c/em\u003e. A total of 7,200 unique diseases were identified, with \u003cem\u003eVata\u003c/em\u003e associated phenotypes showing the largest exclusive share (66.5%). Shared intersections highlight overlapping disease associations across \u003cem\u003eDosha \u003c/em\u003eprofiles, with 360 diseases common to all three.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-6639616/v1/ebd308b2b00b38b6d3183895.png"},{"id":83294277,"identity":"27fef598-d2bd-41ba-a487-496c22a9368a","added_by":"auto","created_at":"2025-05-22 13:30:53","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1580446,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDisease Co-occurrence Network of \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eVata NVs:\u003c/strong\u003e\u003c/em\u003e The figure illustrates the chord network for 78 out of 80 classical \u003cem\u003eVata NV\u003c/em\u003e that mapped to HPO terms. The figure explains the widespread inter-phenotype associations, underscoring the systemic nature of \u003cem\u003eVata\u003c/em\u003e linked disorders. Central players such as seizure or involuntary movement (\u003cem\u003eAakshepaka)\u003c/em\u003e, abdominal distension (\u003cem\u003eUdavarta)\u003c/em\u003e, and short stature (\u003cem\u003eVamantva)\u003c/em\u003e demonstrated strong connectivity, reflecting their frequent co-occurrence across a broad range of neurological, musculoskeletal, and systemic conditions. Phenotypes with a greater number of diseases have been labelled with English terms. All the Ayurveda phenotypes mapped to HPO have been mentioned in Supplementary table S2.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-6639616/v1/aaf5544692ca8faabde00360.png"},{"id":83295197,"identity":"b9e9a9ae-213e-43eb-9260-fa7d111edbc9","added_by":"auto","created_at":"2025-05-22 13:38:53","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":859680,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDisease Co-occurrence Network of \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003ePitta Nanatamja Vikara\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e: \u003c/strong\u003eDepicted here is the co-occurrence pattern of 34 \u003cem\u003ePitta NV\u003c/em\u003e, mapped from a total of 40 classical phenotypes to HPO terms. The chords reflect the extent of shared disease associations between phenotype pairs. Prominent phenotypes such as hot flashes (\u003cem\u003eDaha)\u003c/em\u003e, skin blistering, pustules, vesicles (\u003cem\u003eRaktavisphota\u003c/em\u003e), and eczema (\u003cem\u003eTwakawadaran\u003c/em\u003e) indicating their frequent appearance across diverse \u003cem\u003ePitta\u003c/em\u003e linked clinical profiles—particularly in conditions associated with inflammation, dermatological manifestations. Phenotypes with a greater number of diseases have been labelled with English terms. All the Ayurveda phenotypes mapped to HPO have been mentioned in Supplementary Table S2.\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6639616/v1/6a89cedc54167c24f839d8e8.jpeg"},{"id":83295200,"identity":"fb2e4f88-9895-45f1-96dc-5eb29040c5ee","added_by":"auto","created_at":"2025-05-22 13:38:54","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":651347,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDisease Co-occurrence Network of \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eKapha \u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003eNV:\u003c/strong\u003e Chord diagram visualizes \u003cem\u003eKapha \u003c/em\u003eNV mapped to the Human Phenotype Ontology (HPO). Out of 20 classical \u003cem\u003eKapha\u003c/em\u003ephenotypes, 16 were successfully mapped to HPO terms. One mapped phenotype, Dyspepsia (\u003cem\u003eApakti) \u003c/em\u003ewas excluded from the diagram due to its lack of shared disease co-occurrence. The width and density of the chords represent the frequency of overlapping diseases between phenotypes. Notably, early satiety (\u003cem\u003eTripti\u003c/em\u003e), lethargy (\u003cem\u003eAlasyam\u003c/em\u003e), obesity (\u003cem\u003eAtisthulata\u003c/em\u003e) and pallor (\u003cem\u003eShwetaavabhasata\u003c/em\u003e) emerged as central phenotypic hub, exhibiting strong connectivity and frequent co-occurrence with other traits—reflecting their shared involvement across a spectrum of metabolic and respiratory conditions. Phenotypes with more number of diseases have been labelled with English terms. All the Ayurveda phenotypes mapped to HPO have been mentioned in Supplementary Table S2.\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-6639616/v1/ef5e8e852ca57f309ba08349.png"},{"id":83293083,"identity":"2653607f-ae25-42ea-9f74-7cc5fe3e3edf","added_by":"auto","created_at":"2025-05-22 13:22:53","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":86316,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDistribution of phenotypes across three rare diseases: \u003c/strong\u003e\u003cem\u003eVata\u003c/em\u003e (V), \u003cem\u003ePitta\u003c/em\u003e(P), \u003cem\u003eKapha\u003c/em\u003e (K) and their NV subtypes (nV, nP, nK), with the x-axis representing \u003cem\u003eDosha\u003c/em\u003e and the y-axis indicating the number of associated disease count. (a) For Steinert myotonic dystrophy (SMD), \u003cem\u003eVata\u003c/em\u003e-associated phenotypes predominate, followed by comparable counts of \u003cem\u003eKapha\u003c/em\u003e and \u003cem\u003ePitta\u003c/em\u003e, with no nP phenotypes observed. (b) In Syndromic diarrhea (SD), \u003cem\u003eVata\u003c/em\u003eagain shows the highest association, followed by \u003cem\u003ePitta\u003c/em\u003e and \u003cem\u003eKapha\u003c/em\u003e, with nV and nP subtypes equally represented, and one phenotype categorized under nK. (c) For Alstrom syndrome (ALMS), \u003cem\u003eVata\u003c/em\u003e related phenotypes are dominant, followed by \u003cem\u003ePitta\u003c/em\u003e and \u003cem\u003eKapha\u003c/em\u003e, with a higher count of nP phenotypes and equal representation of nV and nK.\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-6639616/v1/a64bf3e6e17a8d0a98043c8b.png"},{"id":83295658,"identity":"d2952cdb-3525-40ed-9f5d-7ef978a06494","added_by":"auto","created_at":"2025-05-22 13:46:56","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4923506,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6639616/v1/2e8b4cb0-c204-4883-8894-f799505f7f07.pdf"},{"id":83293093,"identity":"03630541-2c4a-402a-b969-afa3de567126","added_by":"auto","created_at":"2025-05-22 13:22:54","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":11665350,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Note Anukta\u003c/p\u003e","description":"","filename":"SupplementarynoteAnukta.docx","url":"https://assets-eu.researchsquare.com/files/rs-6639616/v1/9cfeab107be31ca9fbe1048a.docx"},{"id":83293081,"identity":"66828acd-9f3d-425b-8d74-bc7794c78ff5","added_by":"auto","created_at":"2025-05-22 13:22:53","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":340407,"visible":true,"origin":"","legend":"\u003cp\u003esupplementary Table Anukta\u003c/p\u003e","description":"","filename":"SupplementaryTablesNanatmaj12.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6639616/v1/e554c16d1a0899011428444a.xlsx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003eA systems perspective on rare diseases: integrating human phenotype ontology with the Anukta framework of Ayurveda\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003eRare diseases, collectively affecting 3.5\u0026ndash;5.9% of the population, present a significant challenge to modern healthcare due to their low prevalence, complex etiology, and limited treatment options (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Despite advancements in genomics and precision medicine, the average time to diagnose a rare disease remains 7\u0026ndash;10 years, often leading to delayed or missed interventions (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). These conditions are frequently degenerative, significantly impacting the quality of life and placing a heavy financial burden on affected individuals and healthcare systems (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). As a result, many patients seek alternative and complementary approaches, including Ayurveda\u0026rsquo;s holistic disease management, which offers a personalized and systemic perspective on health and disease progression (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn an Ayurveda setting, patients often present with rare diseases described from a modern medicine perspective, which focuses on specific organs, but Ayurveda looks at disease from a systems perspective, seeing organs as places where the imbalances manifest (\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). For an Ayurveda practitioner, to diagnose and evolve the most appropriate therapeutic approach, these clinical phenotypes must be de-convolved in Ayurveda perspective. One of the key barriers is the absence of a shared interoperable language that unifies the core principles of both medical systems. Disease perturbation in Ayurveda is primarily assessed through examination of imbalance of three physiological entities \u003cem\u003e\u0026ldquo;Tri-\u003c/em\u003edosha\u003cem\u003e\u0026rdquo;\u003c/em\u003e that govern the kinetic (\u003cem\u003eVata\u003c/em\u003e), metabolic (\u003cem\u003ePitta\u003c/em\u003e), and structural (\u003cem\u003eKapha\u003c/em\u003e) axes of the entire system (\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) (Supplementary note). Depending on the proportions of the three \u003cem\u003eDosha\u003c/em\u003e the diseases \u0026ldquo;\u003cem\u003eVikriti\u003c/em\u003e\u0026rdquo; are described (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e) The diseases have been categorized into two distinct groups: endogenous diseases (\u003cem\u003eNija Vyadhi\u003c/em\u003e) and exogenous diseases (\u003cem\u003eAgantuja Vyadhi\u003c/em\u003e) where the former is further classified into \u003cem\u003eNanatamja Vikara\u003c/em\u003e (NV) and \u003cem\u003eSamanyaja Vikara\u003c/em\u003e (SV) depending on the involvement of single or multiple \u003cem\u003eDosha\u003c/em\u003e respectively. NV forms the first foundational principle towards understanding diseases with 80 types of \u003cem\u003eVata\u003c/em\u003e, 40 types of \u003cem\u003ePitta\u003c/em\u003e, and 20 types of \u003cem\u003eKapha NV\u003c/em\u003e herein as nV ,nP and nK are described depending on the dash imbalance involved (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e) (Supplementary note). For example, pain, inflammation and obesogenic phenotype, regardless of its location in the body or general conditions, are each categorized under broad phenotypic groups nV, nP and nK respectively. In contemporary practices of Ayurveda, \u003cem\u003eDosha\u003c/em\u003e imbalances form the initial point of inquiry to understand the diseases. Research spanning over two decades has provided evidence of molecular correlates of \u003cem\u003eDosha\u003c/em\u003e and has led to the development of an Ayurgenomics framework to bridge the ontologies at the molecular level (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eUnlike conventional medicine, Ayurveda describes disease states in a dynamic, system-based manner, and several conditions recognized today are not explicitly named in ancient texts. Ayurveda addresses unlisted or newly emerging diseases under an \u003cem\u003eAnukta Vyadhi\u003c/em\u003e (unexplained or unsaid diseases) framework, where classical scholars emphasized the importance of understanding diseases based on their phenotypic attributes rather than their nomenclature (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). It is explicitly stated that as the number of rare diseases is innumerable (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e) with hundreds of phenotypes and