A consensus conceptual model of meaningful symptoms and functional impacts in early Parkinson’s Disease

A consensus conceptual model of meaningful symptoms and functional impacts in early Parkinson’s Disease | 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 Article A consensus conceptual model of meaningful symptoms and functional impacts in early Parkinson’s Disease Jennifer Mammen, Jamie Adams This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4377805/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Background A comprehensive, widely-accepted, patient-centered conceptual model of Parkinson’s disease (PD) is needed to improve therapeutic development and guide selection of relevant endpoints. Objectives To develop an evidence-based conceptual model of early PD, defined as <3 years since clinical diagnosis, that meets the needs of all relevant stakeholders, including people with PD, researchers, clinicians, industry, and regulators. Method A multi-stakeholder taskforce and patient advisory panel oversaw the systematic review and meta-synthesis of qualitative and quantitative studies using JBI Mixed Methods Review criteria and GRADE-CERQual standards for assessment of evidence quality, with iterative taskforce and advisory meetings to develop the model. Results More than 340 symptoms and impacts were identified from 38 unique study samples. These were grouped into 10 symptom domains (Movement, Cognitive, Psychiatric, Sleep, Sensory, Speech, Digestive, Urinary, Sexual, Autonomic) and two impact domains (Physical functioning, Psychosocial functioning). Synthesis of findings tables (SOFT) indicate that a wide range of motor and non-motor symptoms are prevalent and bothersome in early PD, with strongest evidence for tremor, dexterity, gait, stiffness, and slow movements, as well as cognitive changes (e.g., word finding issues), mood and sleep alterations, urinary dysfunction, constipation, pain, and fatigue. These commonly affected mobility, self-concept, coping, effort of living, interpersonal interactions and important activities, with evidence of many understudied impacts. Conclusion This consensus-based conceptual model of early PD provides the most comprehensive catalogue of meaningful symptoms and functional impacts to date. The model and SOFT offer evidence-based tools for identification of concepts of interest to define endpoints for clinical trials. Health sciences/Signs and symptoms/Neurological manifestations Scientific community and society/Scientific community/Research data Health sciences/Diseases/Neurological disorders/Parkinson's disease early Parkinson’s conceptual model framework meaningful symptoms impacts Figures Figure 1 Figure 2 Figure 3 Figure 4 1. Background Effective treatments to halt or delay progression of Parkinson’s disease (PD) are urgently needed by patients and families [1]. Yet, development of new drugs is a time and resource intensive process accompanied by more failures than successes [2]. This is especially true for diseases with wide heterogeneity in symptom expression and unclear biological mechanisms of progression, such as PD[3]. Phenotypic variability makes selection of pertinent outcomes for trials particularly challenging, as different symptoms or functional impacts may be more (or less) important to different people at different points throughout their disease course [4, 5]. Yet, the success of clinical trials is dependent on having clinical outcome assessments (COA) that are sensitive to treatment effects rather than natural variations in disease progression or situational context [6, 7]. This has created a critical need to know, with reasonable certainty, what experiences are typically most important to the majority of people with PD at a specified stage of disease (i.e., what—who—when). This summative, contextually-defined knowledge of individuals' lived experiences is essential to development and selection of outcome measures that are meaningful from a real-world perspective and in alignment with the regulatory landscape [8, 9]. Recent qualitative work has greatly enhanced understanding of the lived experiences of people living with Parkinson’s [4, 10-13]; however there is no comprehensive nor widely accepted patient-centric conceptual model that can be used to guide the field. For this reason, following the 2022 PD Endpoints Roundtable [14], a global taskforce of experts and patient representatives was convened to develop a consensus-based conceptual model of meaningful symptoms and functional impacts for early PD from systematic review of the literature. The taskforce goals were to create a comprehensive yet parsimonious model that (1) aligns with current Food Drug Administration (FDA) guidance for patient-focused drug development (PFDD) [6-9], (2) can support future research and clinical trials, (3) and is adaptable to emerging knowledge and later-stages of disease. This paper reports methodological approaches and findings of the taskforce. 2. Methods To ensure rigor in model development, best-practice guidelines were followed for each stage of model building, including systematic review of the literature, mixed methods evidence synthesis, and assessment of evidence quality [15-22]. These are shown in Figure 1 and described below. 2.1. Approach to model development Guidelines by Brady et al. (2020) for the development of conceptual models to guide policy, practice, and research include three steps: (1) identifying resources (e.g., existing models, stakeholders, and literature-based sources), (2) considering the broad array of possible factors identified from resources, (3) narrowing down factors for inclusion on the basis of theory, stakeholder perspectives, and evidence [16]. A multi-stakeholder 14-person taskforce convened March of 2023, together with a 9-person patient and family advisory panel ( Table 1) , to develop the methods and approach to review of the literature (Step 1). Stakeholders included people affected by PD (patients and families), researchers, clinicians, PD advocacy groups, industry, and regulatory agencies (FDA). The purpose of the literature review was to identify all reported symptoms and functional impacts of early PD (Step 2), with ultimate intent to identify which concepts are most meaningful for early-stage disease, to inform the final model (Step 3). 2.2. Approach to systematic review for mixed methods evidence synthesis Multiple guidelines exist for the conduct of quantitative systematic reviews and qualitative evidence synthesis [23-25]. Fewer guidelines exist for mixed methods (MM) synthesis which is essential to understanding complex real-world phenomena [15]. The taskforce elected a convergent integrated synthesis approach to identify meaningful symptoms and impacts of early PD in both qualitative and quantitative studies [15, 26, 27]. JBI Mixed Methods Review criteria [15, 27] were used: (1) defining the review question using PICo (population, phenomena, context); (2) determining inclusion/exclusion criteria; (3) defining the search strategy (4) systematic assessment of methodological quality (5) data extraction (6) data synthesis; and (7) presentation of results. 2.2.1. Research Question: What symptoms and impacts are most meaningful in early PD? Per recommendations from the patient panel, people affected by PD were defined as patients/people with PD (PwP) and their intimate social circle, referred to hereafter in this manuscript as “family.” The terms “caregiver” and “care partner” were not used as most people with early PD do not have formal caregivers, and “partner” does not encompass the scope of people affected by PD, such as children and close friends. Definition of symptoms and functional impacts. For this model, "symptoms" were considered to be the subjective or objective physical and mental features (i.e., signs/symptoms of disease) occurring as a direct result of PD, leading or potentially leading to changes in day-to-day physical and psychosocial functioning. "Functional impacts" (hereafter "impacts") were defined in alignment with FDA guidance as experiences occurring as a consequence of disease, such as changes in the way a person functions or feels [6]. Definition of early PD. There is no formal definition of early PD and most studies to date have utilized clinical diagnosis of PD with variable definitions of early-stage disease ranging from 0 to upwards of 6 years. For the model, early PD was defined as less than 3 years since diagnosis (YSD) by expert consensus. The 3-year timeframe aligns with the target population of the Critical Path for Parkinson’s Consortium and with many clinical trials for early PD [28]. Definition of concepts of interest. A concept of interest is the "aspect of an individual’s clinical, biological, physical, or functional state, or experience that the assessment is intended to capture or reflect" [8]. Definition of meaningful symptoms and impacts. Per patient panel and expert discussion, to be deemed "meaningful" a concept (either symptom or impact) had to show evidence of being prevalent as well as personally bothersome to people with early PD <3 years since clinical diagnosis. 2.2.2. Primary source inclusion/exclusion criteria Sources were eligible for inclusion if they were: (a) primary published or unpublished qualitative, quantitative or mixed methods (MM) studies; (b) conducted within an early PD population as defined by source study authors; (c) reported any symptoms and/or impacts of early PD; and (d) contained data that were patient, family, observer, clinician reported or digitally measured. Studies focused on evaluating the effect of a specific medication or intervention were excluded, as were conference proceedings, due to insufficient data to reliably evaluate methods or findings. In longitudinal studies baseline measurement values were used. 2.2.3. Search strategy For the literature review, any source with a study-defined “early PD” population was included to avoid overlooking potential sources during the search process. Four databases were searched as shown in Supplement A . Search Strategy 1 identified sources published within 10 years that referenced early PD and symptoms or impacts anywhere in the title or abstract (search date: May 2023). Strategy 2 identified sources that used early PD and common terms for qualitative research anywhere in the title or abstract without time limits. Strategy 3 consisted of examining reference lists of relevant review articles for additional sources. Strategy 4 used expert consultation to identify key sources > 10 years old or unpublished relevant datasets not captured in the first two search strategies. As shown in Figure 2 , 2006 sources were returned, with 1301 duplicates. Abstracts were screened for 705 sources. Of these 554 were excluded and 151 were selected for full text review. Eighty-nine sources remained after eliminating studies without reportable data on symptoms or impacts within any early PD population. Of these, only 56 studies used samples that were strictly <3 years since diagnosis based on mean and SD. A complete list of sources screened and included/excluded is provided in Supplement E. 2.3. Approach to data analysis All sources that met review inclusion criteria were systematically analyzed, and findings were weighted and aggregated to enable assessment of the total quality of evidence supporting each concept in early PD, as described below. Data extraction for concepts was performed on all studies of early PD (as defined by study authors; N=89; range 0-6 years since diagnosis), however, data regarding frequencies of concepts was limited to PD <3 years since diagnosis (N=56). This was done to maximize identification of potential concepts with reported frequencies specific to early PD. 2.3.1. Data extraction For mixed methods synthesis, JBI guidance recommends codifying quantitative data in a manner compatible with qualitative synthesis to reduce potential for inaccuracies in meta-aggregation across methodologies [26]. Using a matrix spreadsheet ( Supplement B ), all studies were assessed individually for study aims, design, year of publication, sample size, PD stage, diagnostic criteria, years since diagnosis (mean, SD), comparison group, gender distribution, race/ethnicity, country of origin, data source, data collection instruments, PD medication use, levodopa equivalent daily dose (LEDD), Hoehn & Yahr (H&Y), Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III total score if reported [29], any covariates, and a brief study synopsis. Content coding. Each source was then analyzed to extract information about symptoms or impacts of early PD. Where given, frequencies for prevalence were extracted.For studies lacking frequencies but reporting between groups comparisons for early PD vs. Control (e.g., normative cohort, later PD cohort), statistically significant differences were indicated with “ * ” and no statistically significant differences were indicated with “ - “. For studies reporting bothersomeness rather than prevalence, the percentage of people identifying the concept as being actively bothersome was reported in the matrix. 