Comparison of serum vitamin D level and vitamin D receptor gene FokI polymorphism in leprosy patients with and without trophic ulcers: protocol for a case-control study

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Sirait" }, { "@type": "Person", "name": "Eliza Miranda" }, { "@type": "Person", "name": "Yulia Ariani" }, { "@type": "Person", "name": "Wresti Indriatmi" }, { "@type": "Person", "name": "Hok Bing Thio" } ], "publisher": { "@type": "Organization", "name": "F1000Research", "logo": { "@type": "ImageObject", "url": "https://f1000research.com/img/AMP/F1000Research_image.png", "height": 480, "width": 60 } }, "image": { "@type": "ImageObject", "url": "https://f1000research.com/img/AMP/F1000Research_image.png", "height": 1200, "width": 150 }, "description": " Background Leprosy, or Hansen’s disease, is a chronic infectious disease that primarily affects the skin and peripheral nervous system, often leading to disabilities, including trophic ulcers (TU). The role of vitamin D and vitamin D receptor (VDR) gene polymorphisms in the development of TU among leprosy patients remain unclear. Objective This study aims to investigate the differences in serum 25-hydroxyvitamin D [25(OH)D] levels and the frequency of VDR gene FokI polymorphism between leprosy patients with and without TU, and to evaluate their association with the occurrence of TU. Methods This Institutional Review Board-approved, single-center, observational, analytic case-control study will enroll adult leprosy patients from the Dermatology and Venereology Clinic at Dr. Cipto Mangunkusumo Hospital in Jakarta, Indonesia. Participants will be divided into cases (patients with TU) and controls (patients without TU). Serum 25(OH)D levels will be measured using a chemiluminescence immunoassay, and FokI polymorphism detection is conducted through polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. Statistical analysis will be performed to evaluate the differences and associations. Results Data collection commenced in March 2024 and was completed in September 2024. Data analysis and reporting are expected to be finalized by January 2025. Discussion The findings of this study will enhance the current understanding of the role of the vitamin D axis in the development of TU among leprosy patients. This could lead to new therapeutic strategies, such as vitamin D supplementation or personalized medicine based on genetic profiling, potentially reducing the burden of TU among leprosy patients. 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F1000Research 2025, 14 :57 ( https://doi.org/10.12688/f1000research.157869.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Study Protocol Comparison of serum vitamin D level and vitamin D receptor gene FokI polymorphism in leprosy patients with and without trophic ulcers: protocol for a case-control study [version 1; peer review: 1 approved with reservations] Paulus Anthony Halim https://orcid.org/0000-0002-0754-1104 1 , Sondang P. Sirait 1 , Eliza Miranda 1 , Yulia Ariani 2,3 , Wresti Indriatmi 1 , Hok Bing Thio 4 Paulus Anthony Halim https://orcid.org/0000-0002-0754-1104 1 , Sondang P. Sirait 1 , [...] Eliza Miranda 1 , Yulia Ariani 2,3 , Wresti Indriatmi 1 , Hok Bing Thio 4 PUBLISHED 09 Jan 2025 Author details Author details 1 Department of Dermatology and Venereology, Faculty of Medicine Universitas Indonesia, Dr. Cipto Mangunkusumo Hospital, Jakarta, 10430, Indonesia 2 Department of Biology, Faculty of Medicine, Universitas Indonesia, Jakarta, 10430, Indonesia 3 Human Genetic Research Center, Indonesian Medical Education and Research Institute (IMERI), Universitas Indonesia, Jakarta, 10430, Indonesia 4 Department of Dermatology, Erasmus University Medical Center, Rotterdam, The Netherlands Paulus Anthony Halim Roles: Conceptualization, Funding Acquisition, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Sondang P. Sirait Roles: Conceptualization, Funding Acquisition, Methodology, Supervision, Writing – Review & Editing Eliza Miranda Roles: Conceptualization, Methodology, Supervision, Writing – Review & Editing Yulia Ariani Roles: Conceptualization, Methodology, Supervision Wresti Indriatmi Roles: Methodology, Writing – Review & Editing Hok Bing Thio Roles: Funding Acquisition, Methodology, Supervision, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS This article is included in the Genomics and Genetics gateway. This article is included in the Neglected Tropical Diseases collection. Abstract Background Leprosy, or Hansen’s disease, is a chronic infectious disease that primarily affects the skin and peripheral nervous system, often leading to disabilities, including trophic ulcers (TU). The role of vitamin D and vitamin D receptor ( VDR ) gene polymorphisms in the development