clinically heterogeneous, it becomes a challenge to comprehend and map every disease with classical textual descriptions (Supplementary note). This framework offers an opportunity to apply foundational principles to novel diseases through abductive reasoning \u003cem\u003e(Atidesha Tantrayukti)\u003c/em\u003e where analogy and similarity enables systemic understanding beyond direct textual descriptions (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). It aims to elucidate the root cause of the disease by linking its manifestation to \u003cem\u003eDosha\u003c/em\u003e imbalance using a three-pronged approach \u003cem\u003e(Trividha Bodhya Sangraha)\u003c/em\u003e - involved \u003cem\u003eDosha (Vikara Prakrtiti)\u003c/em\u003e, location of disease in body \u003cem\u003e(Adhisthana)\u003c/em\u003e and primary causes of disease \u003cem\u003e(Samutthana)\u003c/em\u003e (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eWe hypothesized that Ayurveda\u0026rsquo;s systems understanding from \u003cem\u003eDosha\u003c/em\u003e perspective when integrated with the standardized phenotypic vocabulary such as the Human Phenotype Ontology provide a novel framework for understanding heterogeneity seen in rare diseases (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). This study attempts to build a framework to bridge ontologies of two contrasting systems of medicine from the first principles of \u003cem\u003eAnukta\u003c/em\u003e i.e. \u003cem\u003eDosha\u003c/em\u003e that define NV and SV (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e) (Supplementary note). We explored the utility of Human Phenotype Ontology (HPO) that provides a standardized vocabulary through unifying human phenotype codes (HP ID\u0026rsquo;s) for describing 10610 phenotypic abnormalities in over 12,678 rare diseases, to address this objective (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). HPO\u0026rsquo;s interoperable interface has been integrated into electronic health records (EHRs) in many bio banks and has been adopted for 10 different languages (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). It has been used extensively for phenotype-driven differential diagnostics, genomic analysis, and translational research (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eBy extensively curating Ayurvedic NV and SV annotating them to corresponding HPO phenotypic descriptors, and synthesizing this information through the \u003cem\u003eAnukta\u003c/em\u003e framework, we demonstrate how this approach: (a) enhances the understanding of rare diseases through the systems perspective of Ayurveda; (b) reveals \u003cem\u003eDosha\u003c/em\u003e-specific signatures underlying clinical heterogeneity; and (c) lays the groundwork for developing an interoperable ontological framework for seamless dialogue in integrative medicine settings.\u003c/p\u003e "},{"header":"Methods","content":"\u003ch3\u003e1. Literature mining for comprehensive understanding of \u003cem\u003eNanatmaja Vikara\u003c/em\u003e\u003c/h3\u003e\n\u003cp\u003eAyurveda literature is primarily descriptive and qualitative, whereas Human Phenotype Ontology (HPO) relies on quantitative, measurable phenotypes. To overcome the divide, a comprehensive mining of Ayurveda literature with respect to basic principles of Ayurveda for 80 nV, 40 nP and 20 nK \u003cem\u003eVikara\u003c/em\u003e was carried out for understanding and diagnosis of diseases (Supplementary note). This included curating information with respect to \u003cem\u003eDosha\u003c/em\u003e (basic humor), \u003cem\u003eDhatu\u003c/em\u003e (Body tissues), \u003cem\u003eMala\u003c/em\u003e (waste product), \u003cem\u003eSrotas\u003c/em\u003e (microchannels), \u003cem\u003eTrisutra\u003c/em\u003e (Cause, symptoms, treatment), \u003cem\u003eAavarana\u003c/em\u003e (obstruction of/by \u003cem\u003eVata\u003c/em\u003e), \u003cem\u003eAnukta\u003c/em\u003e (Unsaid/ undescribed), \u003cem\u003eTrividh Bodhya Sangraha\u003c/em\u003e (triads of disease) etc. \u003cem\u003eCharaka Samhita along\u003c/em\u003e with authoritative commentaries such as \u003cem\u003eAyurvedadipika\u003c/em\u003e by \u003cem\u003eChakrapani\u003c/em\u003e were referenced to ensure authenticity and appropriateness (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://niimh.nic.in/ebooks/ecaraka/?mod=read\u003c/span\u003e\u003c/span\u003e). Contemporary medical interpretations and terminologies were also used for better comprehension and interpretation and mapping to modern terminologies\u003c/p\u003e\n\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n\u003ch2\u003e2. Annotation to HPO from \u003cem\u003eDosha\u003c/em\u003e perspective\u003c/h2\u003e\n\u003cp\u003eDiseases in Ayurveda are broadly classified into NV if caused by a single \u003cem\u003eDosha\u003c/em\u003e imbalance and SV when two or more \u003cem\u003eDosha\u003c/em\u003e are involved. We utilized the HPO version released in October 2022, which included 12,678 diseases and 10,610 non-redundant phenotypic features for annotation (\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e). The following exercise was done:\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003e2.1 Mapping of HPO phenotypes to perspective\u003c/h3\u003e\n\u003cdiv class=\"Heading\"\u003eIn an earlier exercise, a team of Ayurveda doctors manually correlated each of the HPO terms with one of the three \u003cem\u003eDosha (Vata, Pitta\u003c/em\u003e, or \u003cem\u003eKapha)\u003c/em\u003e based on the foundational principles of Ayurveda described in ancient texts (\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e). This annotation encompasses the entire disease spectrum, from onset to progression and prognosis. Each \u003cem\u003eDosha\u003c/em\u003e carries distinct attributes, and its imbalance manifests through characteristic symptoms across multiple organ systems. For instance, \u003cem\u003eVata\u003c/em\u003e imbalance is marked by dryness, which presents in various forms such as dry skin (HP: 0000958), dry mouth (HP: 0000217), vaginal dryness (HP: 0031088), dry cough (HP: 0031246) and many others. In contrast, \u003cem\u003ePitta\u003c/em\u003e imbalance is often associated with increased heat and inflammation, manifesting as bleeding tendencies (HP: 0000421), hemorrhage (HP: 0040242) and burning sensations (HP: 6000420). Meanwhile, \u003cem\u003eKapha\u003c/em\u003e imbalance tends to result in stagnation and heaviness, leading to symptoms such as anorexia (HP: 0002039), excessive salivation (HP: 0003781), and lethargy (HP: 0001254). Also, phenotypic attributes related to sweat, stool, urine etc. and \u003cem\u003eDosha\u003c/em\u003e involvement in symptoms from different tissues like lymph, blood, muscle, adipose, bones, marrow, reproductive tissue, skin, nervous were also considered. By mapping these phenotypic expressions to \u003cem\u003eDosha\u003c/em\u003e imbalances, we create a structured framework that integrates Ayurveda and modern clinical description, through unifying phenotype ontologies. (Supplementary table S1)\u003c/div\u003e\n\u003ch3\u003e2.2 Mapping of \u003cem\u003eNanatamja Vikara\u003c/em\u003e to HPO IDs\u003c/h3\u003e\n\u003cp\u003eThere are some fundamental differences present between Ayurveda and modern medicine for defining diseases. This was taken into consideration during annotation of all NV to HPO interface. For instance- brittle nails (\u003cem\u003eNakhbheda\u003c/em\u003e), in Ayurveda is considered a disorder associated with the \u003cem\u003eVata Dosha\u003c/em\u003e (nV), while HPO classifies it as a phenotypic abnormality of nails (HPO ID: HP:0001808) related to 28 different diseases. Excessive thirst (Polydipsia, \u003cem\u003eTrishna-adhikya\u003c/em\u003e) is a \u003cem\u003ePitta\u003c/em\u003e related disorder (nP), whereas HPO lists it as a symptom (HPO ID: HP: 0001959) found in over 62 diseases. Excessive sleepiness (\u003cem\u003eNidra adhikya)\u003c/em\u003e is categorized as a \u003cem\u003eKapha\u003c/em\u003e related disorder (nK) in Ayurveda HPO (HPO ID: HP: 0100786) associated with 28 diseases. There were few NV feature annotations not found in HPO. (Supplementary table S2)\u003c/p\u003e\n\u003ch3\u003e3. Co-occurrence Network of \u003cem\u003eNanatamja Vikara\u003c/em\u003e\u003c/h3\u003e\n\u003cp\u003eChord diagrams were generated in R using phenotype\u0026ndash;disease association data. The input included all mapped NV \u003cem\u003e\u0026mdash;Vata, Pitta\u003c/em\u003e, and \u003cem\u003eKapha\u003c/em\u003e\u0026mdash;along with their corresponding diseases sourced from the Human Phenotype Ontology (HPO). Co-occurrence was calculated based on the number of diseases shared between two or more phenotypes.\u003c/p\u003e\n\u003ch3\u003e4. Interpretation of rare diseases in Ayurveda setting with HPO integrated \u003cem\u003eAnukta\u003c/em\u003e framework\u003c/h3\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n\u003ch2\u003e4.1 Case Selection\u003c/h2\u003e\n\u003cp\u003eThree rare diseases\u0026mdash;Steinert Myotonic Dystrophy (SMD, ORPHA:273), Syndromic Diarrhea (SD, ORPHA:84064), and Alstrom Syndrome (ALMS, ORPHA:64)\u0026mdash;were selected for analysis from an Ayurveda perspective based on their multisystem involvement and availability of well-annotated phenotypic data in the Human Phenotype Ontology (HPO) and published literature. These disorders exhibit contrasting phenotypic profiles, are clinically heterogeneous, and contain many HPO terms, making them suitable for demonstrating the application of the \u003cem\u003eAnukta Vyadhi\u003c/em\u003e framework.\u003c/p\u003e\n\u003cp\u003eFor each of three diseases, phenotypic features were extracted from the HPO database and further supplemented with clinical information from comprehensive peer-reviewed sources (\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003e4.2 Ayurveda Mapping via the \u003cem\u003eAnukta Vyadhi\u003c/em\u003e Framework\u003c/h3\u003e\n\u003cp\u003ePhenotypes were mapped onto Ayurveda categories using the \u003cem\u003eAnukta Vyadhi\u003c/em\u003e framework, which considers \u003cem\u003eTrividha Bodhya Sangraha\u003c/em\u003e including \u003cem\u003eDosha\u003c/em\u003e involvement (\u003cem\u003eVikara Prakriti)\u003c/em\u003e, site of disease (\u003cem\u003eAdhisthana)\u003c/em\u003e, and observable clinical manifestations (\u003cem\u003eSamutthana)\u003c/em\u003e. Specifically, phenotypes were assigned to one of the NV categories\u0026mdash;\u003cem\u003eVata\u003c/em\u003e (nV), \u003cem\u003ePitta\u003c/em\u003e (nP), or \u003cem\u003eKapha\u003c/em\u003e (nK)\u0026mdash;based on Ayurveda physiological principles and classical interpretations, supported by expert consensus from Ayurveda scholars and clinicians.\u003c/p\u003e\n\u003cp\u003eA two-tiered annotation strategy was employed:\u003c/p\u003e\n\u003col\u003e\n\u003cli\u003e\n\u003cp\u003eNV Mapping: Selected HPO terms that showed a direct conceptual alignment with \u003cem\u003eNanatmaja\u003c/em\u003e categories were annotated accordingly.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eSV Mapping: Remaining HPO terms were classified under the broader \u003cem\u003eDosha\u003c/em\u003e categories (\u003cem\u003eVata, Pitta, Kapha\u003c/em\u003e) based on previously conducted mapping exercises and Ayurveda reasoning.\u003c/p\u003e\n\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eThe distribution of \u003cem\u003eDosha\u003c/em\u003e annotations including counts of nV, nP, nK, and V, P, K categories are visualized using bar plots to identify dominant patterns (Fig.\u0026nbsp;5). These \u003cem\u003eDosha\u003c/em\u003e patterns were then correlated with classical Ayurveda descriptions of disease progression, pathophysiology, and system-level dysfunctions.