2.3.2. Development of the conceptual model schema After content coding, all identified concepts were qualitatively analyzed to derive a best-fit conceptual schema that was intuitive, optimally parsimonious, and able to facilitate measurement consistency and reduce redundancy. Only concepts identified by systematic review were included in the modeling. Initial attempts to group by motor versus non-motor resulted in a poorly organized structure due to the large number of concepts identified and the presence of many concepts with ambiguous classification (e.g., motor vs. non-motor; symptom vs. impact). A series of 10 interactive sessions were held from September to November, 2023, to solicit feedback from all stakeholders (taskforce and patient panel) to derive a consensus-based schema that was intuitive and user-friendly for clinicians, researchers, PwP and families. Sessions were held online using a focus group format, with a moderator who summarized and synthesized perspectives in real time. Using mapping approaches (Xmind app) with screen sharing, concepts were clustered by relatedness and organized into logical groupings [30, 31]. Where possible, full agreement was sought for all analytic decisions, with use of majority vote on best groupings (>80% taskforce and patient panel) when 100% consensus was not achieved in online meetings. Similar concepts were merged and consensus term selected based on taskforce and patient panel agreement. Concepts that related to a broader concept were subsumed as dependent nodes to develop a branching structure moving from broad concepts to progressively more specific aspects of an experience (e.g., shuffling as an aspect of gait). Conceptual distinctness and relatedness were determined by stakeholder consensus regarding interpretation of literature review findings during online sessions. All conceptually distinct items were retained in the final model schema ( Supplement C ). Detailed documentation of stakeholder sessions and revisions to the schema was retained for an audit trail. 2.3.3. Weighting of primary sources preparatory to metasynthesis The PFDD guidance series prioritizes direct report of patient experience from the target population (i.e., people with PD) [9]. When this type of data is limited or the patient population has reduced ability to reliably report experiences, supporting information may be obtained from caregivers, clinicians, or other key informants [8]. Based on discussion with the patient panel and taskforce members, a three-tiered approach was chosen for classification of primary sources. This was done to allow for prioritization of patient voice and weighted synthesis of findings across diverse methodologies and data sources as described below. Tier 1 [4, 10-13, 32-34] comprised qualitative or mixed methods studies that evaluated symptoms and impacts of PD using an open-ended, iterative, and patient-driven approach, in which patients and/or family were asked to freely identify what symptoms or impacts the person experienced without constraints. Tier 1 was further subdivided to Tier 1A (studies reporting a symptom as being bothersome in early PD irrespective of prevalence) and Tier 1B (studies reporting symptoms as present in early PD irrespective of whether it is bothersome). Tier 1 sources were used as primary evidence for the conceptual model. Original study teams from Tier 1 sources were contacted to obtain detailed frequencies for symptoms and impacts if not fully presented in published manuscripts [4, 10-12, 32, 33]. Tier 2 [35-61] and 3 [62-114] consisted of quantitative studies in which predetermined aspects of health were measured using quantitative approaches. Tier 2 included studies that evaluated symptoms and impacts using patient-reported outcome (PRO) measures selected by a study team in which a limited selection of symptoms or impacts were evaluated from the patient perspective. Tier 3 included data from studies with clinician or observer reported symptoms or impacts (i.e., ClinRO, ObsRO). Sources reporting only cumulative scores on validated scales were excluded as they lacked discrete data on symptoms or impacts. Tier2 and 3 studies were included as supporting evidence due to potential for bias in symptom reporting. Pooling of same sample studies . Same sample studies were defined as separate publications that reported findings from the same (identical) participant sample ( Supplement B ). Findings were pooled from same-sample studies to ensure equal weighting during meta-synthesis. For pooling, redundant findings (e.g., demographics – diagnosis of depression) were reported once, while all unique findings retained. Thus, a total of 38 unique study samples were included in the final model. 2.3.4. Aggregation of data for early PD <3 years since diagnosis Data aggregation was performed at the level of unique samples (N=38; Supplement E), rather than at the level of individual studies so that each unique sample was represented only once in the final meta-synthesis. Only samples with data for PD<3 years since diagnosis were included at this stage, based on the final model inclusion criteria. Data and frequencies for the full early PD sample (N=89, 0-6 years since diagnosis) vs. PD <3 years since diagnosis can be viewed in Supplement B. The following metrics were calculated for each symptom and impact in early PD <3 years since diagnosis: Number and percentage of unique samples that measured a concept (within and across all Tiers); Average prevalence of concept (within and across Tiers 1B, 2, & 3 – sum of frequencies in all studies reporting prevalence/total number of studies reporting prevalence); Number and percentage of unique samples disconfirming presence of concept (within and across all Tiers); and Frequency which concept was reported as being actively bothersome (Tier 1A; sum of frequencies in studies reporting bothersomeness/total number of studies reporting bothersomeness). 2.3.5. Assessment of quality of evidence & synthesis of findings Next, evidence synthesis was performed using GRADE-CERQual [17-22]. GRADE-CERQual is a standardized approach to assessment of confidence in the quality of evidence from qualitative studies and is endorsed by the World Health Organization and numerous government agencies for the development guidelines to shape public policy and research [23, 115, 116]. CERQual evaluates four primary areas: (1) methodological limitations, (2) coherence of findings, (3) adequacy of the data, and (4) relevance of the findings. These criteria are presented in Table 2, along with the operationalized approach to assessment. For this model, methodological limitations were addressed a priori using the Tiered approach, in which unique samples were weighted based on underlying methodological strengths and limitations. 2.4. Research community review Lastly, to maximize potential for usefulness and adoption of the consensus model, the model and manuscript and all supporting files were posted online for research community review and feedback over a 1-month period (Jan-Feb 2024). Participants for the community review were solicited via the MJFF research community newsletter (distribution list N= ~9.5K), the UK PD clinical Studies Group (N=65) and by personal invitation to experts identified by the taskforce members, including members of FDA, EMA, MDS, CPP and content experts (N=88). An online form was provided for feedback or feedback could alternately be emailed directly to taskforce members. Final minor clarifications were made to the model, figures, and manuscript on the basis of reviews, with an audit trail of changes available upon request. 3. Results Sample characteristics. A total of 89 studies reported symptoms and impacts in “early PD” (generally defined as 0-5 years from diagnosis) and were utilized for the initial concept identification phase. Of these, 56 sources focused exclusively on PD <3 years since diagnosis. After pooling for same sample studies within the <3 year subset, a total of 38 unique samples from publications during years 2013 to 2023 were used to derive frequencies for the final early PD model. Of these, all qualitative samples (Tier 1; 6 unique samples from 7 studies) were from the UK, USA, and Canada and included predominantly white participants (93-100%). Three of these reported bothersomeness; four reported prevalence; one reported both. Sample sizes ranged from 20 to 134 with one very large sample study of 8536 participants (Fox Insight/PD PROP). Tier 2 (N=13) and Tier 3 (N=19) sources included studies from UK, USA, Canada, Italy, Korea, Serbia, Thailand, Germany, India, China, Singapore, and the Netherlands, in which distribution of race/ethnicity was often not reported. Samples sizes ranged from 54 to 921 participants. The mean age range for all studies in all Tiers was 57-68 years. Gender distribution ranged from 40-74% male, most commonly approaching 60%. In 13 of 38 unique samples (34%), participants were taking PD medications (range 4-100%; mean LEDD 50-544 mg/day). Medication use was not stated in 18% (7/38). Hoehn & Yahr score (H&Y) was reported by 27/38 samples, with mean H&Y<2 for all (100%) studies, but only 12/27 (44%) strictly £2 when factoring +2SD. MDS-UPDRS III (motor) was reported in 25/38 studies and ranged from 9.2-27.0, which is consistent with early PD [117]. Concept characteristics. Approximately 340 symptoms and impacts were identified from the original 89 publications. Substantial variability was observed in terminology and classification of concepts, with certain concepts inconsistently classified as motor vs. non-motor, (e.g., restless leg, constipation, drooling, voice changes, swallowing), impact vs. symptom (e.g., anxiety, depression, frustration), or listed twice under both symptom and impact (e.g., handwriting, anxiety). Diverse terminology was commonly used to describe conceptually similar ideas (e.g., depressed mood, feelings of sadness, negative feelings and emotions). Definitions were rarely provided for terms, requiring reviewers to infer what a concept likely comprised from common language use or from the context in the report (e.g., thermoregulation indicative of heat/cold intolerance vs. body temperature). Consequently, some redundancy due to potentially overlapping concepts might be present in the working model presented below. Consensus conceptual model schema. Concepts were organized using a primary classification schema of Domain—Category—Concept—Experience , with secondary classification of motor or non-motor occurring at the measurement level, as depicted in Figure 3 . Ten systems-based symptom domains were identified (Movement, Cognitive, Psychiatric, Sleep, Sensory, Speech, Digestive, Urinary, Sexual, Autonomic) in addition to two impact domains (Physical functioning; Psychosocial functioning). A map of the top-level conceptual schema is presented in Figure 4 , with maps for all domains is presented in Supplement C. Comprehensive data tables and frequencies by source are presented in Supplement B, and Supplement D presents working definitions for each concept included in the model. SOFT Reports. Synthesis of Findings Tables ( SOFT 1 through 12 ) are presented for each symptom and impact domain, with subdivision by conceptual categories. SOFT reports show (1) issues of coherence in measurement and classification of concepts; (2) adequacy of data supporting conclusions; and (3) the relevance of each concept based on prevalence and extent to which the concept is bothersome in early PD<3 years since diagnosis. From the SOFT reports, the most meaningful motor symptoms of early PD appear to include tremor, fine motor difficulties, gait & balance changes, stiffness, and slow movements—all of which were observed to be prevalent (54-85%) and bothersome (24-57%) within 3 years from diagnosis. The SOFT reports also highlight multiple non-motor symptoms that are commonly experienced and meaningful to people with early disease. These commonly include cognitive and speech changes (e.g., word finding); mood changes such as anxiety, depressed mood, or negative feelings/emotions; alterations in sleep; sensory changes (e.g., increased pain and fatigue); urinary dysfunction; and digestive system changes (e.g., choking, constipation). In addition to identifying common bothersome symptoms and impacts, multiple gap areas were observed, most often in the impact domains. Evidence from the review suggests that impact on mobility-related activities, such as physical exercise, may be a high priority area in early PD (70% prevalence; 31% bothersome). Other concepts, such as “Effort of Living” are comparatively new, with no data on prevalence (Tier 1B to 3) but Tier 1A evidence suggestive of a meaningful experience (29% bothersome). Other concepts that may be relevant at this stage include impacts on self-concept (35% bothersome), personal coping (29% bothersome), interpersonal interactions (e.g., relationships with others), sense of independence, profession, and hobbies—among others. A final finding from the SOFT reports is the substantial research that has been conducted in areas that appear less meaningful to people with PD. Most common examples of this include drooling (30% prevalence; 0% bothersome) and loss of smell (29% prevalence; 2% bothersome). 