of TU among leprosy patients remain unclear. Objective This study aims to investigate the differences in serum 25-hydroxyvitamin D [25(OH)D] levels and the frequency of VDR gene FokI polymorphism between leprosy patients with and without TU, and to evaluate their association with the occurrence of TU. Methods This Institutional Review Board-approved, single-center, observational, analytic case-control study will enroll adult leprosy patients from the Dermatology and Venereology Clinic at Dr. Cipto Mangunkusumo Hospital in Jakarta, Indonesia. Participants will be divided into cases (patients with TU) and controls (patients without TU). Serum 25(OH)D levels will be measured using a chemiluminescence immunoassay, and FokI polymorphism detection is conducted through polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. Statistical analysis will be performed to evaluate the differences and associations. Results Data collection commenced in March 2024 and was completed in September 2024. Data analysis and reporting are expected to be finalized by January 2025. Discussion The findings of this study will enhance the current understanding of the role of the vitamin D axis in the development of TU among leprosy patients. This could lead to new therapeutic strategies, such as vitamin D supplementation or personalized medicine based on genetic profiling, potentially reducing the burden of TU among leprosy patients. READ ALL READ LESS Keywords trophic ulcer, leprosy, vitamin D, vitamin D receptor gene polymorphisms Corresponding Author(s) Sondang P. Sirait ( [email protected] ) Eliza Miranda ( [email protected] ) Close Corresponding authors: Sondang P. Sirait, Eliza Miranda Competing interests: No competing interests were disclosed. Grant information: The study is funded by the Directorate of Research and Development, Universitas Indonesia under the Hibah PUTI 2023 scheme (Grant No. NKB-689/UN2.RST/HKP.05.00/2023). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright: © 2025 Halim PA et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Halim PA, Sirait SP, Miranda E et al. Comparison of serum vitamin D level and vitamin D receptor gene FokI polymorphism in leprosy patients with and without trophic ulcers: protocol for a case-control study [version 1; peer review: 1 approved with reservations] . F1000Research 2025, 14 :57 ( https://doi.org/10.12688/f1000research.157869.1 ) First published: 09 Jan 2025, 14 :57 ( https://doi.org/10.12688/f1000research.157869.1 ) Latest published: 23 Oct 2025, 14 :57 ( https://doi.org/10.12688/f1000research.157869.3 )  There is a newer version of this article available. Suppress this message for one day. Introduction Background Leprosy, also known as Hansen’s disease (HD), is a chronic infectious disease caused by the bacteria Mycobacterium leprae and Mycobacterium lepromatosis. This disease primarily affects the skin and peripheral nervous system, leading to disabilities. Leprosy remains endemic in many parts of the world, with Brazil, India, and Indonesia collectively accounting for 80% of new cases globally. 1 In 2019, the Indonesian Ministry of Health reported 17,439 new cases of HD, while in 2020, only 11,173 new cases were identified. 2 , 3 The COVID-19 pandemic has impacted early detection efforts due to social restrictions and the reallocation of healthcare resources, potentially increasing the incidence of disabilities resulting from delayed diagnosis and treatment. 4 Peripheral nerve damage secondary to leprosy can lead to various types of disabilities. Ulcers are a common complication and are classified as grade 2 disabilities. 5 The rate of grade 2 disabilities is a key indicator in the World Health Organization’s (WHO) 2021-2030 leprosy eradication strategy. In 2021, the rate of grade 2 disabilities in Indonesia was 2.48 cases per 1,000,000 people, whereas the WHO’s 2030 target is 0.12 cases per 1,000,000 people. 2 Disabilities associated with leprosy create social stigma and lead to significant economic losses, including healthcare costs and reduced productivity. 6 Ulcers occur in 10–20% of HD patients and are mostly classified as trophic ulcers (TU). 5 Most ulcers in HD patients occur in the lower extremities, particularly on the plantar surface of the feet. 5 , 7 Static and dynamic deformities of the feet, coupled with reduced sensitivity, lead to recurring wounds that do not heal and become chronic ulcers. 5 , 7 The occurrence of TU in leprosy patients can be influenced by several factors, including neuropathy, physical deformities, nutritional deficiencies, and other systemic comorbidities. In leprosy patients, ulcers are often difficult to treat and frequently recur. If not properly managed, ulcers can become secondarily infected and may even undergo malignant transformation. 