\u003c/p\u003e\n\u003cp\u003eIn addition, Ayurveda textual descriptors were mapped onto clinical phenotypes using interpretative methods grounded in Ayurveda epistemology. This ensured the semantic integrity of Sanskrit terms and avoided superficial or literal translation mismatches.\u003c/p\u003e\n\u003cp\u003eEach disease was then re-contextualized within an Ayurveda clinical framework by identifying:\u003c/p\u003e\n\u003col\u003e\n\u003cli\u003e\n\u003cp\u003e\u003cem\u003eDosha\u003c/em\u003e progression over time,\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003eDisease classification (e.g., \u003cem\u003eSahaja Vyadhi\u003c/em\u003e, \u003cem\u003eAdibala Pravritta Vyadhi\u003c/em\u003e),\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003ePossible categorization under \u003cem\u003eYapya Roga\u003c/em\u003e (manageable but not curable).\u003c/p\u003e\n\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eThe resulting synthesis was used to generate disease-specific Ayurveda profiles and to propose potential therapeutic and palliative strategies based on Ayurveda principles.\u003c/p\u003e"},{"header":"Results and Discussion","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003eHPO descriptors for bridging Ayurveda and modern clinical phenotypes\u003c/h2\u003e\n \u003cp\u003eThe annotation of \u003cem\u003eNV\u003c/em\u003e with modern medical phenotype database through literature mining posed multiple challenges. The principles of Ayurveda are more qualitative, holistic, and non-linear while modern medicine follows a quantitative, pathology-based approach. During the annotation the direct correlations were quite difficult. Another concern was the ambiguous and cryptic nature of Sanskrit terms depending on context and lack of direct equivalents terminology for Ayurveda concepts like cold body temperature (\u003cem\u003eSheeta Agnita\u003c/em\u003e), burning sensation (\u003cem\u003eOsha\u003c/em\u003e) and many more (Supplementary table S2). Ayurveda knowledge varies across different schools and relies on empirical wisdom, which often lacks large-scale clinical validation in the form of modern parameters. To overcome such challenges, we first explored the feasibility of utilizing the \u003cem\u003eAnukta Vyadhi\u003c/em\u003e framework and NV \u003cem\u003ewith\u003c/em\u003e modern medical terminologies for understanding rare diseases as a first milestone.\u003c/p\u003e\n \u003cp\u003eIn an earlier study, through a comprehensive and systematic approach, a total of 10,610 phenotypes spanning 12,678 rare diseases were examined and manually annotated based on their clinical characteristics in alignment with the attributes of \u003cem\u003eVata, Pitta\u003c/em\u003e, and \u003cem\u003eKapha Dosha\u003c/em\u003e, as described in classical Ayurveda literature (\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e). Remarkably, all HPO phenotypes could be mapped to one or more \u003cem\u003eDosha\u003c/em\u003e, highlighting the universal applicability of the \u003cem\u003eTridosha\u003c/em\u003e framework in capturing phenotypic diversity. This supports the possibility of convergence of traditional Ayurveda classifications with modern clinical phenotyping through a unifying language (\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e\n \u003cp\u003eIn addition to this, 140 NV terms \u0026mdash; representing \u003cem\u003eDosha\u003c/em\u003e specific disease manifestations in Ayurveda \u0026mdash; were mapped to the most appropriate corresponding HPO phenotypes. Of these, nearly 92% of the NV terms apart from few (2 nV, 6 nP and 4 nK) could be successfully mapped to at least one HPO phenotype and a few of them were map able to multiple terms. (Table 1)\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003cdiv class=\"colspec\" align=\"char\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eCount of \u003cem\u003eNanatamja Vikara\u003c/em\u003e Mapping to HPO Phenotypes and Rare Diseases\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003enV\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003enP\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003enK\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo. of NV Features\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e140\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo. of NV Mapped to HPO Phenotypes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e128\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo. of HPO Phenotypes Mapped to NV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e134\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e199\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eOver 56% (7200) of all rare diseases were found to have at least one phenotypic feature corresponding to NV. The prevalence of NV features showed distinct differences depending on the \u003cem\u003eDosha\u003c/em\u003e imbalance. Analysis of the mapping revealed that \u003cem\u003eVata\u003c/em\u003e-associated disorders were the most prevalent (4786) among rare diseases, followed by those of \u003cem\u003ePitta\u003c/em\u003e (465) and \u003cem\u003eKapha\u003c/em\u003e dominance (240). However, the disease associated with combination of \u003cem\u003eVata\u003c/em\u003e with \u003cem\u003ePitta\u003c/em\u003e (858) or \u003cem\u003eKapha\u003c/em\u003e (419) were more likely. This resonates with Ayurveda descriptions, wherein \u003cem\u003eVata\u003c/em\u003e, regarded as the most dominant \u003cem\u003eDosha\u003c/em\u003e, affects multiple systems and is prone to early imbalances (\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e). \u003cem\u003ePitta\u003c/em\u003e and \u003cem\u003eKapha\u003c/em\u003e are significantly lower in the number of diseases they uniquely impact. In 5% of the diseases all the three NVs are present (Fig.\u0026nbsp;1).\u003c/p\u003e\n \u003cp\u003eFurther, the \u003cem\u003eDosha\u003c/em\u003e pattern observed in SV (general diseases) was found to be consistent with the fundamental axes defined by NV characteristics. Even for diseases lacking a direct mapping to NV, the predominance of \u003cem\u003eDosha\u003c/em\u003e features within their HPO phenotypic profiles allowed their classification within the Ayurveda \u003cem\u003eTridosha\u003c/em\u003e framework(\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003eTopographical Presentation and Systemic Manifestations of \u003cem\u003eNanatamja Vikara\u003c/em\u003e\u003c/h2\u003e\n \u003cp\u003eThe ordering of nV phenotypes seems much arranged as it first describes the phenotypes from the toe to upward towards the head following the body\u0026apos;s natural axis. These also reflect progressive manifestation of \u003cem\u003eVata\u003c/em\u003e related disorders that primarily impacts the musculo-skeletal, neurological as well as psychological functions encompassing a wide spectrum of phenotypes. For instance:\u003c/p\u003e\n \u003col style=\"list-style-type: lower-alpha;\"\u003e\n \u003cli\u003e\n \u003cp\u003eMusculoskeletal: pain (\u003cem\u003ePadshool, Gud Arti)\u003c/em\u003e, stiffness (\u003cem\u003eUrustambh, Trikgraha\u003c/em\u003e), muscle wasting (\u003cem\u003ePindiko udvestan\u003c/em\u003e), deformities \u003cem\u003e(Vatakhuddata\u003c/em\u003e).\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eNeurological: weakness (\u003cem\u003eAkshivyudas\u003c/em\u003e), sensory loss (\u003cem\u003ePadsuptata\u003c/em\u003e), seizures (\u003cem\u003eAakshepaka\u003c/em\u003e), paralysis (\u003cem\u003eArdita\u003c/em\u003e).\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eAutonomic: bowel irregularities (\u003cem\u003eVidbheda\u003c/em\u003e), abnormal respiration (\u003cem\u003eVaksh uprodha\u003c/em\u003e), tachycardia/bradycardia (\u003cem\u003eHritdrava, Hritmoha\u003c/em\u003e)\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eCranial Sensory: hearing loss (\u003cem\u003eBadhirya\u003c/em\u003e), anosmia (\u003cem\u003eGhran nasha\u003c/em\u003e), tinnitus (\u003cem\u003eAshabdashravana\u003c/em\u003e).\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eCognitive \u0026amp; Psychological: depression (\u003cem\u003eVishada\u003c/em\u003e), insomnia (\u003cem\u003eAswapana\u003c/em\u003e), drowsiness (\u003cem\u003eJarimbha\u003c/em\u003e), syncope (\u003cem\u003eTama\u003c/em\u003e).\u003c/p\u003e\n \u003c/li\u003e\n \u003c/ol\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n \u003cp\u003eUnlike \u003cem\u003eVata\u003c/em\u003e, \u003cem\u003ePitta\u003c/em\u003e NV mainly impacts physiological functions linked to impaired inflammation, metabolism, and blood-related conditions. The phenotypes described have manifestations in skin, mucosa, and sensory tissues. For instance:\u003c/p\u003e\n \u003col style=\"list-style-type: lower-alpha;\"\u003e\n \u003cli\u003e\n \u003cp\u003eThermoregulatory: fever (\u003cem\u003eUshmadhikya\u003c/em\u003e), burning sensations (\u003cem\u003eOsha\u003c/em\u003e).\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eDigestive and hepatic: reflux (\u003cem\u003eAmlak\u003c/em\u003e), biliary dysfunction (\u003cem\u003eKamla\u003c/em\u003e), halitosis (\u003cem\u003eputimukhata\u003c/em\u003e).\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eBlood and Immune: purpura (\u003cem\u003eRakta kotha\u003c/em\u003e), abnormal bleeding (\u003cem\u003eRakta pitta\u003c/em\u003e), jaundice (\u003cem\u003eHaritata\u003c/em\u003e).\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eDermatological: skin lesions (\u003cem\u003eRakta visphota\u003c/em\u003e), ulcers (\u003cem\u003eAngavadarana\u003c/em\u003e), flushing (\u003cem\u003eDaha\u003c/em\u003e) hyperhidrosis (\u003cem\u003eAtiswedasch\u003c/em\u003e).\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eOral and Upper Respiratory: stomatitis (\u003cem\u003eAasyapaka\u003c/em\u003e), pharyngitis (\u003cem\u003eGalapaka\u003c/em\u003e).\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eOcular: conjunctival icterus (\u003cem\u003eNilika\u003c/em\u003e).\u003c/p\u003e\n \u003c/li\u003e\n \u003c/ol\u003e\n \u003cp\u003e\u003cem\u003eKapha\u003c/em\u003e disorders predominantly reflect hypo-functionality \u0026mdash; a slowing down of physiological activities, accumulation of fluids, decreased metabolism, and cooling of body systems. This is in sharp contrast to the hyperactivity and inflammatory profile of \u003cem\u003ePitta\u003c/em\u003e and the degenerative/mobility spectrum of \u003cem\u003eVata\u003c/em\u003e. The phenotypes of these also manifest in various systems. For instance:\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n \u003col style=\"list-style-type: lower-alpha;\"\u003e\n \u003cli\u003eNeurological: lethargy (\u003cem\u003eAlasyam\u003c/em\u003e), excessive sleep (\u003cem\u003eNidradhikyam\u003c/em\u003e)\u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eGastrointestinal: poor appetite (\u003cem\u003eTripti\u003c/em\u003e), dyspepsia (\u003cem\u003eApakti\u003c/em\u003e).\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eCardiovascular and Metabolic: obesity (\u003cem\u003eAtisthulata\u003c/em\u003e), atherosclerosis (\u003cem\u003eDhamani pratichaya\u003c/em\u003e), pericardial effusion (\u003cem\u003eHridya upalepa\u003c/em\u003e).\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eRespiratory and Mucosal: excessive salivation (\u003cem\u003eMukhshrava\u003c/em\u003e), abnormal sputum (\u003cem\u003eShleshm udeernam\u003c/em\u003e), laryngeal edema (\u003cem\u003eKanth upalepa\u003c/em\u003e).\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eCold Disorders: coldness (Balasaka9), hypothermia (\u003cem\u003eStaimitya\u003c/em\u003e).\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eSkin and Immunological: urticarial (\u003cem\u003eUdard\u003c/em\u003e), pallor (\u003cem\u003eSweta avabhasata\u003c/em\u003e).