4. Discussion The consensus conceptual model presented here is the most comprehensive catalogue of meaningful symptoms and impacts in PD, based on literature to date. This effort expands on prior models derived from individual studies [4, 10, 12, 13]. Like others, we found a wide range of symptoms and impacts that are meaningful in early PD, with strongest initial evidentiary support for movement, cognitive, mood, speech, and sleep-related symptoms, which corresponds with a recent systematic review by Tosin et al [118]. Cumulatively, these findings provide compelling evidence that treatments for early-PD should address one or more of these domains of patient experience, which could require the identification or development of clinical outcome assessments that are valid and reliable for evaluating them in the early-PD population. However, the present report also highlights multiple other concepts with preliminary evidence of meaningfulness that have been insufficiently studied. Further research will be needed to evaluate prevalence and relative importance to patients before definitive conclusions can be made as to which concepts are most broadly relevant for early-stage PD. 4.1. Recommendations for use and limitations of SOFT reports SOFT reports can support evidence-based rationales for concepts of interest for use in research or clinical assessment. However, it is important to note that these reports should be used with caution due to limitations inherent in the data collection and reporting processes of primary sources. Evidence for these reports was compiled from diverse sources, and methodological flaws in primary sources might have resulted in over, under, or selective reporting, which in turn affect aggregated frequencies for this study. Thus, the term "SOFT report" is intentional and should serve as a reminder that data are not conclusive and should be treated as an estimation rather than an exact measurement. Future work will enable more accurate and detailed understanding of concepts in defined populations over time, which can support the identification of a parsimonious set of core outcomes for early-PD populations. Conduct multifaceted Concept of Interest (COI) assessments. Selection of meaningful concepts requires recognizing that "meaningfulness" is multifaceted. No single metric in the SOFT reports should be used in isolation to justify selection of COI. Consideration should be given to all metrics, including estimates of prevalence in the population, evidence that it is truly relevant to people with early PD, and the total weight of evidence (Grade/Level) that justifies these conclusions. Explore gap areas. Gap areas are concepts that have insufficient data to justify inclusion or exclusion in the early PD model on the basis of SOFT reports. Absence of a concept in SOFT reports, or lack of specific supporting data does not imply absence of a meaningful experience in early PD, and rather might mean the concept has not been sufficiently studied or reported. Particular attention should be paid to concepts with limited or missing evidence. Further research will be needed in many areas to define the scope of these concepts and determine relevant approaches to measurement. Evaluate coherence and disconfirming evidence. Close attention should also be paid to disconfirming evidence and discrepancies in findings. For instance, the categorical concept of "gait" appears to be highly relevant in early PD, but there is little data to indicate which aspects of walking are problematic, noticeable, or bothersome to people with PD (i.e., specific health experiences such as shuffling or sensation of foot being stuck to floor). Disconfirming evidence existing side-by-side with confirming evidence can raise questions about cohesiveness of the concept and adequacy of prior measurement approaches (e.g., both confirming and disconfirming evidence regarding dyskinesia in early PD in all Tiers). Conflicting evidence can highlight areas of limited or imprecise understanding that might benefit by further clarifying work. Identifying the specific patient experiences that comprise a concept will improve consistency in concept definitions and measurement approaches. 4.2. Pragmatic considerations in selection of COI Change over time. SOFT reports can help identify what is important to people affected by PD, however, additional pragmatic considerations are needed during COI selection and development of measures for clinical trials. Once potential COI have been identified, it is important to consider measurability for clinical trials and if the experience is likely to significantly change within the time frame of the average trial (e.g., 6-18 months). Similarly, selection of the COI might be dependent on whether it is likely to be affected by a potential treatment, which is contingent on the mechanism of action of the treatment being evaluated. For example, "stigma" may be highly relevant to PwP (i.e., good evidence of being prevalent and bothersome), but is unlikely to change rapidly with treatment, thus might be unsuitable for certain measurement situations. Context of use. The context in which a COI will be used in drug development decision making will also affect choice. Important points to consider are universality and participant characteristics that may affect how an individual experiences it. Individual characteristics such as age, life-stage (pre/post retirement), sex, gender, geographic location, and culture can affect the meaningfulness of certain concepts more than others. For example, the impact of PD on driving may be different for people in rural areas than for urban residents, which could affect the suitability of the concept for geographically diverse trials testing treatment efficacy. Similarly, COIs may be sex specific (e.g., erectile dysfunction) and attention should be given to maximize applicability to both sexes. Culture may also play a key role in COI selection, however there is very limited data on this due to the predominance of white participants of higher socio-economic status in most trials to date. Measurement validity. Other practical considerations include recall and social biasing. Some experiences may be more difficult to recall over time than others. Some concepts may be subject to social desirability bias (e.g., people may downplay or be reluctant to report experiences such as sexual dysfunction or compulsive behaviors), leading to potential for increased measurement error. Ability for participants to tell if a symptom is attributable to PD may also be an important consideration, which was highlighted by the patient panel. Ways to enhance validity in measurement should be considered during COI selection. Symptom concepts that are clearly linked to a functional impact may be particularly useful, allowing for triangulated assessment of the symptom and/or impact on function (e.g., what the person can or cannot do because of fatigue). This requires establishing an evidence-based connection between specific symptoms and related functional impacts and demonstrating the prevalence and meaningfulness of these sets of experiences to people with early PD. 4.3. Future directions Key strengths of the present approach include exhaustive review and meta-synthesis of methodologically diverse studies, inclusion of all key stakeholders throughout the model-building process, and use of an iterative consensus-based design. We believe that this has contributed to a maximally inclusive model reflective of the current state of the science, with an intuitive and easily understood interface. This can increase utility of the model, contribute to improved COAs for early PD trials, and enhance potential for broad uptake and harmonization of approaches across research, health care practice, and other endeavors. However, several areas remain in need of substantial future work and will enhance the long term utility of data from this report. Need for diverse perspectives. There remains a marked lack of participant diversity in PD research, which is a well-known issue in the field [119]. All Tier 1 evidence was elicited from the UK, USA, and Canada, with samples that were >93% white. Tier 2 and 3 data contained greater diversity in country of origin but limitation to PD duration of <3 years since diagnosis excluded a number of these studies from inclusion in final frequencies. This data has been retained and is available in Supplement B . Future work should aim to expand knowledge of meaningful symptoms and functional impacts in culturally, geographically, and racially diverse populations. This recommendation corresponds with FDA PFDD guidance [6-9]. In particular, evidence from countries in certain parts of Asia, Africa, and South America is limited and would help to inform the utility of the current conceptual model for more diverse populations. Similarly, evidence from cultural and racial minorities living within predominantly white countries is needed. Lastly, only one study in the review reported the perspectives of family separately from patient perspectives with regards to most bothersome symptoms [33]. Due to the model parameters and significant differences in PwP vs. family perspectives, this data was removed from the final model frequencies as an outlier but is reported in Supplement B . Further research to understand the wholistic impact of PD on patients and their family might be warranted, given growing emphasis on family centric and palliative care. Need for harmonization. Another key call to action is for harmonization of concepts and concept definitions, which will be needed to improve coherence in classification and measurement for future studies. All terms in the present model have been given preliminary working definitions derived from evidence-based resources [120, 121] and common language usage of terms [122] ( Supplement D ) with the recognition that these may require revision or refinement as the field matures. Revisions or additions to domains, categories or concepts should be made cautiously and grounded in rigorous evidence, with careful attention to existing items in the model. This will help to avoid redundancy and maximize parsimony. Where possible, researchers will benefit by building on prior work instead of duplicating efforts. When needed, clear and compelling scientific justification should be provided for alternative terms for similar concepts. Finally, in selecting "best" terms, reflecting the experiences of the people living with PD should remain a top priority – which was unanimously emphasized by the patient panel. Thus, where possible, patient centric terms that are understandable to most patients will be preferred over complex technical terms exclusive to the scientific community (e.g., slow movements vs. bradykinesia). Expectation of evolution. It is expected that this model will evolve over time based on refinements and expansion of knowledge within early PD and later stages of disease. It is important to note that the conceptual categorization proposed here is not intended to be prescriptive. Clear documentation of rationales for alternative approaches to concepts, definitions, or classification will help with refinement over time. Intermittent, systematic re-evaluation might also be necessary. In particular, reevaluation will be needed to ensure alignment with emerging PD biological definition and staging systems for neuronal synuclein disease (NSD) [123]. The use of an integrated biological- and clinical-staging model (based on degree of functional impairment) can improve participant selection for future studies. Historically, patient experience studies have not used biomarkers to define target populations, and all studies in the present conceptual model relied on time since clinical PD diagnosis, which might differ from disease stage. Thus, this model might not be generalizable to biologically-staged NSD and people with other neuronal synucleinopathies, such as dementia with Lewy bodies. Findings likely reflect PD/NSD individuals with mild symptoms and slight functional impairment to mild functional impairment (NSD Stage 3 or 4). As such, the proposed conceptual model should be treated as "best fit now" to prevent loss of forward momentum while striving for greater harmonization. Future work will be needed to test the model in biologically-defined NSD populations. This will allow for more precise understanding of what is important at each stage and can better support selection of stage-appropriate COI and COA for clinical trials. 