8 Vitamin D is a steroid hormone that plays a crucial role as an immune system modulator. 9 , 10 Over the past decade, studies have reported the role of vitamin D in wound healing. 9 , 11 – 13 Vitamin D enhances the differentiation of fibroblasts and keratinocytes, mainly through the modulation of growth factors and cytokine production. 14 , 15 In vivo, vitamin D is converted to its active form, 25-hydroxyvitamin D [25(OH)D], by the hepatic hydroxylase enzymes, which is an indicator of vitamin D status. In the innate immune system, 25(OH)D can trigger the production of antimicrobial peptides (AMPs) by monocytes and macrophages. 10 Additionally, 25(OH)D reduces the production of proinflammatory cytokines and increases anti-inflammatory responses. 16 The kidneys or injured tissues can convert 25(OH)D into 1,25-dihydroxy vitamin D3 or calcitriol, which regulates the expression of cathelicidin and defensins. 15 , 17 These AMPs can kill intracellular bacteria and play a significant role in wound healing. 10 , 15 The biological effects of vitamin D are mediated by the vitamin D receptor (VDR), which is encoded by the VDR gene on chromosome 12. Animal studies have reported that loss of VDR inhibits tissue re-epithelialization and inflammatory response in wound healing. 18 , 19 Various single nucleotide polymorphisms (SNPs) can affect the structure and function of VDR. The FokI polymorphism (rs2228570), which involves a nucleotide substitution from thymine (T) to cytosine (C) at the start codon of the VDR gene, is the only polymorphism known to structurally alter the VDR protein. The mutant T allele ( f allele) yields a receptor with a longer amino acid chain compared to the wild-type C allele ( F allele). 20 The F allele produces a VDR with more optimal gene transcription effects, thereby triggering increased immune responses and wound healing. 20 , 21 A study in Medan, Indonesia reported that the frequency of homozygous mutant subjects for the FokI polymorphism was 19.2% in multibacillary HD patients and 13.7% in healthy household contacts of HD patients. 22 Previous studies have shown that serum 25(OH)D levels in patients with other chronic ulcers (e.g., venous or diabetic ulcers) are decreased, 23 , 24 and vitamin D supplementation can improve wound healing in these conditions. 12 , 13 The role of vitamin D in leprosy is increasingly investigated, with previous studies reporting varied results. 25 – 27 However, to the best of our knowledge, no research has compared vitamin D levels and the polymorphisms of its receptor in leprosy patients with and without TU. Aim The aim of this study is to investigate whether vitamin D and the polymorphisms of its receptor ( VDR ) play a role in the development of TU in leprosy patients. The primary and secondary objectives of the study are displayed in Table 1 . Table 1. Primary and secondary objectives. Objective type Description Primary • To analyze the differences of 25-hydroxyvitamin D [25(OH)D] levels in leprosy patients with and without trophic ulcers. • To analyze the proportion difference of FokI polymorphism in leprosy patients with and without trophic ulcers. • To evaluate whether 25(OH)D levels and FokI polymorphism are associated with the occurrence of trophic ulcers in leprosy patients. Secondary To determine whether there is any correlation between 25(OH)D levels and the severity of trophic ulcers. Protocol Study design This study is a single-center, observational, analytic case-control study. Site and population Leprosy patients with and without TU who are attending the Dermatology and Venereology Clinic at Dr. Cipto Mangunkusumo Hospital in Jakarta, Indonesia will be recruited. Serum 25(OH)D levels will be analyzed at the Clinical Pathology Laboratory of the same hospital. Examination of the FokI polymorphism will be conducted at the Laboratory of the Medical Biology Department, Faculty of Medicine, Universitas Indonesia, Jakarta. Case and control definitions Both cases and controls include adult leprosy patients diagnosed according to the cardinal signs defined by WHO. Patients who are newly diagnosed, currently undergoing treatment, or have been released from treatment are eligible for inclusion. The inclusion and exclusion criteria are detailed in Table 2 . The control group will consist of leprosy patients without TU, who meet the same inclusion and exclusion criteria as the case group. Table 2. Inclusion and exclusion criteria. Criteria Description Inclusion • Patients willing to participate in the study by completing and signing an informed consent form. • Male or female patients aged ≥18 years old. • Patients who meet the World Health Organization (WHO) diagnostic criteria for leprosy, including those who are