\u003c/p\u003e\n \u003c/li\u003e\n \u003c/ol\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\n \u003ch2\u003eCo-occurrence Network of \u003cem\u003eNanatamja Vikara\u003c/em\u003e\u003c/h2\u003e\n \u003cp\u003eIn all the groups of NVs there were several features that emerged as the most reported in the context of rare disease associations while others were relatively less frequent (Fig.\u0026nbsp;2\u0026ndash;4) as described below:\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\n \u003ch2\u003e1. Vata Nanatamja Vikara\u003c/h2\u003e\n \u003cp\u003eWithin the subset of 80 nV features, seizure or involuntary movement (\u003cem\u003eAakshepaka), short\u003c/em\u003e as well as severely short stature (\u003cem\u003eVamantva)\u003c/em\u003e, and abdominal distension (\u003cem\u003eUdavarta)\u003c/em\u003e were the most frequently co-occurring phenotypes. The co-occurrence was associated with 2426, 1921, 837 rare diseases respectively. Conversely, features like stiff ankle (\u003cem\u003eGulphagraha\u003c/em\u003e), proximal limb muscle stiffness (\u003cem\u003eUrusaada\u003c/em\u003e), and parageusia (\u003cem\u003eKashayasyata\u003c/em\u003e) were reported only in single diseases. Also, multiple NVs were reported in many rare diseases (Fig.\u0026nbsp;2).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\n \u003ch2\u003e2. Pitta Nanatamja Vikara\u003c/h2\u003e\n \u003cp\u003eAmong the 40 nP features, hot flashes (\u003cem\u003eDaha)\u003c/em\u003e, skin blistering, pustules, vesicles (\u003cem\u003eRaktavisphota\u003c/em\u003e), eczema (\u003cem\u003eTwakawadaran\u003c/em\u003e) emerged as the most mapped phenotypes, associated with 431, 216, 191 rare diseases respectively. On the other hand, phenotypes like parageusia (\u003cem\u003eTiktasyata\u003c/em\u003e) and balanitis, penile freckling (\u003cem\u003eMedhrapaka\u003c/em\u003e), and abnormal liver physiology (\u003cem\u003eKamala\u003c/em\u003e) associated with single rare diseases (Fig.\u0026nbsp;3).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\n \u003ch2\u003e3. Kapha Nanatamja Vikara\u003c/h2\u003e\n \u003cp\u003eWithin the 20 nK features, Early satiety (\u003cem\u003eTripti\u003c/em\u003e), lethargy (\u003cem\u003eAlasyam\u003c/em\u003e), obesity (\u003cem\u003eAtisthulata\u003c/em\u003e) was the most frequently reported, associated with 163, 189, 340, rare diseases respectively. In contrast, features like abnormal sputum (\u003cem\u003eShleshmodirnam\u003c/em\u003e), laryngeal edema (\u003cem\u003eKanthuplaepha\u003c/em\u003e), and dyspepsia (\u003cem\u003eApakti\u003c/em\u003e) were the least frequently reported (Fig.\u0026nbsp;4).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\n \u003ch2\u003eApplication of \u003cem\u003eAnukta\u003c/em\u003e Framework in Interpretation of three Rare Diseases\u003c/h2\u003e\n \u003cp\u003e\u003cstrong\u003eCase Study 1\u003c/strong\u003e: \u003cem\u003eDosha\u003c/em\u003e Based Interpretation of Steinert Myotonic Dystrophy (SMD) (ORPHA: 273)\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec20\" class=\"Section2\"\u003e\n \u003ch2\u003e1.1 Overview of the disease based on synthesis from HPO\u003c/h2\u003e\n \u003cp\u003eSteinert Myotonic Dystrophy (SMD) is a multisystem muscle disorder characterized by myotonia, progressive muscle weakness, cardiac conduction abnormalities, cataracts, endocrine dysfunction, sleep disorders, and baldness. Among the 108 documented HPO phenotypes (Supplementary table S3), the most frequently observed includes:\u003c/p\u003e\n \u003col\u003e\n \u003cli\u003e\n \u003cp\u003eNeuromuscular Abnormalities: Facial muscle weakness, masticatory muscle abnormality, distal muscle weakness, myotonia with warm-up phenomenon, foot dorsiflexor weakness.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eCardiac and Endocrine Manifestations: Prolonged QRS complex, conduction abnormalities, atrial fibrillation.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eNeurological and Behavioral Symptoms: Personality impairment, cognitive decline, hypersomnia, abnormal REM sleep, atypical behavior, sleep apnea, excessive daytime somnolence.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003eMotor and Sensory Dysfunction: Poor fine motor coordination, gait disturbance.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003ePain and Fatigue: Myalgia, fatigue.\u003c/p\u003e\n \u003c/li\u003e\n \u003c/ol\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec21\" class=\"Section2\"\u003e\n \u003ch2\u003e1.2 \u003cem\u003eDosha\u003c/em\u003e Annotation of SMD Phenotypes\u003c/h2\u003e\n \u003cp\u003eAnnotation of SMD-associated phenotypes through the \u003cem\u003eAnukta Vyadhi\u003c/em\u003e framework reveal predominant involvement of nV (six) followed by nK (two) and no nP. The features of \u003cem\u003eNanatmaja\u003c/em\u003e along with the HPO terms are given in table 2.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eAssociated \u003cem\u003eNanatamja\u003c/em\u003e (nV,nP,nK) features with SMD, SD and ALMS in HPO\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDisease Name\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNV\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHPO ID\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHPO Term\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"7\" align=\"left\"\u003e\n \u003cp\u003eSMD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAtipralapa (nV)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHP:0000712\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEmotional lability\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVishada (nV)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHP:0000716\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDepression\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVidbheda (nV)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHP:0002014\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDiarrhea\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePadbhransa (nV)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHP:0009027\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFoot dorsiflexor weakness\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAnavasthita Chitta (nV)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHP:0031466\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eImpairment in personality\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVata Khuddata (nV)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHP:0001762\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTalipes equinovarus\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNidradhikyam (nK)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHP:0001262\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eExcessive daytime somnolence\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"5\" align=\"left\"\u003e\n \u003cp\u003eSD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRukshata (nV)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHP:0000958\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDry skin\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVamantva (nV)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHP:0004322\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eShort stature\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eJiva Dan (nP)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHP:0025085\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBloody diarrhea\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAntrdaha (nP)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHP:0005263\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGastritis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eShweta Avabhasata (nK)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHP:0007513\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGeneralized hypopigmentation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"5\" align=\"left\"\u003e\n \u003cp\u003eALMS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVamantva (nV)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHP:0004322\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eShort stature\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAmlak (nP)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHP:0002020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGastroesophageal reflux\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAtitriptisch (nP)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHP:0002591\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePolyphagia\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eKamla (nP)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHP:0031865\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAbnormal liver physiology\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAtisthulata (nK)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHP:0001513\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eObesity\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eRemaining of phenotypes mapped to V (94), P (\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e) and K (\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e) (Fig.\u0026nbsp;5).\u003c/p\u003e\n \u003cp\u003eThis clearly demonstrates \u003cem\u003eVata\u003c/em\u003e predominance in SMD, both at the phenotype and \u003cem\u003eNV\u003c/em\u003e levels, with lesser involvement of \u003cem\u003eKapha\u003c/em\u003e and minimal association with \u003cem\u003ePitta\u003c/em\u003e. The \u003cem\u003eDosha\u003c/em\u003e distribution pattern, visualized in the accompanying histogram (Fig.\u0026nbsp;5), underscores the central role of \u003cem\u003eVata\u003c/em\u003e vitiation in SMD\u0026apos;s clinical manifestation.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec22\" class=\"Section2\"\u003e\n \u003ch2\u003e1.3 Utilization of \u003cem\u003eAnukta\u003c/em\u003e Framework in the Perspective of SMD\u003c/h2\u003e\n \u003cp\u003eSMD is a rare disorder caused by mutations in the \u003cem\u003eDMPK\u003c/em\u003e gene. It acts as a non-receptor serine/threonine protein kinase which is necessary for the maintenance of skeletal muscle structure and function (\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e). According to Ayurveda, this would also belong to the class of congenital (\u003cem\u003eSahaja Vyadhi\u003c/em\u003e) and hereditary disorder (\u003cem\u003eAdibala Pravritta Vyadhi)\u003c/em\u003e (\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e); (\u003cem\u003eBeeja Bhaga Avyava Dusti\u003c/em\u003e) which is not curable but manageable (\u003cem\u003eYapya Roga\u003c/em\u003e) (\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e) (Supplementary note).\u003c/p\u003e\n \u003cp\u003eUsing the \u003cem\u003eAnukta Vyadhi\u003c/em\u003e principle in conjunction with the detailed SMD description (\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e), the following insights from Ayurveda perspective can be threaded (Table\u0026nbsp;3).