4.4. Conclusions A widely accepted consensus conceptual model is an essential initial step in development of meaningful and reliable fit-for-purpose COAs for clinical trials in early PD. Collaborative efforts, leveraging prior work, and consensus on key concepts is crucial to advancing the science, reducing inefficiency and duplication of efforts, and ultimately developing the disease-modifying treatments that are so desperately needed. We believe the methods and outcomes described in this report can help address gaps in outcome measure development and selection in early PD trials and serve more broadly as a model for future efforts to develop conceptual models in diseases beyond PD. Declarations Data availability Data for the consensus model literature review are included in supplemental materials. Acknowledgements This study was funded by the Michael J Fox Foundation. The researchers thank the many individuals who contributed to this work including Dr. Michelle Campbell of the FDA. The content is based solely on the perspectives of the authors and does not necessarily represent the official views of the Critical Path Institute nor an endorsement by FDA/HHS or the U.S. Government. Author contributions Authorship contributions were as follows: development of consensus model and literature review approaches (all), review of literature and data analysis (JM), interpretation of findings, drafting and revising of model and manuscript (all). Conflict of Interest and Disclosures CM has received funding from Michael J. Fox Foundation for Parkinson’s Research (MJFF). GTS is an employee of Rush University and has consulting and advisory board membership with honoraria for: Acadia Pharmaceuticals; Adamas Pharmaceuticals, Inc.; Biogen, Inc.; Ceregene, Inc.; CHDI Management, Inc.; the Cleveland Clinic Foundation; Ingenix Pharmaceutical Services (i3 Research); MedGenesis Therapeutix, Inc.; Neurocrine Biosciences, Inc.; Pfizer, Inc.; Tools-4-Patients; Ultragenyx, Inc.; and the Sunshine Care Foundation. He has received grants from and done research for: the National Institutes of Health, the Department of Defense, the Michael J. Fox Foundation for Parkinson's Research, the Dystonia Coalition, CHDI, the Cleveland Clinic Foundation, the International Parkinson and Movement Disorder Society, and CBD Solutions, and has received honoraria from: the International Parkinson and Movement Disorder Society, the American Academy of Neurology, the Michael J. Fox Foundation for Parkinson's Research, the FDA, the National Institutes of Health, and the Alzheimer's Association. JLA has received research support from the Michael J. Fox Foundation for Parkinson’s Research, Critical Path for Parkinson’s, NIH/NINDS, Biogen, the Huntington Study Group, and PhotoPharmics; received compensation as a consultant/steering committee/advisory board member from the Huntington Study Group, the Parkinson Study Group, AbbVie, VisualDx, BioSensics, Sana Biotechnology, Neuron23, Biohaven, and the Michael J. Fox Foundation for Parkinson’s Research; received honoraria for speaking from the Huntington Study Group, the Parkinson Study Group, American Neurological Association, Lundbeck, and the Ohio State University. JRM has received research support from the NIH/NINR, Michael J. Fox Foundation for Parkinson’s Research (MJFF) and consulted for MJFF and Lundbeck HS. MT has received funding from Michael J. Fox Foundation for Parkinson’s Research (MJFF). TM is an employee of UCB Pharma. In the last 12 months TS has served as a consultant for AskBio, Amneal, Blue Rock Therapeutics, Critical Path for Parkinson's Consortium (CPP), Denali, General Electric, Kyowa, Neuroderm/ MTPA, Prevail/ Lilly, Roche, Sanofi, Sinopia, Takeda and Vanqua Bio. Dr. Simuni served on the ad board for AskBio, Amneal, Biohaven, Denali, GAIN, General Electric, Kyowa, MJFF, Neuron23, Parkinson Study Group, Prevail/ Lilly, and Roche. Dr. Simuni has served as a member of the scientific advisory board of Koneksa, Neuroderm/ MTPA, Sanofi and UCB. Dr. Simuni has received research funding from Amneal, Biogen, Neuroderm, Prevail, Roche,UCB and is an investigator for NINDS, MJFF, Parkinson’s Foundation. DW has received funding from Michael J. Fox Foundation for Parkinson’s Research (MJFF). The remaining authors (YX, WB, MT, CR, MC, CC, KC, RC, HM, JM, GS, CT, CB, ED, CK, DS,) have no relevant conflict of interest to disclose. 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Siddiqi B, Koemeter-Cox A (2021) A Call to Action: Promoting Diversity, Equity, and Inclusion in Parkinson's Research and Care. J Parkinsons Dis 11 , 905-908. O'Toole MT (2022) Mosby's medical dictionary , Elsevier, St. Louis, Missouri. Giddens JF (2017) Concepts for nursing practice Elsevier. Merriam-Webster, https://www.merriam-webster.com/dictionary/, Simuni T, Chahine, L., Poston, K., Brumm, M., Buracchio, T., Campbell, M., Chowdhury, S., Coffey, C., Concha-Marambio, L., Dam, T., DiBiaso, P., Foroud, T., Frasier, M., Gochanour, C., Jennings, D., Kieburtz, K., Kopil, C. M., Merchant, K., Mollenhauer, B., … Marek, K. (2023) Biological Definition of Neuronal alpha-Synuclein Disease: Towards an Integrated Staging System for Research. Zenodo . Tables Tables 1 and 2 are available in the Supplementary Files section. Additional Declarations (Not answered) Supplementary Files Table1.pdf Table 1. Stakeholder participation in development of the consensus conceptual model Table2.pdf Table 2. Operationalized Criteria for assessment of quality of evidence based on GRADE-CERQual SOFT1.pdf SOFT 1. Movement Domain SOFT2.pdf SOFT 2. Cognitive Domain SOFT3.pdf SOFT 3. Psychiatric Domain SOFT4.pdf SOFT 4. Sensory Domain SOFT5.pdf SOFT 5. Speech Domain SOFT6.pdf SOFT 6. Sleep Domain SOFT7.pdf SOFT 7. Digestive Domain SOFT8.pdf SOFT 8. Urinary Domain SOFT9.pdf SOFT 9. Sexual Domain SOFT10.pdf SOFT 10. Autonomic Domain SOFT11.pdf SOFT 11. Physical Functioning Domain SOFT12.pdf SOFT 12. Psychosocial Functioning Domain SupplementA.pdf Supplement A. Multi-database search strategy SupplementB.AllDataConsensusModelofEarlyPD.xlsx Supplement B. Supporting data (XL file) SupplementC.Domainmaps.pdf Supplement C. Domain maps for conceptual model SupplementD.ConceptDefinitions.pdf Supplement D. Concept Dictionary SupplementEAudittrail.pdf Supplement E. Audit trail of sources included in the systematic review Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: revise 22 Nov, 2024 Review # 3 received at journal 17 Nov, 2024 Reviewer # 3 agreed at journal 31 Oct, 2024 Reviewer # 2 agreed at journal 12 Sep, 2024 Review # 1 received at journal 08 Sep, 2024 Reviewer # 1 agreed at journal 29 Aug, 2024 Reviewers invited by journal 26 Jun, 2024 Submission checks completed at journal 08 May, 2024 Editor assigned by journal 06 May, 2024 First submitted to journal 06 May, 2024 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. 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Multi-database search strategy\u003c/p\u003e","description":"","filename":"SupplementA.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4377805/v1/72b1f2d8a1c8e67a8d731402.pdf"},{"id":59593749,"identity":"ce3be5e9-7584-4a93-88b8-102dbf6b9296","added_by":"auto","created_at":"2024-07-03 15:20:44","extension":"xlsx","order_by":16,"title":"","display":"","copyAsset":false,"role":"supplement","size":2116768,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplement B.\u003c/strong\u003e Supporting data \u0026nbsp;(XL file)\u003c/p\u003e","description":"","filename":"SupplementB.AllDataConsensusModelofEarlyPD.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4377805/v1/679edd50c2df6eddc4bc54ae.xlsx"},{"id":59593755,"identity":"4ce4dd6c-cb06-45fb-b8e5-eb379633a7c5","added_by":"auto","created_at":"2024-07-03 15:20:44","extension":"pdf","order_by":17,"title":"","display":"","copyAsset":false,"role":"supplement","size":896115,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplement C.\u003c/strong\u003e Domain maps for conceptual model\u003c/p\u003e","description":"","filename":"SupplementC.Domainmaps.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4377805/v1/e39f601894f32a0af958a20e.pdf"},{"id":59593751,"identity":"51a6b453-35a7-4a06-aaee-c6d597b3b30c","added_by":"auto","created_at":"2024-07-03 15:20:44","extension":"pdf","order_by":18,"title":"","display":"","copyAsset":false,"role":"supplement","size":320919,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplement D.\u003c/strong\u003e Concept Dictionary\u003c/p\u003e","description":"","filename":"SupplementD.ConceptDefinitions.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4377805/v1/e67ee50db2701c84dce87fcb.pdf"},{"id":59593754,"identity":"06888642-76e3-4b3b-9264-cd4986a75504","added_by":"auto","created_at":"2024-07-03 15:20:44","extension":"pdf","order_by":19,"title":"","display":"","copyAsset":false,"role":"supplement","size":641761,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplement E.\u003c/strong\u003e Audit trail of sources included in the systematic review\u003c/p\u003e","description":"","filename":"SupplementEAudittrail.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4377805/v1/6f2d8ff6598cef1669a68c5b.pdf"}],"financialInterests":"(Not answered)","formattedTitle":"A consensus conceptual model of meaningful symptoms and functional impacts in early Parkinson’s Disease","fulltext":[{"header":"1. Background","content":"\u003cp\u003eEffective treatments to halt or delay progression of Parkinson\u0026rsquo;s disease (PD) are urgently needed by patients and families [1]. \u0026nbsp;Yet, development of new drugs is a time and resource intensive process accompanied by more failures than successes [2]. \u0026nbsp;This is especially true for diseases with wide heterogeneity in symptom expression and unclear biological mechanisms of progression, such as PD[3]. \u0026nbsp;Phenotypic variability makes selection of pertinent outcomes for trials particularly challenging, as different symptoms or functional impacts may be more (or less) important to different people at different points throughout their disease course [4, 5]. \u0026nbsp;Yet, the success of clinical trials is dependent on having clinical outcome assessments (COA) that are sensitive to treatment effects rather than natural variations in disease progression or situational context [6, 7]. \u0026nbsp;This has created a critical need to know, with reasonable certainty, what experiences are typically most important to the majority of people with PD at a specified stage of disease (i.e., what\u0026mdash;who\u0026mdash;when). \u0026nbsp;This summative, contextually-defined knowledge of individuals\u0026apos; lived experiences is essential to development and selection of outcome measures that are meaningful from a real-world perspective and in alignment with the regulatory landscape [8, 9]. Recent qualitative work has greatly enhanced understanding of the lived experiences of people living with Parkinson\u0026rsquo;s [4, 10-13]; however there is no comprehensive nor widely accepted patient-centric conceptual model that can be used to guide the field. \u0026nbsp; For this reason, following the 2022 PD Endpoints Roundtable [14], a global taskforce of experts and patient representatives was convened to develop a consensus-based conceptual model of meaningful symptoms and functional impacts for early PD from systematic review of the literature. \u0026nbsp;The taskforce goals were to create a comprehensive yet parsimonious model that (1) aligns with current Food Drug Administration (FDA) guidance for patient-focused drug development (PFDD)\u0026nbsp;[6-9], (2) can support future research and clinical trials, (3) and is adaptable to emerging knowledge and later-stages of disease. This paper reports methodological approaches and findings of the taskforce.