newly diagnosed, currently undergoing treatment, or have been released from treatment. • Leprosy patients with trophic ulcers (case group), adhering to the following criteria: ○ Ulcer duration of ≥4 weeks, with no history of sharp debridement or callus thinning during this period. ○ Wound depth not exceeding the subcutaneous layer. ○ Ulcer not secondarily infected or only mildly infected (characterized by erythema <2 cm around the ulcer, potential signs of edema, pain, minimal purulent secretions, or warmth on palpation). Exclusion • Patients who have consumed vitamin D supplementation within the past 4 weeks. • Patients exhibiting signs and symptoms of leprosy reactions. • Patients with concurrent systemic infections, diabetes mellitus, severe liver dysfunction, end-stage kidney disease, malignancy, and autoimmune diseases. Subject recruitment Subjects will be recruited consecutively based on the eligibility criteria. All leprosy patients attending the Dermatology and Venereology Clinic of Dr. Cipto Mangunkusumo Hospital will be given the opportunity to participate in this study and will be screened according to the inclusion and exclusion criteria. Before further examination, each potential subject will be informed about the purpose and methods of the study, as well as the benefits and potential disadvantages of participating. We will explain to potential subjects that participation is voluntary and does not affect the management provided at the hospital. Written informed consent will be obtained from each subject. Procedures and examinations History taking and physical examination will be conducted in a structured manner following a standardized study data collection form. Data collected during anamnesis will include identity, sociodemographic history, leprosy history (duration, treatment, and reaction history), duration of sun exposure, smoking status, and ulcer duration. Physical examination will include vital signs, anthropometric measurements, dermatologic status of the ulcer, presence of deformities other than ulcers, and sensory function of the extremities. Sensory function examination will be assessed using 0.2-gram (blue) Semmes-Weinstein monofilaments for hands and the 2-gram (purple) monofilaments for feet. 28 Clinical photographs of the subjects’ hands and feet are collected, clearly showing the ulcers if present. If ulcers occur on other areas of the extremities (e.g., knee or elbow), documentation will also be performed on these areas. Photos are taken using an iPhone 12 camera (12 megapixel, aperture size F1.6, focal length 26 mm, sensor size 1/2.55", pixel size 1.7 μm) from a distance of 15 cm. A blue cloth will be used as the background during photo taking. The dimensions of the ulcer are measured using a digital caliper, with the ulcer area calculated by the multiplying the largest vertical and horizontal lengths that intersect perpendicularly. Ulcer depth will be qualitatively evaluated according to the Pressure Ulcer Scoring System (grades I to III). Ulcer severity will be assessed using the Pressure Ulcer Scale for Healing (PUSH) criteria, which encompasses ulcer area, exudate amount, and wound tissue type ( Table 3 ). In patients with multiple ulcers, the largest ulcer by area will be selected for reporting and further statistical analysis. Table 3. Pressure Ulcer Scale for Healing (PUSH). Characteristics Score Subscore Length × Width (in cm 2 ) 0 0 1 24.0 Exudate amount 0 None 1 Light 2 Moderate 3 Heavy Tissue type 0 Closed 1 Epithelial Tissue 2 Granulation Tissue 3 Slough 4 Necrotic tissue Total: Laboratory prodecures Blood samples totaling 6 mL will be collected from each subjects into plain (red-capped) and K 3 EDTA (purple-capped) tubes and temporarily stored in a cool box at 2–8°C. The blood samples will be sent to the laboratories within 2 hours of collection. 25(OH)D Level quantification Blood collected in a plain tube will be analyzed for 25(OH)D levels using the Architect 25(OH)D vitamin kit (Abbott Diagnostics, Lake Forest, IL, USA) based on the chemiluminescence immunoassay method. Vitamin D status will be classified under four categories: severe deficiency (30 ng/mL). 29 FokI polymorphism detection The anticoagulated blood will be used for FokI polymorphism detection, which consists of DNA extraction, subsequent amplification using polymerase chain reaction (PCR), and polymorphism detection using the restriction fragment length polymorphism (RFLP) method. DNA extraction from EDTA blood samples will be performed using the salting out method. 