\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eClinical presentation of SMD with associated key symptoms and Ayurveda overview\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eClinical Presentation\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAge at Onset\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eKey Symptoms\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAyurvedic Overview\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCongenital DM1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIntrauterine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePolyhydramnios, fetal weakness, hypotonia, delayed milestones, cerebral atrophy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eV/K \u0026ndash; Severe \u003cem\u003eVata\u003c/em\u003e derangement (Vyana, Prana); Kapha impairs growth\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChildhood Onset DM1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEarly Childhood\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFacial weakness, myotonia, psychosocial issues\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eV \u0026ndash; Delayed cognition due to Kapha (Gurutva) \u0026amp; \u003cem\u003eVata\u003c/em\u003e (Chala Guna)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eClassical Adult Onset\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAdult\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMuscle weakness, ptosis, facial wasting\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eV \u0026ndash; \u003cem\u003eVyana Vata\u003c/em\u003e degeneration\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMyotonia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAdult\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHandgrip, percussion, eye closure myotonia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eV \u0026ndash; \u003cem\u003eVyana Vata\u003c/em\u003e in neuromuscular conduction\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOcular\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAdult\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePosterior subcapsular cataracts\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eV \u0026ndash; \u003cem\u003eTimira\u003c/em\u003e; \u003cem\u003eVata\u003c/em\u003e NV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCardiac\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAdult\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eArrhythmias, conduction defects, cardiomyopathy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eV \u0026ndash; \u003cem\u003ePrana/Vyana Vata\u003c/em\u003e affecting \u003cem\u003ePranavaha Srotas\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAdult\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCognitive issues, apneas, personality disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eV \u0026ndash; \u003cem\u003eManovaha Srotas\u003c/em\u003e affected\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGastrointestinal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAdult\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eConstipation, diarrhea, IBS, aspiration pneumonia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eV\u0026thinsp;+\u0026thinsp;P \u0026ndash; \u003cem\u003eApana Vata\u003c/em\u003e with \u003cem\u003ePitta\u003c/em\u003e affecting metabolism\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEndocrinopathy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAdult\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eThyroid, gonadal disturbances, infertility\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eV\u0026thinsp;+\u0026thinsp;K \u0026ndash; \u003cem\u003eVata\u003c/em\u003e affects signaling; \u003cem\u003eKapha\u003c/em\u003e impacts glands\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSkin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAdult\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBalding, cysts, tumors\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP\u0026thinsp;+\u0026thinsp;V\u0026thinsp;+\u0026thinsp;K \u0026ndash; Inflammation (P), cysts (K), hair loss (V, P)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRespiratory\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAdult\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDiaphragm myotonia, aspiration pneumonia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eV \u0026ndash; \u003cem\u003eUdana/Prana Vata\u003c/em\u003e disturbance\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePsychiatry\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAdult\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAnxiety, depression\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eV \u0026ndash; \u003cem\u003eRajo Guna\u003c/em\u003e and \u003cem\u003eVata\u003c/em\u003e predominance\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePregnancy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAdult\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSpontaneous abortion, prolonged labor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eV\u0026thinsp;+\u0026thinsp;P \u0026ndash; \u003cem\u003eApana Vata\u003c/em\u003e and \u003cem\u003eRakta/Pitta\u003c/em\u003e imbalance\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNeuropathology\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAdult\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLimbic issues, apathy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eV \u0026ndash; \u003cem\u003eManovaha Srotas\u003c/em\u003e derangement\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cdiv id=\"Sec23\" class=\"Section3\"\u003e\n \u003ch2\u003e1.4 \u003cem\u003eNanatamja Vikara\u003c/em\u003e based in HPO vis-a-vis with \u003cem\u003eDosha\u003c/em\u003e based data interpretation\u003c/h2\u003e\n \u003cp\u003eThe above mapping shows concordance between Ayurveda NV and SMD phenotypes from HPO and clinical summary from (\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e):\u003c/p\u003e\n \u003col\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cem\u003eAtipralapa\u003c/em\u003e (irrelevant talkativeness) aligns with emotional lability (HP: 0000712), reflecting \u003cem\u003eVata\u003c/em\u003e in psychiatric/CNS manifestations.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cem\u003eVidbheda\u003c/em\u003e corresponds to diarrhea (HP: 0002014), linked to \u003cem\u003eVata\u003c/em\u003e disturbance.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cem\u003ePadbhransa\u003c/em\u003e maps to foot dorsiflexor weakness (HP: 0009027), showing \u003cem\u003eVata\u003c/em\u003e dysfunction.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cem\u003eVishada\u003c/em\u003e (depression) and \u003cem\u003eAnavasthita\u003c/em\u003e Chitta (unstable mind) match depression and personality impairment, pointing to \u003cem\u003eVata\u003c/em\u003e imbalance in \u003cem\u003eManovaha Srotas\u003c/em\u003e.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cem\u003eVata Khuddata\u003c/em\u003e (deformity) aligns with talipes equinovarus (HP: 0001762), another \u003cem\u003eVata\u003c/em\u003e related anomaly.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cem\u003eNidradhikyam\u003c/em\u003e corresponds to Excessive Somnolence (HP: 0001262), indicative of \u003cem\u003eKapha\u003c/em\u003e vitiation.\u003c/p\u003e\n \u003c/li\u003e\n \u003c/ol\u003e\n \u003cp\u003eThis analysis demonstrates the explanatory power of Ayurveda \u003cem\u003eDosha\u003c/em\u003e theory, especially \u003cem\u003eVata\u003c/em\u003e derangement, in SMD\u0026apos;s multisystem involvement.\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec24\" class=\"Section2\"\u003e\n \u003ch2\u003e1.5 Inference of SMD in Ayurveda clinical setting\u003c/h2\u003e\n \u003cp\u003eThe documented phenotypes and progression of SMD clearly show \u003cem\u003eVata Dosha\u003c/em\u003e predominance, with secondary roles for \u003cem\u003eKapha and Pitta\u003c/em\u003e. This is supported by both quantitative phenotype mapping and alignment with Ayurveda principles.\u003c/p\u003e\n \u003cp\u003eFeatures involving the musculoskeletal and nervous systems, pain, and degeneration strongly resonate with classical signs of \u003cem\u003eVata\u003c/em\u003e vitiation. These findings are consistent with (\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e), validating the \u003cem\u003eAnukta\u003c/em\u003e framework\u0026apos;s application.\u003c/p\u003e\n \u003cp\u003eGiven the Ayurveda understanding that \u003cem\u003eVata\u003c/em\u003e aggravation increases with age and disease progression, early regulation of \u003cem\u003eVata\u003c/em\u003e \u0026mdash; beginning in childhood \u0026mdash; could offer therapeutic advantage. Addressing associated \u003cem\u003ePitta\u003c/em\u003e and \u003cem\u003eKapha\u003c/em\u003e imbalances may help delay progression and mitigate complications.\u003c/p\u003e\n \u003cp\u003eThus, a holistic Ayurvedic approach may offer valuable palliative strategies for improving function, delaying degeneration, and enhancing the quality of life in SMD.\u003c/p\u003e\n \u003cp\u003eMoreover, the implicated gene DMPK has a role in cardiac conduction, ion homeostasis and muscle contraction, and all the functions map able to the reported activity of \u003cem\u003eVata Dosha\u003c/em\u003e which governs the kinetic components in a system.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eCase Study 2\u003c/strong\u003e: \u003cem\u003eDosha\u003c/em\u003e Based Understanding of Syndromic Diarrhea (ORPHA:84064)\u003c/p\u003e\n \u003cdiv id=\"Sec25\" class=\"Section3\"\u003e\n \u003ch2\u003e2.1 Overview of the disease based on synthesis from HPO\u003c/h2\u003e\n \u003cp\u003eSyndromic Diarrhea (SD) is a severe congenital enteropathy characterized by intractable diarrhea in the first month of life, leading to failure to thrive. It is commonly associated with facial dysmorphism, hair abnormalities, immune disorders, and intrauterine growth restriction. Among the 52 documented phenotypic features of SD (Supplementary table S4), the most frequently observed include:\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv id=\"Sec26\" class=\"Section3\"\u003e\n \u003col\u003e\n \u003cli\u003eGastrointestinal Manifestations: Intractable diarrhea, failure to thrive\u003c/li\u003e\n \u003cli\u003eImmune and Metabolic Dysfunction: Immunodeficiency, hepatomegaly, cirrhosis\u003c/li\u003e\n \u003cli\u003eDermatological and Structural Features: Abnormal skin, caf\u0026eacute;-au-lait spots, woolly hair, abnormal facial shape\u003c/li\u003e\n \u003cli\u003e\u0026nbsp;Developmental Abnormalities: Intrauterine growth restriction\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec28\" class=\"Section2\"\u003e\n \u003cdiv id=\"Sec29\" class=\"Section3\"\u003e\n \u003ch2\u003e2.2 \u003cem\u003eDosha\u003c/em\u003e Annotation of SD Phenotypes\u003c/h2\u003e\n \u003cp\u003eAnnotation of SD-associated phenotypes through the \u003cem\u003eAnukta Vyadhi\u003c/em\u003e framework revealed involvement of nV (two) followed by nP (two) and nK (one) features. Table\u0026nbsp;2 lists the \u003cem\u003eNanatamja\u003c/em\u003e features along with the HPO terms. The remaining phenotypes mapped to V (43), P (\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e) and K (\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e) (Fig.\u0026nbsp;5).\u003c/p\u003e\n \u003cp\u003eThe dual-layered annotation clearly demonstrates the dominance of \u003cem\u003eVata\u003c/em\u003e and \u003cem\u003ePitta Dosha\u003c/em\u003e in SD\u0026rsquo;s clinical expression, with minimal \u003cem\u003eKapha\u003c/em\u003e involvement. The \u003cem\u003eDosha\u003c/em\u003e distribution, illustrated in (Fig.\u0026nbsp;5), underscores the central role of \u003cem\u003eVata-Pitta\u003c/em\u003e vitiation in SD pathophysiology.\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec30\" class=\"Section2\"\u003e\n \u003ch2\u003e2.3 Utilization of \u003cem\u003eAnukta\u003c/em\u003e Framework in the Perspective of SD\u003c/h2\u003e\n \u003cp\u003eSyndromic Diarrhea (SD), is caused by mutations in the \u003cem\u003eSKIC2\u003c/em\u003e and \u003cem\u003eSKIC3\u003c/em\u003e genes, a multi-protein complex that assists the RNA-degrading exosome during the mRNA decay and quality-control pathways(\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e). As in SD, Ayurveda would also classify this as a congenital hereditary disorder which is not curable but can be managed (Supplementary note).\u003c/p\u003e\n \u003cp\u003eUsing the \u003cem\u003eAnukta Vyadhi\u003c/em\u003e principle in conjunction with the detailed description from (\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e), the following insights from Ayurveda perspective can be threaded as mentioned in\u003c/p\u003e\n \u003cp\u003eTable\u0026nbsp;4.