\u003c/p\u003e\n"},{"header":"2. Methods","content":"\u003cp\u003eTo ensure rigor in model development, best-practice guidelines were followed for each stage of model building, including systematic review of the literature, mixed methods evidence synthesis, and assessment of evidence quality [15-22]. These are shown in \u003cstrong\u003eFigure 1 \u003c/strong\u003eand described below.\u003c/p\u003e\n\u003ch2\u003e2.1. Approach to model development\u003c/h2\u003e\n\u003cp\u003eGuidelines by Brady et al. (2020) for the development of conceptual models to guide policy, practice, and research include three steps: (1) identifying resources (e.g., existing models, stakeholders, and literature-based sources), (2) considering the broad array of possible factors identified from resources, (3) narrowing down factors for inclusion on the basis of theory, stakeholder perspectives, and evidence [16]. A multi-stakeholder 14-person taskforce convened March of 2023, together with a 9-person patient and family advisory panel (\u003cstrong\u003eTable 1)\u003c/strong\u003e, to develop the methods and approach to review of the literature (Step 1). Stakeholders included people affected by PD (patients and families), researchers, clinicians, PD advocacy groups, industry, and regulatory agencies (FDA). The purpose of the literature review was to identify all reported symptoms and functional impacts of early PD (Step 2), with ultimate intent to identify which concepts are most meaningful for early-stage disease, to inform the final model (Step 3).\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003e2.2. Approach to systematic review for mixed methods evidence synthesis\u003c/h2\u003e\n\u003cp\u003eMultiple guidelines exist for the conduct of quantitative systematic reviews and qualitative evidence synthesis [23-25]. Fewer guidelines exist for mixed methods (MM) synthesis which is essential to understanding complex real-world phenomena [15]. The taskforce elected a \u003cem\u003econvergent\u003c/em\u003e\u003cem\u003eintegrated synthesis\u003c/em\u003e approach to identify meaningful symptoms and impacts of early PD in both qualitative and quantitative studies [15, 26, 27]. JBI Mixed Methods Review criteria [15, 27] were used: (1) defining the review question using PICo (population, phenomena, context); (2) determining inclusion/exclusion criteria; (3) defining the search strategy (4) systematic assessment of methodological quality (5) data extraction (6) data synthesis; and (7) presentation of results.\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003e2.2.1. Research Question: What symptoms and impacts are most meaningful in early PD?\u003c/h3\u003e\n\u003cp\u003ePer recommendations from the patient panel, people affected by PD were defined as patients/people with PD (PwP) and their intimate social circle, referred to hereafter in this manuscript as \u0026ldquo;family.\u0026rdquo; The terms \u0026ldquo;caregiver\u0026rdquo; and \u0026ldquo;care partner\u0026rdquo; were not used as most people with early PD do not have formal caregivers, and \u0026ldquo;partner\u0026rdquo; does not encompass the scope of people affected by PD, such as children and close friends.\u003c/p\u003e\n\u003cp\u003eDefinition of symptoms and functional impacts. For this model, \"symptoms\" were considered to be the subjective or objective physical and mental features (i.e., signs/symptoms of disease) occurring as a direct result of PD, leading or potentially leading to changes in day-to-day physical and psychosocial functioning. \"Functional impacts\" (hereafter \"impacts\") were defined in alignment with FDA guidance as experiences occurring as a consequence of disease, such as changes in the way a person functions or feels [6].\u003c/p\u003e\n\u003cp\u003eDefinition of early PD. There is no formal definition of early PD and most studies to date have utilized clinical diagnosis of PD with variable definitions of early-stage disease ranging from 0 to upwards of 6 years. For the model, early PD was defined as less than 3 years since diagnosis (YSD) by expert consensus. The 3-year timeframe aligns with the target population of the Critical Path for Parkinson\u0026rsquo;s Consortium and with many clinical trials for early PD [28].\u003c/p\u003e\n\u003cp\u003eDefinition of concepts of interest. A concept of interest is the \"aspect of an individual\u0026rsquo;s clinical, biological, physical, or functional state, or experience that the assessment is intended to capture or reflect\" [8].\u003c/p\u003e\n\u003cp\u003eDefinition of meaningful symptoms and impacts. Per patient panel and expert discussion, to be deemed \"meaningful\" a concept (either symptom or impact) had to show evidence of being prevalent as well as personally bothersome to people with early PD \u0026lt;3 years since clinical diagnosis.\u003c/p\u003e\n\u003ch3\u003e2.2.2. Primary source inclusion/exclusion criteria\u003c/h3\u003e\n\u003cp\u003eSources were eligible for inclusion if they were: (a) primary published or unpublished qualitative, quantitative or mixed methods (MM) studies; (b) conducted within an early PD population as defined by source study authors; (c) reported any symptoms and/or impacts of early PD; and (d) contained data that were patient, family, observer, clinician reported or digitally measured. Studies focused on evaluating the effect of a specific medication or intervention were excluded, as were conference proceedings, due to insufficient data to reliably evaluate methods or findings. In longitudinal studies baseline measurement values were used.\u003c/p\u003e\n\u003ch3\u003e2.2.3. Search strategy\u003c/h3\u003e\n\u003cp\u003eFor the literature review, any source with a study-defined \u0026ldquo;early PD\u0026rdquo; population was included to avoid overlooking potential sources during the search process. Four databases were searched as shown in\u003cstrong\u003e Supplement A\u003c/strong\u003e. Search \u003cstrong\u003e\u003cem\u003eStrategy 1\u003c/em\u003e\u003c/strong\u003e identified sources published within 10 years that referenced early PD and symptoms or impacts anywhere in the title or abstract (search date: May 2023). \u003cstrong\u003e\u003cem\u003eStrategy 2\u003c/em\u003e\u003c/strong\u003e identified sources that used early PD and common terms for qualitative research anywhere in the title or abstract \u003cem\u003ewithout\u003c/em\u003e time limits. \u003cstrong\u003e\u003cem\u003eStrategy 3\u003c/em\u003e\u003c/strong\u003e consisted of examining reference lists of relevant review articles for additional sources. \u003cstrong\u003e\u003cem\u003eStrategy 4\u003c/em\u003e\u003c/strong\u003e used expert consultation to identify key sources \u0026gt; 10 years old or unpublished relevant datasets not captured in the first two search strategies. As shown in \u003cstrong\u003eFigure 2\u003c/strong\u003e, 2006 sources were returned, with 1301 duplicates. Abstracts were screened for 705 sources. Of these 554 were excluded and 151 were selected for full text review. Eighty-nine sources remained after eliminating studies without reportable data on symptoms or impacts within any early PD population. Of these, only 56 studies used samples that were strictly \u0026lt;3 years since diagnosis based on mean and SD. A complete list of sources screened and included/excluded is provided in \u003cstrong\u003eSupplement E.\u003c/strong\u003e\u003c/p\u003e\n\u003ch2\u003e2.3. Approach to data analysis\u003c/h2\u003e\n\u003cp\u003eAll sources that met review inclusion criteria were systematically analyzed, and findings were weighted and aggregated to enable assessment of the total quality of evidence supporting each concept in early PD, as described below. Data extraction for \u003cem\u003econcepts\u003c/em\u003e was performed on all studies of early PD (as defined by study authors; N=89; range 0-6 years since diagnosis), however, data regarding \u003cem\u003efrequencies\u003c/em\u003e of concepts was limited to PD \u0026lt;3 years since diagnosis (N=56). This was done to maximize identification of potential concepts with reported frequencies specific to early PD.\u003c/p\u003e\n\u003ch3\u003e2.3.1. Data extraction\u003c/h3\u003e\n\u003cp\u003eFor mixed methods synthesis, JBI guidance recommends codifying quantitative data in a manner compatible with qualitative synthesis to reduce potential for inaccuracies in meta-aggregation across methodologies [26]. Using a matrix spreadsheet (\u003cstrong\u003eSupplement B\u003c/strong\u003e), all studies were assessed individually for study aims, design, year of publication, sample size, PD stage, diagnostic criteria, years since diagnosis (mean, SD), comparison group, gender distribution, race/ethnicity, country of origin, data source, data collection instruments, PD medication use, levodopa equivalent daily dose (LEDD), Hoehn \u0026amp; Yahr (H\u0026amp;Y), Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III total score if reported [29], any covariates, and a brief study synopsis.\u003c/p\u003e\n\u003cp\u003eContent coding. Each source was then analyzed to extract information about symptoms or impacts of early PD. Where given, frequencies for prevalence were extracted.For studies lacking frequencies but reporting between groups comparisons for \u003cem\u003eearly PD vs. Control\u003c/em\u003e (e.g., normative cohort, later PD cohort), statistically significant differences were indicated with \u0026ldquo;\u003cstrong\u003e*\u003c/strong\u003e\u0026rdquo; and no statistically significant differences were indicated with \u0026ldquo;\u003cstrong\u003e-\u003c/strong\u003e\u0026ldquo;. For studies reporting bothersomeness rather than prevalence, the percentage of people identifying the concept as being actively bothersome was reported in the matrix.\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003e2.3.2. Development of the conceptual model schema\u003c/h3\u003e\n\u003cp\u003eAfter content coding, all identified concepts were qualitatively analyzed to derive a best-fit conceptual schema that was intuitive, optimally parsimonious, and able to facilitate measurement consistency and reduce redundancy. Only concepts identified by systematic review were included in the modeling. Initial attempts to group by motor versus non-motor resulted in a poorly organized structure due to the large number of concepts identified and the presence of many concepts with ambiguous classification (e.g., motor vs. non-motor; symptom vs. impact).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA series of 10 interactive sessions were held from September to November, 2023, to solicit feedback from all stakeholders (taskforce and patient panel) to derive a consensus-based schema that was intuitive and user-friendly for clinicians, researchers, PwP and families. Sessions were held online using a focus group format, with a moderator who summarized and synthesized perspectives in real time.