30 Extracted genetic materials will be stored on a -80°C freezer for subsequent analysis. Amplification of the genetic materials are performed using PCR. The primers for the reaction are based on a previous study by Soroush et al., 20 with a forward primer 5′-CACTGACTCTGGCTCTGACCGT-3′ and a reverse primer 5′-AACACCTTGCTTCTTCTCCCTCC-3′. Initial denaturation of the genetic material will be performed at 95°C for 5 minutes. Amplification will be conducted for 35 cycles with denaturation at 95°C for 30 seconds, annealing at 60°C for 30 seconds, and extension at 72°C for 30 seconds. The final extension will be performed at 72°C for 7 minutes, resulting in a nucleic acid product of 250 base pairs (bp) in length. The RFLP will be conducted using the FokI restriction enzyme (New England Biolabs, Ipwich, MA, USA). After incubation, the results will be visualized with 2% agarose gel electrophoresis. The genetic material fractions that will be detected are 192 and 58 bp in homozygous ff genotype samples, 250 bp, 192 bp, and 58 bp in heterozygous Ff genotype samples, and an intact 250 bp fragment in FF genotype samples. Sample size estimates The calculation of sample size is carried out using a type I error probability of 0.05 and type II error of 0.20, corresponding to a power of 80%. To test the difference in mean 25(OH)D levels, sample size calculation for the difference between the mean values of two independent groups is performed using the following formula 31 : n 1 = n 2 = 2 [ ( z ∝ + z β ) s ( x 1 − x 2 ) ] 2 where n 1 = n 2 = minimum sample size for each group; z α = z -score corresponding to the type I error probability, which is 1.96; z β = z -score corresponding to the type II error probability ( β = 0.20), which is 0.84); s = standard deviation; and ( x 1 − x 2 ) = clinically significant mean difference. The clinically significant mean difference is determined to be 5 ng/mL. Since there has been no studies reporting the difference in 25(OH)D levels between leprosy groups with and without TU, the standard deviation value used is based on a previous study in general leprosy patients, which is 5.42 ng/mL. 27 Thus, the sample size needed to detect a difference in 25(OH)D levels in leprosy patients with and without TU is 19 per group. To test the effect of FokI polymorphism on the occurrence of TU in leprosy patients, the sample size for an unmatched case-control study is calculated using the formula 31 : n 1 = n 2 = ( z α 2 PQ + z β P 1 Q 1 + P 2 Q 2 ) 2 ( P 1 − P 2 ) 2 where n 1 = n 2 = minimum sample size for each group; z α = 1.96; z β = 0.84; P 1 = estimated proportion of effect in the case group calculated using P 1 = OR × P 2 ( 1 − P 2 ) + ( OR × P 2 ) ; OR = estimated odds ratio; P 2 = proportion of effect in the control group; P = ½ ( P 1 + P 2 ); and Q = 1 – P. The proportion of the homozygous ff genotype in leprosy patients based on a previous study by Lubis et al. 22 is 19.2%. Assuming an estimated odds ratio (OR) of 3.9 as the effect size of FokI polymorphism on TU occurrence in leprosy patients, the formula corresponds to a sample size of 41 for each of the case and control groups. Finally, to test the correlation between 25(OH)D levels and ulcer severity, sample size calculation for correlation is conducted using the following formula 31 : n = [ ( z ∝ + z β ) 0.5 ln ( 1 + r 1 − r ) ] 2 + 3 where n = minimum sample size for the group; z α = 1.96; z β = 0.84; and r = estimated correlation coefficient. A moderate correlation ( r = 0.5–0.7) is estimated between ulcer severity score and serum 25(OH)D levels. Thus, setting the correlation coefficient at 0.5, the minimal sample size is 29 for this analysis. The overall sample size for this study is determined based on the largest minimum sample size required to test all outcomes, which is 41 for each group of leprosy with and without TU, totaling 82 subjects. Data analysis All data obtained from anamnesis, physical examinations, and laboratory tests are recorded in the research file. The collected data will be reviewed, coded, and then entered into a master table in Excel version 16 (Microsoft Corporation, Washington, USA). Data analysis will be conducted using STATA version 16.0 (StataCorp LLC, College Station, TX, USA) and the online software SNPStats ( www.snpstats.net , Catalan Institute of Oncology, Spain). Sociodemographic and clinical characteristics data will be processed descriptively and presented in tables to understand the distribution of data across groups. Clinical characteristics of TU will also be described and presented in a table. Data normality will be tested using the Kolmogorov-Smirnov test. Numerical data will be presented as mean and standard deviation (SD), or as median and interquartile range (IQR) if not normally distributed. A significance level of p < 0.05 will be used throughout the study. The comparison of means between two groups will be conducted using the independent t-test for normally distributed data or the Mann-Whitney U test