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003ctable id=\"Tab4\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eClinical presentation of SD with associated key symptoms and Ayurveda overview\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eClinical Presentation\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAge at Onset\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eKey Symptoms \u0026amp; \u003cem\u003eDosha\u003c/em\u003e Association\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAyurveda Overview\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChronic diarrhea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInfancy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFeeding issues, colitis, gastritis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eV\u0026thinsp;+\u0026thinsp;P \u0026ndash; \u003cem\u003eUdana, Samana Vata\u003c/em\u003e and \u003cem\u003ePachaka Pitta\u003c/em\u003e derangement\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHair abnormalities\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChildhood\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBrittle, woolly, unmanageable hair\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eV\u0026thinsp;+\u0026thinsp;P \u0026ndash; \u003cem\u003eVyana Vata, Bhrajaka Pitta\u003c/em\u003e derangement; \u003cem\u003eRuksha Guna\u003c/em\u003e of \u003cem\u003eVata\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFacial dysmorphism\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChildhood\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWide forehead, coarse features\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eV \u0026ndash; \u003cem\u003eVata\u003c/em\u003e derangement\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eImmune defect\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChildhood\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLow immunoglobulins, low lymphocytes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eV\u0026thinsp;+\u0026thinsp;P \u0026ndash; \u003cem\u003eRanjaka Pitta\u003c/em\u003e and \u003cem\u003eVyana Vata\u003c/em\u003e derangement\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIUGR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIntrauterine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLow birth weight, preterm birth\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eV \u0026ndash; \u003cem\u003eVata\u003c/em\u003e vitiation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLiver disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChildhood\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCirrhosis, hepatomegaly, hepatoblastoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP \u0026ndash; \u003cem\u003ePachaka Pitta\u003c/em\u003e and \u003cem\u003eSamana Vata\u003c/em\u003e imbalance\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSkin abnormalities\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChildhood\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCaf\u0026eacute;-au-lait spots, xerosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP \u0026ndash; \u003cem\u003eBhrajaka Pitta;\u003c/em\u003e with \u003cem\u003eVata\u0026rsquo;s Ruksha Guna\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCardiac abnormalities\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChildhood\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTetralogy of Fallot, septal defects\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eV \u0026ndash; \u003cem\u003eVyana Vata\u003c/em\u003e derangement\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlatelet abnormality\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChildhood\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIncreased platelet size\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP\u0026thinsp;+\u0026thinsp;V \u0026ndash; \u003cem\u003eRanjaka Pitta\u003c/em\u003e and \u003cem\u003eVyana Vata\u003c/em\u003e involvement\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec31\" class=\"Section2\"\u003e\n \u003ch2\u003e2.4 \u003cem\u003eNanatamja Vikara\u003c/em\u003e based in HPO vis-a-vis with \u003cem\u003eDosha\u003c/em\u003e based data interpretation\u003c/h2\u003e\n \u003cp\u003eThe above mapping shows concordance between Ayurveda NV and SD phenotypes from HPO and clinical summary from(\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e). Mapping NV with HPO terms and clinical features shows clear Ayurveda parallels:\u003c/p\u003e\n \u003col\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cem\u003eRukshata\u003c/em\u003e (dryness), a \u003cem\u003eVata\u003c/em\u003e NV, maps to dry skin (HP: 0000958), correlating with xerosis and rubbery skin in SD.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cem\u003eVamantva\u003c/em\u003e (short stature), also a \u003cem\u003eVata\u003c/em\u003e NV, aligns with \u003cem\u003eshort stature\u003c/em\u003e (HP: 0004322), linked to IUGR and growth retardation.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cem\u003eJiva Dan\u003c/em\u003e (bloody diarrhea), a \u003cem\u003ePitta\u003c/em\u003e NV, maps to bloody diarrhea (HP: 0025085), reflecting colitis and chronic digestive issues.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cem\u003eAntrdaha\u003c/em\u003e (internal burning), a \u003cem\u003ePitta Vikara\u003c/em\u003e, corresponds to gastritis (HP: 0005263), commonly reported in SD.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cem\u003eShweta Avabhasata\u003c/em\u003e (hypopigmentation), a \u003cem\u003eKapha\u003c/em\u003e NV, maps to generalized hypopigmentation (HP: 0007513), associated with skin anomalies.\u003c/p\u003e\n \u003c/li\u003e\n \u003c/ol\u003e\n \u003cp\u003eThis integrative mapping underscores Ayurveda\u0026rsquo;s potential in rare disease phenotyping by linking traditional observations to modern clinical taxonomies.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e2.5 Inference of SD in Ayurveda clinical settin\u003c/strong\u003e \u003cspan class=\"BoldUnderline\"\u003eg\u003c/span\u003e\u003c/p\u003e\n \u003cp\u003eA detailed analysis of clinical phenotypes and disease trajectory in Syndromic Diarrhea (SD) indicates predominant \u003cem\u003eVata\u003c/em\u003e and \u003cem\u003ePitta Dosha\u003c/em\u003e involvement, with lesser \u003cem\u003eKapha\u003c/em\u003e contribution. This \u003cem\u003eDosha\u003c/em\u003e pattern is supported by both phenotype annotation and NV mapping.\u003c/p\u003e\n \u003cp\u003eWithin the HPO framework, SD features \u0026mdash; particularly gastrointestinal dysfunction, metabolic disturbances, skin anomalies, and IUGR \u0026mdash; align with classical symptoms of \u003cem\u003eVata-Pitta\u003c/em\u003e vitiation. These findings are consistent with the clinical descriptions provided by(\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e), reinforcing the Ayurveda interpretation.\u003c/p\u003e\n \u003cp\u003eIn Ayurveda, \u003cem\u003eVata\u003c/em\u003e often amplifies \u003cem\u003ePitta\u003c/em\u003e derangement. Hence, early intervention should focus on regulating both \u003cem\u003eVata\u003c/em\u003e and \u003cem\u003ePitta\u003c/em\u003e, while supportive strategies aimed at \u003cem\u003eKapha\u003c/em\u003e stabilization may help slow disease progression and improve patient outcomes. A holistic Ayurveda approach to SD may thus offer valuable palliative care, enhance functional capacity, mitigate complications, and improve quality of life.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eCase Study 3\u003c/strong\u003e: \u003cem\u003eDosha\u003c/em\u003e Based Understanding of Alstrom Syndrome (ORPHA: 64)\u003c/p\u003e\n \u003cdiv id=\"Sec32\" class=\"Section3\"\u003e\n \u003ch2\u003e3.1 Overview of the disease based on synthesis from HPO\u003c/h2\u003e\n \u003cp\u003eAlstrom Syndrome (ALMS) is a rare multi-systemic disorder characterized by cone-rod dystrophy, progressive hearing loss, obesity, insulin resistance, type 2 diabetes mellitus, dilated cardiomyopathy (DCM), and progressive hepatic and renal dysfunction.\u003c/p\u003e\n \u003cp\u003eAmong the 117 documented phenotypic features of AS (Supplementary table S5), the most frequently observed includes:\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv id=\"Sec33\" class=\"Section3\"\u003e\n \u003col\u003e\n \u003cli\u003eDevelopmental and Growth Abnormalities: Short stature, obesity\u003c/li\u003e\n \u003cli\u003eSensory and Neurological Manifestations: Otitis media, progressive sensorineural hearing loss, visual loss, retinal dystrophy, blindness\u003c/li\u003e\n \u003cli\u003eMetabolic and Endocrine Dysfunction: Insulin resistance, hypertriglyceridemia, type 2 diabetes mellitus\u003c/li\u003e\n \u003cli\u003eCardiac and Systemic Complications: Dilated cardiomyopathy, progressive hepatic and renal dysfunction\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec35\" class=\"Section2\"\u003e\n \u003cdiv id=\"Sec36\" class=\"Section3\"\u003e\n \u003ch2\u003e3.2 \u003cem\u003eDosha\u003c/em\u003e Annotation of ALMS Phenotypes\u003c/h2\u003e\n \u003cp\u003eAnnotation of ALMS-associated phenotypes through the \u003cem\u003eAnukta Vyadhi\u003c/em\u003e framework reveal involvement of nV (one) followed by nP (three) and nK (one). The features of \u003cem\u003eNanatmaja\u003c/em\u003e features along with the HPO terms are given in Table\u0026nbsp;2. The remaining phenotypes mapped to V (83), P (43) and to K (\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e) (Fig.\u0026nbsp;5).\u003c/p\u003e\n \u003cp\u003eThis annotation underscores the multi-systemic nature of ALMS, with all three \u003cem\u003eDosha\u003c/em\u003e involved in the disease\u0026apos;s expression. \u003cem\u003ePitta\u003c/em\u003e-related NV are most frequent, followed by those associated with \u003cem\u003eVata\u003c/em\u003e and \u003cem\u003eKapha\u003c/em\u003e.\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec37\" class=\"Section2\"\u003e\n \u003ch2\u003e3.3 Utilization of \u003cem\u003eAnukta\u003c/em\u003e Framework in the Perspective of ALMS\u003c/h2\u003e\n \u003cp\u003eAlstrom Syndrome, caused by mutations in the \u003cem\u003eALMS1\u003c/em\u003e gene. The encoded protein functions in microtubule organization, particularly in the formation and maintenance of cilia. According to Ayurveda this could also be classified as a congenital hereditary disorder that is manageable but not curable (Supplementary note).\u003c/p\u003e\n \u003cp\u003eUsing data from(\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e), and applying the \u003cem\u003eAnukta Vyadhi\u003c/em\u003e principle, the disease expression is interpreted through \u003cem\u003eDosha\u003c/em\u003e specific characteristics (Table\u0026nbsp;5).