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eUsing mapping approaches (Xmind app) with screen sharing, concepts were clustered by relatedness and organized into logical groupings [30, 31]. Where possible, full agreement was sought for all analytic decisions, with use of majority vote on best groupings (\u0026gt;80% taskforce and patient panel) when 100% consensus was not achieved in online meetings. Similar concepts were merged and consensus term selected based on taskforce and patient panel agreement. Concepts that related to a broader concept were subsumed as dependent nodes to develop a branching structure moving from broad concepts to progressively more specific aspects of an experience (e.g., shuffling as an aspect of gait). Conceptual distinctness and relatedness were determined by stakeholder consensus regarding interpretation of literature review findings during online sessions. All conceptually distinct items were retained in the final model schema (\u003cstrong\u003eSupplement C\u003c/strong\u003e). Detailed documentation of stakeholder sessions and revisions to the schema was retained for an audit trail.\u003c/p\u003e\n\u003ch3\u003e2.3.3. Weighting of primary sources preparatory to metasynthesis\u003c/h3\u003e\n\u003cp\u003eThe PFDD guidance series prioritizes \u003cem\u003edirect report\u003c/em\u003e of patient experience from the target population (i.e., people with PD) [9]. When this type of data is limited or the patient population has reduced ability to reliably report experiences, supporting information may be obtained from caregivers, clinicians, or other key informants [8]. Based on discussion with the patient panel and taskforce members, a three-tiered approach was chosen for classification of primary sources. This was done to allow for prioritization of patient voice and weighted synthesis of findings across diverse methodologies and data sources as described below.\u003c/p\u003e\n\u003cp\u003eTier 1 [4, 10-13, 32-34] comprised qualitative or mixed methods studies that evaluated symptoms and impacts of PD using an open-ended, iterative, and patient-driven approach, in which patients and/or family were asked to freely identify what symptoms or impacts the person experienced without constraints. Tier 1 was further subdivided to \u003cstrong\u003e\u003cem\u003eTier 1A\u003c/em\u003e\u003c/strong\u003e (studies reporting a symptom as being \u003cem\u003ebothersome\u003c/em\u003e in early PD irrespective of prevalence) and \u003cstrong\u003e\u003cem\u003eTier 1B\u003c/em\u003e\u003c/strong\u003e (studies reporting symptoms as \u003cem\u003epresent\u003c/em\u003e in early PD irrespective of whether it is bothersome). Tier 1 sources were used as \u003cem\u003eprimary evidence\u003c/em\u003e for the conceptual model. Original study teams from Tier 1 sources were contacted to obtain detailed frequencies for symptoms and impacts if not fully presented in published manuscripts [4, 10-12, 32, 33].\u003c/p\u003e\n\u003cp\u003eTier 2 [35-61] and 3 [62-114] consisted of quantitative studies in which predetermined aspects of health were measured using quantitative approaches. \u003cstrong\u003e\u003cem\u003eTier 2 \u003c/em\u003e\u003c/strong\u003eincluded studies that evaluated symptoms and impacts using patient-reported outcome (PRO) measures selected by a study team in which a limited selection of symptoms or impacts were evaluated from the patient perspective. \u003cstrong\u003e\u003cem\u003eTier 3 \u003c/em\u003e\u003c/strong\u003eincluded data from studies with clinician or observer reported symptoms or impacts (i.e., ClinRO, ObsRO). Sources reporting only cumulative scores on validated scales were excluded as they lacked discrete data on symptoms or impacts. Tier2 and 3 studies were included as \u003cem\u003esupporting evidence\u003c/em\u003e due to potential for bias in symptom reporting.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePooling of same sample studies\u003cstrong\u003e\u003cem\u003e.\u003c/em\u003e\u003c/strong\u003e Same sample studies were defined as separate publications that reported findings from the same (identical) participant sample (\u003cstrong\u003eSupplement B\u003c/strong\u003e). Findings were pooled from same-sample studies to ensure equal weighting during meta-synthesis. For pooling, redundant findings (e.g., demographics \u0026ndash; diagnosis of depression) were reported once, while all unique findings retained. Thus, a total of 38 unique study samples were included in the final model.\u003c/p\u003e\n\u003ch3\u003e2.3.4. Aggregation of data for early PD \u0026lt;3 years since diagnosis\u003c/h3\u003e\n\u003cp\u003eData aggregation was performed at the level of \u003cem\u003eunique samples\u003c/em\u003e (N=38; Supplement E), rather than at the level of individual studies so that each unique sample was represented only once in the final meta-synthesis. Only samples with data for PD\u0026lt;3 years since diagnosis were included at this stage, based on the final model inclusion criteria. Data and frequencies for the full early PD sample (N=89, 0-6 years since diagnosis) vs. PD \u0026lt;3 years since diagnosis can be viewed in \u003cstrong\u003eSupplement B.\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe following metrics were calculated for each symptom and impact in early PD \u0026lt;3 years since diagnosis:\u003c/p\u003e\n\u003col\u003e\n\u003cli\u003eNumber and percentage of unique samples that measured a concept (within and across all Tiers);\u003c/li\u003e\n\u003cli\u003eAverage prevalence of concept (within and across Tiers 1B, 2, \u0026amp; 3 \u0026ndash; sum of frequencies in all studies reporting prevalence/total number of studies reporting prevalence);\u003c/li\u003e\n\u003cli\u003eNumber and percentage of unique samples disconfirming presence of concept (within and across all Tiers); and\u003c/li\u003e\n\u003cli\u003eFrequency which concept was reported as being actively bothersome (Tier 1A; sum of frequencies in studies reporting bothersomeness/total number of studies reporting bothersomeness).\u003c/li\u003e\n\u003c/ol\u003e\n\u003ch3\u003e2.3.5. Assessment of quality of evidence \u0026amp; synthesis of findings\u003c/h3\u003e\n\u003cp\u003eNext, evidence synthesis was performed using GRADE-CERQual [17-22]. GRADE-CERQual is a standardized approach to assessment of confidence in the quality of evidence from qualitative studies and is endorsed by the World Health Organization and numerous government agencies for the development guidelines to shape public policy and research [23, 115, 116]. CERQual evaluates four primary areas: (1) methodological limitations, (2) coherence of findings, (3) adequacy of the data, and (4) relevance of the findings. These criteria are presented in \u003cstrong\u003eTable 2,\u003c/strong\u003e along with the operationalized approach to assessment. For this model, methodological limitations were addressed \u003cem\u003ea priori\u003c/em\u003e using the Tiered approach, in which unique samples were weighted based on underlying methodological strengths and limitations.\u003c/p\u003e\n\u003ch2\u003e2.4. Research community review\u003c/h2\u003e\n\u003cp\u003eLastly, to maximize potential for usefulness and adoption of the consensus model, the model and manuscript and all supporting files were posted online for research community review and feedback over a 1-month period (Jan-Feb 2024). Participants for the community review were solicited via the MJFF research community newsletter (distribution list N= ~9.5K), the UK PD clinical Studies Group (N=65) and by personal invitation to experts identified by the taskforce members, including members of FDA, EMA, MDS, CPP and content experts (N=88). An online form was provided for feedback or feedback could alternately be emailed directly to taskforce members. Final minor clarifications were made to the model, figures, and manuscript on the basis of reviews, with an audit trail of changes available upon request.\u003c/p\u003e"},{"header":"3. Results","content":"\u003cp\u003eSample characteristics. \u0026nbsp;A total of 89 studies reported symptoms and impacts in \u0026ldquo;early PD\u0026rdquo; (generally defined as 0-5 years from diagnosis) and were utilized for the initial concept identification phase. \u0026nbsp;Of these, 56 sources focused exclusively on PD \u0026lt;3 years since diagnosis. \u0026nbsp; After pooling for same sample studies within the \u0026lt;3 year subset, a total of 38 unique samples from publications during years 2013 to 2023 were used to derive frequencies for the final early PD model. Of these, all qualitative samples (Tier 1; 6 unique samples from 7 studies) were from the UK, USA, and Canada and included predominantly white participants (93-100%). \u0026nbsp;Three of these reported bothersomeness; four reported prevalence; one reported both. \u0026nbsp;Sample sizes ranged from 20 to 134 with one very large sample study of 8536 participants (Fox Insight/PD PROP). Tier 2 (N=13) and Tier 3 (N=19) sources included studies from UK, USA, Canada, Italy, Korea, Serbia, Thailand, Germany, India, China, Singapore, and the Netherlands, in which distribution of race/ethnicity was often not reported. \u0026nbsp;Samples sizes ranged from 54 to 921 participants. \u0026nbsp; The mean age range for all studies in all Tiers was 57-68 years. \u0026nbsp;Gender distribution ranged from 40-74% male, most commonly approaching 60%. \u0026nbsp;In 13 of 38 unique samples (34%), participants were taking PD medications (range 4-100%; mean LEDD 50-544 mg/day). Medication use was not stated in 18% (7/38). \u0026nbsp;Hoehn \u0026amp; Yahr score (H\u0026amp;Y) was reported by 27/38 samples, with mean H\u0026amp;Y\u0026lt;2 for all (100%) studies, but only 12/27 (44%) strictly \u0026pound;2 when factoring +2SD. \u0026nbsp;MDS-UPDRS III (motor) was reported in 25/38 studies and ranged from 9.2-27.0, which is consistent with early PD [117].\u003c/p\u003e\n\u003cp\u003eConcept characteristics. \u0026nbsp; Approximately 340 symptoms and impacts were identified from the original 89 publications. \u0026nbsp;Substantial variability was observed in terminology and classification of concepts, with certain concepts inconsistently classified as motor vs. non-motor, (e.g., restless leg, constipation, drooling, voice changes, swallowing), impact vs. symptom (e.g., anxiety, depression, frustration), or listed twice under both symptom and impact (e.g., handwriting, anxiety). \u0026nbsp;Diverse terminology was commonly used to describe conceptually similar ideas (e.g., depressed mood, feelings of sadness, negative feelings and emotions). \u0026nbsp;Definitions were rarely provided for terms, requiring reviewers to infer what a concept likely comprised from common language use or from the context in the report (e.g., thermoregulation indicative of heat/cold intolerance vs. body temperature). \u0026nbsp;Consequently, some redundancy due to potentially overlapping concepts might be present in the working model presented below.\u003c/p\u003e\n\u003cp\u003eConsensus conceptual model schema. \u0026nbsp; \u0026nbsp;Concepts were organized using a primary classification schema of \u003cstrong\u003eDomain\u0026mdash;Category\u0026mdash;Concept\u0026mdash;Experience\u003c/strong\u003e, with secondary classification of motor or non-motor occurring at the measurement level, as depicted in \u003cstrong\u003eFigure 3\u003c/strong\u003e. \u0026nbsp;Ten systems-based symptom domains were identified (Movement, Cognitive, Psychiatric, Sleep, Sensory, Speech, Digestive, Urinary, Sexual, Autonomic) in addition to two impact domains (Physical functioning; Psychosocial functioning). \u0026nbsp;A map of the top-level conceptual schema is presented in \u003cstrong\u003eFigure 4\u003c/strong\u003e, with maps for all domains is presented in \u003cstrong\u003eSupplement C.\u003c/strong\u003e\u0026nbsp; Comprehensive data tables and frequencies by source are presented in \u003cstrong\u003eSupplement B,\u003c/strong\u003e and \u003cstrong\u003eSupplement D\u003c/strong\u003e presents working definitions for each concept included in the model. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSOFT Reports. \u0026nbsp;Synthesis of Findings Tables (\u003cstrong\u003eSOFT 1 through 12\u003c/strong\u003e) are presented for each symptom and impact domain, with subdivision by conceptual categories. \u0026nbsp; SOFT reports show (1) issues of coherence in measurement and classification of concepts; (2) adequacy of data supporting conclusions; and (3) the relevance of each concept based on prevalence and extent to which the concept is bothersome in early PD\u0026lt;3 years since diagnosis. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFrom the SOFT reports, the most meaningful motor symptoms of early PD appear to include tremor, fine motor difficulties, gait \u0026amp; balance changes, stiffness, and slow movements\u0026mdash;all of which were observed to be prevalent (54-85%) and bothersome (24-57%) within 3 years from diagnosis. \u0026nbsp;The SOFT reports also highlight multiple non-motor symptoms that are commonly experienced and meaningful to people with early disease. \u0026nbsp;These commonly include cognitive and speech changes (e.g., word finding); mood changes such as anxiety, depressed mood, or negative feelings/emotions; alterations in sleep; sensory changes (e.g., increased pain and fatigue); urinary dysfunction; and digestive system changes (e.g., choking, constipation).\u003c/p\u003e\n\u003cp\u003eIn addition to identifying common bothersome symptoms and impacts, multiple gap areas were observed, most often in the impact domains. \u0026nbsp;Evidence from the review suggests that impact on mobility-related activities, such as physical exercise, may be a high priority area in early PD (70% prevalence; 31% bothersome). \u0026nbsp; Other concepts, such as \u0026ldquo;Effort of Living\u0026rdquo; are comparatively new, with no data on prevalence (Tier 1B to 3) but Tier 1A evidence suggestive of a meaningful experience (29% bothersome). \u0026nbsp;Other concepts that may be relevant at this stage include impacts on self-concept (35% bothersome), personal coping (29% bothersome), interpersonal interactions (e.g., relationships with others), sense of independence, profession, and hobbies\u0026mdash;among others. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA final finding from the SOFT reports is the substantial research that has been conducted in areas that appear less meaningful to people with PD. \u0026nbsp;Most common examples of this include drooling (30% prevalence; 0% bothersome) and loss of smell (29% prevalence; 2% bothersome). \u0026nbsp;\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThe consensus conceptual model presented here is the most comprehensive catalogue of meaningful symptoms and impacts in PD, based on literature to date. This effort expands on prior models derived from individual studies [4, 10, 12, 13]. Like others, we found a wide range of symptoms and impacts that are meaningful in early PD, with strongest initial evidentiary support for movement, cognitive, mood, speech, and sleep-related symptoms, which corresponds with a recent systematic review by Tosin et al [118]. Cumulatively, these findings provide compelling evidence that treatments for early-PD should address one or more of these domains of patient experience, which could require the identification or development of clinical outcome assessments that are valid and reliable for evaluating them in the early-PD population. However, the present report also highlights multiple other concepts with preliminary evidence of meaningfulness that have been insufficiently studied. Further research will be needed to evaluate prevalence and relative importance to patients before definitive conclusions can be made as to which concepts are most broadly relevant for early-stage PD.\u003c/p\u003e\n\u003ch2\u003e4.1. Recommendations for use and limitations of SOFT reports\u003c/h2\u003e\n\u003cp\u003eSOFT reports can support evidence-based rationales for concepts of interest for use in research or clinical assessment. However, it is important to note that these reports should be used with caution due to limitations inherent in the data collection and reporting processes of primary sources. Evidence for these reports was compiled from diverse sources, and methodological flaws in primary sources might have resulted in over, under, or selective reporting, which in turn affect aggregated frequencies for this study. Thus, the term \"SOFT report\" is intentional and should serve as a reminder that data are not conclusive and should be treated as an estimation rather than an exact measurement. Future work will enable more accurate and detailed understanding of concepts in defined populations over time, which can support the identification of a parsimonious set of core outcomes for early-PD populations.\u003c/p\u003e\n\u003cp\u003eConduct multifaceted Concept of Interest (COI) assessments. Selection of meaningful concepts requires recognizing that \"meaningfulness\" is multifaceted. No single metric in the SOFT reports should be used in isolation to justify selection of COI. Consideration should be given to all metrics, including estimates of prevalence in the population, evidence that it is truly relevant to people with early PD, and the total weight of evidence (Grade/Level) that justifies these conclusions.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eExplore gap areas. Gap areas are concepts that have insufficient data to justify inclusion or exclusion in the early PD model on the basis of SOFT reports. Absence of a concept in SOFT reports, or lack of specific supporting data does not imply absence of a meaningful experience in early PD, and rather might mean the concept has not been sufficiently studied or reported. Particular attention should be paid to concepts with limited or missing evidence. Further research will be needed in many areas to define the scope of these concepts and determine relevant approaches to measurement.\u003c/p\u003e\n\u003cp\u003eEvaluate coherence and disconfirming evidence. Close attention should also be paid to disconfirming evidence and discrepancies in findings. For instance, the categorical concept of \"gait\" appears to be highly relevant in early PD, but there is little data to indicate which aspects of walking are problematic, noticeable, or bothersome to people with PD (i.e., specific health experiences such as shuffling or sensation of foot being stuck to floor). Disconfirming evidence existing side-by-side with confirming evidence can raise questions about cohesiveness of the concept and adequacy of prior measurement approaches (e.g., both confirming and disconfirming evidence regarding dyskinesia in early PD in all Tiers). Conflicting evidence can highlight areas of limited or imprecise understanding that might benefit by further clarifying work. Identifying the specific patient experiences that comprise a concept will improve consistency in concept definitions and measurement approaches.\u003c/p\u003e\n\u003ch2\u003e4.2. Pragmatic considerations in selection of COI\u003c/h2\u003e\n\u003cp\u003eChange over time. SOFT reports can help identify what is important to people affected by PD, however, additional pragmatic considerations are needed during COI selection and development of measures for clinical trials. Once potential COI have been identified, it is important to consider measurability for clinical trials and if the experience is likely to significantly change within the time frame of the average trial (e.g., 6-18 months). Similarly, selection of the COI might be dependent on whether it is likely to be affected by a potential treatment, which is contingent on the mechanism of action of the treatment being evaluated. For example, \"stigma\" may be highly relevant to PwP (i.e., good evidence of being prevalent and bothersome), but is unlikely to change rapidly with treatment, thus might be unsuitable for certain measurement situations.\u003c/p\u003e\n\u003cp\u003eContext of use. The context in which a COI will be used in drug development decision making will also affect choice. Important points to consider are universality and participant characteristics that may affect how an individual experiences it. Individual characteristics such as age, life-stage (pre/post retirement), sex, gender, geographic location, and culture can affect the meaningfulness of certain concepts more than others. For example, the impact of PD on driving may be different for people in rural areas than for urban residents, which could affect the suitability of the concept for geographically diverse trials testing treatment efficacy. Similarly, COIs may be sex specific (e.g., erectile dysfunction) and attention should be given to maximize applicability to both sexes. Culture may also play a key role in COI selection, however there is very limited data on this due to the predominance of white participants of higher socio-economic status in most trials to date.\u003c/p\u003e\n\u003cp\u003eMeasurement validity. Other practical considerations include recall and social biasing. Some experiences may be more difficult to recall over time than others. Some concepts may be subject to social desirability bias (e.g., people may downplay or be reluctant to report experiences such as sexual dysfunction or compulsive behaviors), leading to potential for increased measurement error. Ability for participants to tell if a symptom is attributable to PD may also be an important consideration, which was highlighted by the patient panel. Ways to enhance validity in measurement should be considered during COI selection. Symptom concepts that are clearly linked to a functional impact may be particularly useful, allowing for triangulated assessment of the symptom and/or impact on function (e.g., what the person can or cannot do because of fatigue). This requires establishing an evidence-based connection between specific symptoms and related functional impacts and demonstrating the prevalence and meaningfulness of these sets of experiences to people with early PD.\u003c/p\u003e\n\u003ch2\u003e4.3. Future directions\u003c/h2\u003e\n\u003cp\u003eKey strengths of the present approach include exhaustive review and meta-synthesis of methodologically diverse studies, inclusion of all key stakeholders throughout the model-building process, and use of an iterative consensus-based design. We believe that this has contributed to a maximally inclusive model reflective of the current state of the science, with an intuitive and easily understood interface. This can increase utility of the model, contribute to improved COAs for early PD trials, and enhance potential for broad uptake and harmonization of approaches across research, health care practice, and other endeavors. However, several areas remain in need of substantial future work and will enhance the long term utility of data from this report.\u003c/p\u003e\n\u003cp\u003eNeed for diverse perspectives. There remains a marked lack of participant diversity in PD research, which is a well-known issue in the field [119]. All Tier 1 evidence was elicited from the UK, USA, and Canada, with samples that were \u0026gt;93% white. Tier 2 and 3 data contained greater diversity in country of origin but limitation to PD duration of \u0026lt;3 years since diagnosis excluded a number of these studies from inclusion in final frequencies. This data has been retained and is available in \u003cstrong\u003eSupplement B\u003c/strong\u003e. Future work should aim to expand knowledge of meaningful symptoms and functional impacts in culturally, geographically, and racially diverse populations. This recommendation corresponds with FDA PFDD guidance [6-9]. In particular, evidence from countries in certain parts of Asia, Africa, and South America is limited and would help to inform the utility of the current conceptual model for more diverse populations. Similarly, evidence from cultural and racial minorities living within predominantly white countries is needed.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLastly, only one study in the review reported the perspectives of family separately from patient perspectives with regards to most bothersome symptoms [33]. Due to the model parameters and significant differences in PwP vs. family perspectives, this data was removed from the final model frequencies as an outlier but is reported in \u003cstrong\u003eSupplement B\u003c/strong\u003e. Further research to understand the wholistic impact of PD on patients and their family might be warranted, given growing emphasis on family centric and palliative care.