if the data are not normally distributed. Relationship between two categorical variables will be analyzed using the chi-square or Fisher’s exact test, as appropriate. Correlations between two numeric variables will be calculated using the Pearson’s correlation coefficient for normally distributed data or Spearman’s rank correlation coefficient if the data are not normally distributed. The Hardy-Weinberg equilibrium will be assessed to determine if the observed genotype frequencies are consistent with those expected in a population for both case and control groups. Different genetic models (i.e. codominant, dominant. recessive, overdominant, and log-additive) for the FokI polymorphism will be evaluated. Both the Akaike information criterion (AIC) and the Bayesian information criterion (BIC) will be used to compare these models. The genetic model yielding the lowest AIC and BIC values will be considered the best-fitting model. Finally, multivariate logistic regression analyses will be conducted to identify factors associated with the occurrence of TU in leprosy patients. Variables with a p-value < 0.25 in bivariate analysis will be included in the multivariate model. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) will be reported for the variables included in the final model. Ethics and consent This study protocol has received ethical clearance from the Health Research Ethics Committee –Faculty of Medicine Universitas Indonesia and Dr. Cipto Mangunkusumo Hospital (HREC FMUI-CMH), with the approval letter number KET-82/UN2.F1/ETIK/PPM.00.02/2024, dated January 15, 2024. We will explain to potential subjects that participation is voluntary and does not affect the management provided at the hospital. Written informed consent will be obtained from each subject. Dissemination The results of the study will be disseminated through peer-reviewed publications and will be made available in an open-access format. Any significant changes to the protocol will be communicated directly to HREC FMUI-CMH. We also plan to publish any modifications made to this protocol during publication of the study results. Study status Subject recruitment, assessment, and laboratory work for 25(OH)D level measurement and FokI polymorphism detection have been completed. Formal data analysis is currently ongoing. Discussion Summary This study aims to investigate the association between serum vitamin D levels and FokI polymorphism of VDR in leprosy patients, comparing those with and without TU. Leprosy often leads to peripheral nerve damage, with TU as a common complication. We hypothesize that vitamin D and its receptor polymorphisms, particularly FokI , might influence ulcer development in these patients. Our study is a single-center, case-control study involving adult leprosy patients with and without TU. Serum vitamin D levels are quantified using chemiluminescence immunoassay, while the FokI polymorphism of the VDR gene is detected through PCR-RFLP method. The primary objectives are to analyze differences in 25(OH)D levels and the proportion of FokI polymorphism between the two groups, and to evaluate their association with TU occurrence. Secondary objectives include examining the correlation between vitamin D level and the severity of TU. Perspective and clinical implications Trophic ulcers may still occur in leprosy patients long after treatment completion. As the world approaches the leprosy post-elimination era, TU will continue to cause significant morbidity. Therefore, the study’s focus on the potential influence of vitamin D and its receptor polymorphisms on TU development in leprosy is of significant clinical importance. 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Publisher Full Text Comments on this article Comments (0) Version 3 VERSION 3 PUBLISHED 09 Jan 2025 ADD YOUR COMMENT Comment Author details Author details 1 Department of Dermatology and Venereology, Faculty of Medicine Universitas Indonesia, Dr. Cipto Mangunkusumo Hospital, Jakarta, 10430, Indonesia 2 Department of Biology, Faculty of Medicine, Universitas Indonesia, Jakarta, 10430, Indonesia 3 Human Genetic Research Center, Indonesian Medical Education and Research Institute (IMERI), Universitas Indonesia, Jakarta, 10430, Indonesia 4 Department of Dermatology, Erasmus University Medical Center, Rotterdam, The Netherlands Paulus Anthony Halim Roles: Conceptualization, Funding Acquisition, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Sondang P. Sirait Roles: Conceptualization, Funding Acquisition, Methodology, Supervision, Writing – Review & Editing Eliza Miranda Roles: Conceptualization, Methodology, Supervision, Writing – Review & Editing Yulia Ariani Roles: Conceptualization, Methodology, Supervision Wresti Indriatmi Roles: Methodology, Writing – Review & Editing Hok Bing Thio Roles: Funding Acquisition, Methodology, Supervision, Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information The study is funded by the Directorate of Research and Development, Universitas Indonesia under the Hibah PUTI 2023 scheme (Grant No. NKB-689/UN2.RST/HKP.05.00/2023). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Article Versions (3) version 3 Revised Published: 23 Oct 2025, 14:57 https://doi.org/10.12688/f1000research.157869.3 version 2 Revised Published: 05 Sep 2025, 14:57 https://doi.org/10.12688/f1000research.157869.2 version 1 Published: 09 Jan 2025, 14:57 https://doi.org/10.12688/f1000research.157869.1 Copyright © 2025 Halim PA et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Halim PA, Sirait SP, Miranda E et al. Comparison of serum vitamin D level and vitamin D receptor gene FokI polymorphism in leprosy patients with and without trophic ulcers: protocol for a case-control study [version 1; peer review: 1 approved with reservations] . F1000Research 2025, 14 :57 ( https://doi.org/10.12688/f1000research.157869.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 1 VERSION 1 PUBLISHED 09 Jan 2025 Views 0 Cite How to cite this report: Djawad K. Reviewer Report For: Comparison of serum vitamin D level and vitamin D receptor gene FokI polymorphism in leprosy patients with and without trophic ulcers: protocol for a case-control study [version 1; peer review: 1 approved with reservations] . F1000Research 2025, 14 :57 ( https://doi.org/10.5256/f1000research.173385.r392598 ) The direct URL for this report is: https://f1000research.com/articles/14-57/v1#referee-response-392598 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 29 Jul 2025 Khairuddin Djawad , dermatovenereologi, Hasanuddin University (Ringgold ID: 64739), Makassar, South Sulawesi, Indonesia; Wahidin Sudirohusodo General Hospital, Makassar, Indonesia Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.173385.r392598 This research has novel value regarding the polymorphism of the fokI gene in ulcers and non-ulcers in leprosy sufferers, but it is necessary to exclude possible confounding factors such as the possibility of other systemic diseases accompanying leprosy such as ... Continue reading READ ALL This research has novel value regarding the polymorphism of the fokI gene in ulcers and non-ulcers in leprosy sufferers, but it is necessary to exclude possible confounding factors such as the possibility of other systemic diseases accompanying leprosy such as osteophorosis, cardiovascular disease, other chronic infectious diseases, etc. Information is also needed on what tests you use to exclude the disease. This examination needs to be disclosed so that this research can be repeated by other researchers. How do you ensure that the wound does not pass through the subcutis? What tests do you use? However, what needs to be taken into account is that wounds in leprosy patients are closely related to factors such as the severity of the leprosy, the patient's environment and the patient's lifestyle which have not been taken into account in this research protocol. Is the rationale for, and objectives of, the study clearly described? Yes Is the study design appropriate for the research question? Yes Are sufficient details of the methods provided to allow replication by others? Yes Are the datasets clearly presented in a useable and accessible format? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: dermatologyst I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Djawad K. Reviewer Report For: Comparison of serum vitamin D level and vitamin D receptor gene FokI polymorphism in leprosy patients with and without trophic ulcers: protocol for a case-control study [version 1; peer review: 1 approved with reservations] . F1000Research 2025, 14 :57 ( https://doi.org/10.5256/f1000research.173385.r392598 ) The direct URL for this report is: https://f1000research.com/articles/14-57/v1#referee-response-392598 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 11 Sep 2025 P. Anthony Halim , Department of Dermatology and Venereology, Faculty of Medicine Universitas Indonesia, Dr. Cipto Mangunkusumo Hospital, Jakarta, 10430, Indonesia 11 Sep 2025 Author Response We thank the reviewer for the constructive feedback on our work. Below, we provide point-by-point responses to each of the concerns raised. 1. Regarding potential confounders and inclusion/exclusion criteria: ... Continue reading We thank the reviewer for the constructive feedback on our work. Below, we provide point-by-point responses to each of the concerns raised. 