\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003ctable id=\"Tab5\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eClinical presentation of ALMS with associated key symptoms and Ayurveda overview\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eClinical Presentation\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAge at Onset\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eKey Symptoms\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAyurveda overview\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVisual impairment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;6 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRetinal dystrophy, photophobia, strabismus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eAalochaka Pitta\u003c/em\u003e with \u003cem\u003eVata\u003c/em\u003e disturbance\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDeafness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEarly childhood\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSensorineural hearing loss\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eChala Guna\u003c/em\u003e of \u003cem\u003eVata\u003c/em\u003e disturbance\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCardiovascular disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInfant to adult\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCardiomyopathy, obesity, pulmonary issues\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eMargavarodhjanya Vyana Vata\u003c/em\u003e with \u003cem\u003eAvabodhaka\u003c/em\u003e Kapiha vitiation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEndocrine/metabolic issues\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAfter puberty\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHypothyroidism, short stature, scoliosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eAsthivaha Srotas\u003c/em\u003e vitiation with \u003cem\u003eKapha\u003c/em\u003e disturbance\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMale hypogonadism\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAfter puberty\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTesticular atrophy, erectile dysfunction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eShukravaha Srotodusti\u003c/em\u003e due to \u003cem\u003eVata\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFemale hyperandrogenism\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAfter puberty\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHirsutism, PCOS, obesity, hyperinsulinemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eKapha\u003c/em\u003e vitiation with \u003cem\u003eApana Vata\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChildhood obesity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEarly childhood\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHyperphagia, obesity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eAtisthulya; Kapha\u003c/em\u003e NV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDiabetes and dyslipidemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEarly childhood\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT2DM, pancreatitis, hypertriglyceridemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eTridosha\u003c/em\u003e involvement\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFatty liver disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEarly childhood\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCirrhosis, liver fibrosis, insulin resistance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003ePachaka Pitta\u003c/em\u003e with \u003cem\u003eSamana Vata\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRespiratory issues\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEarly childhood\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOtitis, pneumonia, fibrosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInflammatory pathology; \u003cem\u003ePranavaha Srotas\u003c/em\u003e vitiation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRenal/urological complications\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMid-childhood\u0026ndash;adulthood\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRenal failure, hypertension, uricemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eTridosha\u003c/em\u003e vitiation; \u003cem\u003eMutravaha Srotas\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDysuria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLate teens\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUrinary incontinence, pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eApana Vata\u003c/em\u003e disturbance\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGastrointestinal dysfunction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChildhood\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGERD, nausea, volvulus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003ePachaka Pitta\u003c/em\u003e with \u003cem\u003eVata\u003c/em\u003e vitiation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNeurodevelopmental issues\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEarly childhood\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAutism, seizures, sleep issues\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eVyana Vata\u003c/em\u003e with \u003cem\u003ePitta\u003c/em\u003e; \u003cem\u003eManovaha Srotas\u003c/em\u003e involvement\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePsychosocial symptoms\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAdolescence\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAnxiety, depression, learning difficulties\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eManovaha Srotas\u003c/em\u003e vitiation; \u003cem\u003eVishada\u003c/em\u003e (nV)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cdiv id=\"Sec38\" class=\"Section3\"\u003e\n \u003ch2\u003e3.4 \u003cem\u003eNanatamja Vikara\u003c/em\u003e based on HPO vis-a-vis with \u003cem\u003eDosha\u003c/em\u003e based data interpretation\u003c/h2\u003e\n \u003cp\u003eMapping NV to HPO terms and clinical features reported by(\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e) reveals strong correlations:\u003c/p\u003e\n \u003col\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cem\u003eVamantva\u003c/em\u003e (short stature), a \u003cem\u003eVata\u003c/em\u003e NV, corresponds to short stature (HP: 0004322), aligning with developmental delay.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cem\u003eAmlak\u003c/em\u003e (acid reflux) and \u003cem\u003eAtitriptisch\u003c/em\u003e (polyphagia), both \u003cem\u003ePitta\u003c/em\u003e NV, correspond to gastroesophageal reflux (HP: 0002020) and polyphagia (HP: 0002591), seen in metabolic and GI dysfunctions.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cem\u003eKamala\u003c/em\u003e (abnormal liver physiology), a \u003cem\u003ePitta\u003c/em\u003e NV, maps to abnormal liver physiology (HP: 0031865), present in hepatic disorders and systemic complications.\u003c/p\u003e\n \u003c/li\u003e\n \u003cli\u003e\n \u003cp\u003e\u003cem\u003eAtisthulata\u003c/em\u003e (obesity), a \u003cem\u003eKapha\u003c/em\u003e NV, maps to obesity (HP: 0001513), characteristic of early ALMS presentation.\u003c/p\u003e\n \u003c/li\u003e\n \u003c/ol\u003e\n \u003cp\u003eThis mapping demonstrates the translational value of Ayurveda \u003cem\u003eDosha\u003c/em\u003e theory in explaining the phenotypic complexity of ALMS.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e3.5 Inference of ALMS in Ayurveda clinical setting\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eA comprehensive evaluation of ALMS through both HPO and Ayurvedic lenses reveals a sequential manifestation of \u003cem\u003eDosha\u003c/em\u003e, beginning with \u003cem\u003eKapha\u003c/em\u003e predominance in early childhood (\u003cem\u003eBalavastha\u003c/em\u003e), followed by \u003cem\u003ePitta\u003c/em\u003e and \u003cem\u003eVata\u003c/em\u003e aggravation with disease progression.\u003c/p\u003e\n \u003cp\u003ePhenotypes involving vision, metabolism, endocrine functions, neurological development, and hepatic/renal systems reflect \u003cem\u003eTridosha\u003c/em\u003e involvement and corroborates with ciliary dysfunction causing systemic manifestation(\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e). The predominance of \u003cem\u003ePitta\u003c/em\u003e NV aligns with the systemic inflammatory and metabolic dysfunctions documented in ALMS.\u003c/p\u003e\n \u003cp\u003eThese findings underscore the utility of the \u003cem\u003eAnukta Vyadhi\u003c/em\u003e framework in interpreting rare genetic disorders like ALMS. Early Ayurveda intervention focusing on \u003cem\u003eKapha\u003c/em\u003e regulation, followed by targeted strategies for managing \u003cem\u003eVata\u003c/em\u003e and \u003cem\u003ePitta\u003c/em\u003e aggravation, may offer a holistic approach for palliative care, functional support, and enhanced quality of life in affected individuals.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eComparative Summary of\u003c/strong\u003e \u003cstrong\u003eDosha\u003c/strong\u003e \u003cstrong\u003eProfiles\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eAcross all three diseases, distinct \u003cem\u003eDosha\u003c/em\u003e signatures were observed (Table\u0026nbsp;6).\u0026nbsp;\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab6\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003e\u003cem\u003eDosha\u003c/em\u003e count in SMD, SD and ALMS:\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDisease\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDominant \u003cem\u003eDosha\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNV Count (nV/nP/nK)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTotal \u003cem\u003eDosha\u003c/em\u003e-Linked Phenotypes (V/P/K)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSMD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eVata-Kapha\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 / 0 / 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e94 / 24 / 25\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eVata-Pitta\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 / 2 / 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e43 / 16 / 7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eALMS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eTridoshaja\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 / 3 / 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e83 / 43 / 21\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eThis integrative annotation revealed disease-specific Ayurveda pathophysiological patterns. The mapping not only demonstrated semantic compatibility between Ayurveda and contemporary phenotyping but also provided insights into \u003cem\u003eDosha\u003c/em\u003e progression and systemic involvement. The \u003cem\u003eAnukta Vyadhi\u003c/em\u003e framework thus offers a valuable lens for interpreting complex, heterogeneous phenotypes in rare diseases and guiding personalized, \u003cem\u003eDosha\u003c/em\u003e oriented clinical strategies.\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe innovative \u003cem\u003eDosha\u003c/em\u003e centric \u003cem\u003eAnukta Vyadhi\u003c/em\u003e framework proposed here provides a deeper systems-level model for understanding the complexity of multi-systemic rare diseases. It not only enhances explanatory power but also opens new avenues for integrative phenotyping and context-specific complementary therapeutic strategies aimed at improving the quality of life for individuals affected by rare diseases.\u003c/p\u003e \u003cp\u003eImportantly, the \u003cem\u003eAnukta\u003c/em\u003e framework has been developed based on Human Phenotype Ontology (HPO) annotations of rare diseases. However, given that modern medicine predominantly adopts an organ-centric approach, many phenotypic manifestations described in Ayurveda may not be catalogued within existing databases. This underscores the need for a reassessment strategy that systematically captures Ayurveda phenotypic attributes, particularly through the lens of NV, in rare disease clinics. This might also reduce the time to diagnosis of rare diseases.\u003c/p\u003e \u003cp\u003eSuch an approach could open new possibilities for holistic management and palliative care of rare disease patients. Furthermore, the integration of curated rare disease datasets with Ayurveda-based phenotyping, supported by artificial intelligence and large language models, could significantly augment the future of integrative medicine. Coupled with Ayurgenomics, this could also enable novel drug repurposing strategies guided by \u003cem\u003eDosha\u003c/em\u003e based endophenotypes, offering a transformative pathway for rare disease therapeutics.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo ethical approval and consent was required.