\u003c/p\u003e\n\u003cp\u003eNeed for harmonization. Another key call to action is for harmonization of concepts and concept definitions, which will be needed to improve coherence in classification and measurement for future studies. All terms in the present model have been given preliminary working definitions derived from evidence-based resources [120, 121] and common language usage of terms [122] (\u003cstrong\u003eSupplement D\u003c/strong\u003e) with the recognition that these may require revision or refinement as the field matures. Revisions or additions to domains, categories or concepts should be made cautiously and grounded in rigorous evidence, with careful attention to existing items in the model. This will help to avoid redundancy and maximize parsimony. Where possible, researchers will benefit by building on prior work instead of duplicating efforts. When needed, clear and compelling scientific justification should be provided for alternative terms for similar concepts. Finally, in selecting \"best\" terms, reflecting the experiences of the people living with PD should remain a top priority \u0026ndash; which was unanimously emphasized by the patient panel. Thus, where possible, patient centric terms that are understandable to most patients will be preferred over complex technical terms exclusive to the scientific community (e.g., slow movements vs. bradykinesia).\u003c/p\u003e\n\u003cp\u003eExpectation of evolution. It is expected that this model will evolve over time based on refinements and expansion of knowledge within early PD and later stages of disease. It is important to note that the conceptual categorization proposed here is not intended to be prescriptive. Clear documentation of rationales for alternative approaches to concepts, definitions, or classification will help with refinement over time. Intermittent, systematic re-evaluation might also be necessary.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;In particular, reevaluation will be needed to ensure alignment with emerging PD biological definition and staging systems for neuronal synuclein disease (NSD) [123]. The use of an integrated biological- and clinical-staging model (based on degree of functional impairment) can improve participant selection for future studies. Historically, patient experience studies have not used biomarkers to define target populations, and all studies in the present conceptual model relied on time since clinical PD diagnosis, which might differ from disease stage. Thus, this model might not be generalizable to biologically-staged NSD and people with other neuronal synucleinopathies, such as dementia with Lewy bodies. Findings likely reflect PD/NSD individuals with mild symptoms and slight functional impairment to mild functional impairment (NSD Stage 3 or 4). As such, the proposed conceptual model should be treated as \"best fit now\" to prevent loss of forward momentum while striving for greater harmonization. Future work will be needed to test the model in biologically-defined NSD populations. This will allow for more precise understanding of what is important at each stage and can better support selection of stage-appropriate COI and COA for clinical trials.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003e4.4. Conclusions\u003c/h2\u003e\n\u003cp\u003eA widely accepted consensus conceptual model is an essential initial step in development of meaningful and reliable fit-for-purpose COAs for clinical trials in early PD. Collaborative efforts, leveraging prior work, and consensus on key concepts is crucial to advancing the science, reducing inefficiency and duplication of efforts, and ultimately developing the disease-modifying treatments that are so desperately needed. We believe the methods and outcomes described in this report can help address gaps in outcome measure development and selection in early PD trials and serve more broadly as a model for future efforts to develop conceptual models in diseases beyond PD.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eData availability\u003c/p\u003e\n\u003cp\u003eData for the consensus model literature review are included in supplemental materials.\u003c/p\u003e\n\u003cp\u003eAcknowledgements\u003c/p\u003e\n\u003cp\u003eThis study was funded by the Michael J Fox Foundation. \u0026nbsp;The researchers thank the many individuals who contributed to this work including Dr. Michelle Campbell of the FDA. The content is based solely on the perspectives of the authors and does not necessarily represent the official views of the Critical Path Institute nor an endorsement by FDA/HHS or the U.S. Government.\u003c/p\u003e\n\u003cp\u003eAuthor contributions\u003c/p\u003e\n\u003cp\u003eAuthorship contributions were as follows: development of consensus model and literature review approaches (all), review of literature and data analysis (JM), interpretation of findings, drafting and revising of model and manuscript (all).\u003c/p\u003e\n\u003cp\u003eConflict of Interest and Disclosures\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCM\u003c/strong\u003e has received funding from\u0026nbsp;Michael J. Fox Foundation for Parkinson\u0026rsquo;s Research (MJFF). \u0026nbsp;\u0026nbsp;\u003cstrong\u003eGTS\u003c/strong\u003e is an employee of Rush University and has consulting and advisory board membership with honoraria for: Acadia Pharmaceuticals; Adamas Pharmaceuticals, Inc.; Biogen, Inc.; Ceregene, Inc.; CHDI Management, Inc.; the Cleveland Clinic Foundation; Ingenix Pharmaceutical Services (i3 Research); MedGenesis Therapeutix, Inc.; Neurocrine Biosciences, Inc.; Pfizer, Inc.; Tools-4-Patients; Ultragenyx, Inc.; and the Sunshine Care Foundation. He has received grants from and done research for: the National Institutes of Health, the Department of Defense, the Michael J. Fox Foundation for Parkinson\u0026apos;s Research, the Dystonia Coalition, CHDI, the Cleveland Clinic Foundation, the International Parkinson and Movement Disorder Society, and CBD Solutions, and has received honoraria from: the International Parkinson and Movement Disorder Society, the American Academy of Neurology, the Michael J. Fox Foundation for Parkinson\u0026apos;s Research, the FDA, the National Institutes of Health, and the Alzheimer\u0026apos;s Association. \u0026nbsp;\u0026nbsp;\u003cstrong\u003eJLA\u003c/strong\u003e has received research support from the Michael J. Fox Foundation for Parkinson\u0026rsquo;s Research, Critical Path for Parkinson\u0026rsquo;s, NIH/NINDS, Biogen, the Huntington Study Group, and PhotoPharmics; received compensation as a consultant/steering committee/advisory board member from the Huntington Study Group, the Parkinson Study Group, AbbVie, VisualDx, BioSensics, Sana Biotechnology, Neuron23, Biohaven, and the Michael J. Fox Foundation for Parkinson\u0026rsquo;s Research; received honoraria for speaking from the Huntington Study Group, the Parkinson Study Group, American Neurological Association, Lundbeck, and the Ohio State University.\u0026nbsp;\u0026nbsp; \u003cstrong\u003eJRM\u003c/strong\u003e has received research support from the NIH/NINR, Michael J. Fox Foundation for Parkinson\u0026rsquo;s Research (MJFF) and consulted for MJFF and Lundbeck HS. \u0026nbsp; \u003cstrong\u003eMT\u003c/strong\u003e has received funding from\u0026nbsp;Michael J. Fox Foundation for Parkinson\u0026rsquo;s Research (MJFF). \u0026nbsp;\u0026nbsp;\u003cstrong\u003eTM\u003c/strong\u003e is an employee of UCB Pharma. \u0026nbsp;In the last 12 months TS has served as a consultant for AskBio, Amneal, Blue Rock Therapeutics, Critical Path for Parkinson\u0026apos;s Consortium (CPP), Denali, General Electric, Kyowa, Neuroderm/ MTPA, Prevail/ Lilly, Roche, Sanofi, Sinopia, Takeda and Vanqua Bio. Dr. Simuni served on the ad board for AskBio, Amneal, Biohaven, Denali, GAIN, General Electric, Kyowa, MJFF, Neuron23, Parkinson Study Group, Prevail/ Lilly, and Roche. Dr. Simuni has served as a member of the scientific advisory board of Koneksa, Neuroderm/ MTPA, Sanofi and UCB. Dr. Simuni has received research funding from Amneal, Biogen, Neuroderm, Prevail, \u0026nbsp;Roche,UCB and is an investigator for NINDS, MJFF, Parkinson\u0026rsquo;s Foundation. DW has received funding from Michael J. Fox Foundation for Parkinson\u0026rsquo;s Research (MJFF). \u0026nbsp; The remaining authors (YX, WB, MT, CR, MC, CC, KC, RC, HM, JM, GS, CT, CB, ED, CK, DS,) have no relevant conflict of interest to disclose.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eEspay AJ, Hausdorff JM, Sanchez-Ferro A, Klucken J, Merola A, Bonato P, Paul SS, Horak FB, Vizcarra JA, Mestre TA, Reilmann R, Nieuwboer A, Dorsey ER, Rochester L, Bloem BR, Maetzler W, Movement Disorder Society Task Force on T (2019) A roadmap for implementation of patient-centered digital outcome measures in Parkinson's disease obtained using mobile health technologies. \u003cem\u003eMov Disord\u003c/em\u003e\u003cstrong\u003e34\u003c/strong\u003e, 657-663.\u003c/li\u003e\n\u003cli\u003eSertkaya A, Birkenbach A, Berlind A, Eyraud J (2014), ed. 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e208028.\u003c/li\u003e\n\u003cli\u003e Siddiqi B, Koemeter-Cox A (2021) A Call to Action: Promoting Diversity, Equity, and Inclusion in Parkinson's Research and Care. \u003cem\u003eJ Parkinsons Dis\u003c/em\u003e\u003cstrong\u003e11\u003c/strong\u003e, 905-908.\u003c/li\u003e\n\u003cli\u003e O'Toole MT (2022) \u003cem\u003eMosby's medical dictionary\u003c/em\u003e, Elsevier, St. Louis, Missouri.\u003c/li\u003e\n\u003cli\u003e Giddens JF (2017) \u003cem\u003eConcepts for nursing practice \u003c/em\u003eElsevier.\u003c/li\u003e\n\u003cli\u003e Merriam-Webster, https://www.merriam-webster.com/dictionary/,\u003c/li\u003e\n\u003cli\u003e Simuni T, Chahine, L., Poston, K., Brumm, M., Buracchio, T., Campbell, M., Chowdhury, S., Coffey, C., Concha-Marambio, L., Dam, T., DiBiaso, P., Foroud, T., Frasier, M., Gochanour, C., Jennings, D., Kieburtz, K., Kopil, C. M., Merchant, K., Mollenhauer, B., \u0026hellip; Marek, K. (2023) Biological Definition of Neuronal alpha-Synuclein Disease: Towards an Integrated Staging System for Research. \u003cem\u003eZenodo\u003c/em\u003e.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"npj-parkinsons-disease","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"npjparkd","sideBox":"Learn more about [npj Parkinson's Disease](http://www.nature.com/npjparkd/)","snPcode":"41531","submissionUrl":"https://submission.springernature.com/new-submission/41531/3","title":"npj Parkinson's Disease","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"NPJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"early Parkinson’s, conceptual model, framework, meaningful, symptoms, impacts","lastPublishedDoi":"10.21203/rs.3.rs-4377805/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4377805/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA comprehensive, widely-accepted, patient-centered conceptual model of Parkinson’s disease (PD) is needed to improve therapeutic development and guide selection of relevant endpoints.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjectives\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo develop an evidence-based conceptual model of early PD, defined as \u0026lt;3 years since clinical diagnosis, that meets the needs of all relevant stakeholders, including people with PD, researchers, clinicians, industry, and regulators.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethod\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA multi-stakeholder taskforce and patient advisory panel oversaw the systematic review and meta-synthesis of qualitative and quantitative studies using JBI Mixed Methods Review criteria and GRADE-CERQual standards for assessment of evidence quality, with iterative taskforce and advisory meetings to develop the model.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMore than 340 symptoms and impacts were identified from 38 unique study samples. These were grouped into 10 symptom domains (Movement, Cognitive, Psychiatric, Sleep, Sensory, Speech, Digestive, Urinary, Sexual, Autonomic) and two impact domains (Physical functioning, Psychosocial functioning). Synthesis of findings tables (SOFT) indicate that a wide range of motor and non-motor symptoms are prevalent and bothersome in early PD, with strongest evidence for tremor, dexterity, gait, stiffness, and slow movements, as well as cognitive changes (e.g., word finding issues), mood and sleep alterations, urinary dysfunction, constipation, pain, and fatigue. These commonly affected mobility, self-concept, coping, effort of living, interpersonal interactions and important activities, with evidence of many understudied impacts.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis consensus-based conceptual model of early PD provides the most comprehensive catalogue of meaningful symptoms and functional impacts to date. 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