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003cbr\u003eConsent from all authors taken.\u0026nbsp;\u003cbr\u003e\u0026nbsp;\u003cbr\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003cbr\u003eThe data is provided within the manuscript and Supplementary files.\u003cbr\u003e\u0026nbsp;\u003cbr\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003cbr\u003eThe authors declare no competing interests.\u003cbr\u003e\u0026nbsp;\u003cbr\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003cbr\u003eAuthors receive financial support from MoA (Ministry of Ayush)\u003cbr\u003e\u0026nbsp;\u003cbr\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMM designed the study. DJ, SRT, and AK contributed to the Ayurveda interpretation. DJ curated HPO terms and conducted Ayurveda mining. DJ, AJ, and MM performed the data analysis and prepared the figures. DJ, AJ, and MM wrote the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;MM and DJ would like to thank Dr. Ravi Pratap Singh for valuable discussion. Authors acknowledge financial support from MOA (Ministry Of AYUSH) for Center of Excellence “AyurTech” (S/MOA/MTM/AA/20210105), IIT Jodhpur. Authors acknowledge IIT Jodhpur for infrastructure support.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eNguengang Wakap S, Lambert DM, Olry A, Rodwell C, Gueydan C, Lanneau V et al (2020) Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. Eur J Hum Genet 28(2):165\u0026ndash;173\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePavisich K, Jones H, Baynam G (2024) The diagnostic odyssey for children living with a rare disease \u0026ndash; Caregiver and patient perspectives: A narrative review with recommendations. Rare 2:100022\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBauskis A, Strange C, Molster C, Fisher C (2022) The diagnostic odyssey: insights from parents of children living with an undiagnosed condition. Orphanet J Rare Dis. ;17(1)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAustin CP, Cutillo CM, Lau LPL, Jonker AH, Rath A, Julkowska D et al (2018) Future of Rare Diseases Research 2017\u0026ndash;2027: An IRDiRC Perspective. Clin Transl Sci 11:21\u0026ndash;27\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCosta-Font J, Sato A (2024) Cultural persistence and the \u0026lsquo;herbal medicine paradox\u0026rsquo;: Evidence from European data. J Health Psychol. Feb 1\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAstin JA Why Patients Use Alternative Medicine Results of a National Study [Internet]. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://jama.jamanetwork.com/\u003c/span\u003e\u003cspan address=\"http://jama.jamanetwork.com/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePogue RE, Cavalcanti DP, Shanker S, Andrade RV, Aguiar LR, de Carvalho JL et al (2018) Rare genetic diseases: update on diagnosis, treatment and online resources. Drug Discovery Today 23:187\u0026ndash;195\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLoscalzo J, Barabasi AL (2011) Systems biology and the future of medicine. Wiley Interdiscip Rev Syst Biol Med 3(6):619\u0026ndash;627\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJoshi A, Jangir D, Sharma A, Anand T, Verma H, Yadav M et al (2024) Ayurveda based phenotype annotation integrated with Expectation Maximization algorithm reveal six biological clusters of rare diseases: potential in resolving ciliopathies [Internet]. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://biorxiv.org/lookup/doi/10.1101/2024.09.13.612844\u003c/span\u003e\u003cspan address=\"http://biorxiv.lookup/doi/10.1101/2024.09.13.612844\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVrat Sharma P \u003cem\u003eJaikrishnadas Ayurveda Series Caraka-Samhita Seminar\u003c/em\u003e. CHAUKHAMBHA ORIENTALIA\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePrasher B, Gibson G, Mukerji M (2016) Genomic insights into ayurvedic and western approaches to personalized medicine. J Genet 95(1):209\u0026ndash;228\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMukerji M (2023) Ayurgenomics-based frameworks in precision and integrative medicine: Translational opportunities. Camb Prisms: Precision Med. ;1\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKumari H, Cs P (2023) Concept of NV in Ayurveda. \u003cem\u003eIJBPAS\u003c/em\u003e [Internet]. ;12(2):950\u0026ndash;4. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.31032/IJBPAS/2023/12.2.6893\u003c/span\u003e\u003cspan address=\"10.31032/IJBPAS/2023/12.2.6893\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKumari H, Pandey CS Perspectives of Understanding Vataja NV. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.46607/iamj2410052022\u003c/span\u003e\u003cspan address=\"10.46607/iamj2410052022\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eB PS (2020) Maharoga Adhyaya. In: K AC, R S, D YS, B G (eds) Charak Samhita New Edition. Charak Samhita Research, Training and Skill Development Centre (CSRTSDC), pp 22\u0026ndash;22\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eK AC, R S, D YS, B G (eds) (2020) Trishothiya Adhyaya. Charak Samhita New Edition. Charak Samhita Research, Training and Skill Development Centre (CSRTSDC), pp 20\u0026ndash;20\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThe Library of the University of California Los Angeles [Internet] Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.arcliive.org/details/englislitranslati03susr\u003c/span\u003e\u003cspan address=\"http://www.arcliive.org/details/englislitranslati03susr\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e\u003cem\u003eSusruta-Samhita Kalpasthana and Uttaratantra\u003c/em\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGargano MA, Matentzoglu N, Coleman B, Addo-Lartey EB, Anagnostopoulos AV, Anderton J et al (2024) The Human Phenotype Ontology in 2024: phenotypes around the world. Nucleic Acids Res 52(D1):D1333\u0026ndash;D1346\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSon JH, Xie G, Yuan C, Ena L, Li Z, Goldstein A et al (2018) Deep Phenotyping on Electronic Health Records Facilitates Genetic Diagnosis by Clinical Exomes. Am J Hum Genet 103(1):58\u0026ndash;73\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSmedley D, Robinson PN (2015) Phenotype-driven strategies for exome prioritization of human Mendelian disease genes. Genome Med. ;7(1)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eD\u0026iacute;az-Santiago E, Moya-Garc\u0026iacute;a AA, P\u0026eacute;rez-Garc\u0026iacute;a J, Yahyaoui R, Orengo C, Pazos F et al (2024) Better understanding the phenotypic effects of drugs through shared targets in genetic disease networks. Front Pharmacol. ;15\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTurner C, Hilton-Jones D (2010) The myotonic dystrophies: Diagnosis and management. J Neurol Neurosurg Psychiatry 81:358\u0026ndash;367\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFabre A, Martinez-Vinson C, Goulet O, Badens C (2013) Syndromic diarrhea/Tricho-hepato-enteric syndrome. Orphanet J Rare Dis. ;8\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTahani N, Maffei P, Dollfus H, Paisey R, Valverde D, Milan G et al (2020) Consensus clinical management guidelines for Alstr\u0026ouml;m syndrome. Orphanet J Rare Dis. ;15(1)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSwetha BM, Kulkarni M, Hullur Y (2024) A review on Janusandhigata Vata. J Ayurveda Integr Med Sci 9(2):258\u0026ndash;262\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSafran M, Dalah I, Alexander J, Rosen N, Iny Stein T, Shmoish M et al (2010) GeneCards Version 3: the human gene integrator. \u003cem\u003eDatabase (Oxford)\u003c/em\u003e. ;2010\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSharma SPV \u003cem\u003eSusruta-Samhita: Text with English Translation, Dalhana\u0026rsquo;s Commentary along with Critical Notes\u003c/em\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Indian Institute of Technology Jodhpur","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Rare diseases, Human Phenotype Ontology, Anukta Vyadhi, Nanatamja Vikara, personalized medicine","lastPublishedDoi":"10.21203/rs.3.rs-6639616/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6639616/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eRare diseases pose significant diagnostic and management challenges. In Ayurveda, these conditions are not explicitly mentioned (referred as \u003cem\u003eAnukta Vyadhi)\u003c/em\u003e and are interpreted using foundational principles of \u003cem\u003eDosha\u003c/em\u003e imbalance with a systems perspective. This study examines the potential of the \u003cem\u003eAnukta Vyadhi\u003c/em\u003e framework to deconvolute rare diseases. Human Phenotype Ontology (HPO), comprising 10,610 phenotypic terms across 12,678 rare diseases, was used to create a unifying vocabulary for mapping with Ayurvedic classifications. 140 \u003cem\u003eNanatamja Vikara\u003c/em\u003e (NV) based phenotypic descriptions that map to imbalance of specific \u003cem\u003eDosha Vata\u003c/em\u003e (80 nV), \u003cem\u003ePitta\u003c/em\u003e (40 nP) and \u003cem\u003eKapha\u003c/em\u003e (20 nK) curated from classical Ayurveda texts were mapped to HPO phenotypes. An extensive exercise was undertaken to preserve the meaning and context of Sanskrit descriptions while mapping HPO phenotypes and applying the structured principles of the \u003cem\u003eAnukta Vyadhi\u003c/em\u003e framework. Rare diseases were re-annotated with nV, nP, and nK-labeled phenotypes and reinterpreted through this lens. The framework was further applied to three exemplary rare diseases\u0026mdash;Steinert Myotonic Dystrophy (108 HPO terms), Syndromic Diarrhea (52 HPO terms), and Alstrom Syndrome (117 HPO terms)\u0026mdash;to demonstrate its utility. Of the total NVs (140), 92% (128) mapped to 199 HPO IDs which corresponded to 7,200 rare diseases. Among these, 66% were uniquely enriched in nV associated phenotypes, followed by nP (6.5%) and nK (3.3%). Approximately 18% of diseases exhibited dual NV involvement, while 5% had contributions from all three \u003cem\u003eDosha.\u003c/em\u003e Seizures, short stature, and ptosis were predominant features of nV; gastroesophageal reflux, fever, and abnormal skin blistering of nP; and obesity, lethargy, and pallor were dominant of nK. Detailed case interpretations revealed that Steinert Myotonic Dystrophy (SMD) was primarily associated with \u003cem\u003eVata\u003c/em\u003e and secondarily with Kapha, Syndromic Diarrhea (SD) with \u003cem\u003eVata-Pitta\u003c/em\u003e involvement, and Alstrom Syndrome (ALMS) with contributions from all three doshas.This \u003cem\u003eAnukta Vyadhi\u003c/em\u003e framework provides an innovative approach for interpreting rare diseases through foundational principles of \u003cem\u003eDosha\u003c/em\u003e. Integration of this framework with HPO provides (a) an assistive tool for rare disease diagnostics in Ayurveda clinics and (b) opens avenues of redefining rare diseases from systems perspective and (c) palliative management through complementary therapies.\u003c/p\u003e","manuscriptTitle":"A systems perspective on rare diseases: integrating human phenotype ontology with the Anukta framework of Ayurveda","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-22 13:22:49","doi":"10.21203/rs.3.rs-6639616/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e5718786-14a7-4bb3-a8c7-de83d3ba8722","owner":[],"postedDate":"May 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":48733497,"name":"Integrative \u0026 Complementary Medicine"}],"tags":[],"updatedAt":"2025-05-22T13:22:49+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-22 13:22:49","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6639616","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6639616","identity":"rs-6639616","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}