1. Regarding potential confounders and inclusion/exclusion criteria: Thank you for your thoughtful comment. We agree that addressing potential confounding factors is critical to ensure internal validity. In designing the exclusion criteria (Table 2), we focused on systemic conditions that are known to significantly alter vitamin D metabolism or immune function, including diabetes mellitus, end-stage kidney disease, severe liver dysfunction, malignancy, autoimmune disorders, and systemic infections. To operationalize this, we screen participants using a combination of structured clinical interviews and medical record reviews, including relevant laboratory and radiologic findings when available. We have clarified these procedures in the revised manuscript (“Case and control definitions” section). 2. Regarding methods to ensure wound depth: We appreciate this important point. As stated in the inclusion criteria, eligible wounds must not extend beyond the subcutaneous layer. Wound depth is primarily assessed through clinical inspection of the ulcer base. In cases where slough or necrotic tissue obscures the wound base, we would perform sharp debridement as part of standard clinical practice to allow proper visualization. Patients are eligible for inclusion if, following debridement, the wound bed is confined to the subcutaneous layer. Any wound showing evidence of deeper tissue involvement, such as fascia, tendon, or bone exposure, would be excluded. This has been clarified in the revised manuscript (“Procedures and examinations” section ) to support reproducibility. 3. Regarding other factors that might influence the presence of trophic ulceration: We thank the reviewer for this important observation. We fully agree that trophic ulceration in leprosy is multifactorial. In this study, we collect detailed sociodemographic data (including occupation, education level, and household income) as well as clinical variables (nutritional status, smoking history, disease duration, WHO classification, Ridley-Jopling classification, history of leprosy reactions, presence of peripheral neuropathy, and other deformities). These variables serve as proxies for disease severity, environmental conditions, and lifestyle-related factors. All these factors are incorporated into bivariate and multivariate analyses to assess their potential as confounding factors. We have clarified this approach in both the “Procedures and Examinations” and “Data Analysis”. We thank the reviewer for the constructive feedback on our work. Below, we provide point-by-point responses to each of the concerns raised. 1. Regarding potential confounders and inclusion/exclusion criteria: Thank you for your thoughtful comment. We agree that addressing potential confounding factors is critical to ensure internal validity. In designing the exclusion criteria (Table 2), we focused on systemic conditions that are known to significantly alter vitamin D metabolism or immune function, including diabetes mellitus, end-stage kidney disease, severe liver dysfunction, malignancy, autoimmune disorders, and systemic infections. To operationalize this, we screen participants using a combination of structured clinical interviews and medical record reviews, including relevant laboratory and radiologic findings when available. We have clarified these procedures in the revised manuscript (“Case and control definitions” section). 2. Regarding methods to ensure wound depth: We appreciate this important point. As stated in the inclusion criteria, eligible wounds must not extend beyond the subcutaneous layer. Wound depth is primarily assessed through clinical inspection of the ulcer base. In cases where slough or necrotic tissue obscures the wound base, we would perform sharp debridement as part of standard clinical practice to allow proper visualization. Patients are eligible for inclusion if, following debridement, the wound bed is confined to the subcutaneous layer. Any wound showing evidence of deeper tissue involvement, such as fascia, tendon, or bone exposure, would be excluded. This has been clarified in the revised manuscript (“Procedures and examinations” section ) to support reproducibility. 3. Regarding other factors that might influence the presence of trophic ulceration: We thank the reviewer for this important observation. We fully agree that trophic ulceration in leprosy is multifactorial. In this study, we collect detailed sociodemographic data (including occupation, education level, and household income) as well as clinical variables (nutritional status, smoking history, disease duration, WHO classification, Ridley-Jopling classification, history of leprosy reactions, presence of peripheral neuropathy, and other deformities). These variables serve as proxies for disease severity, environmental conditions, and lifestyle-related factors. All these factors are incorporated into bivariate and multivariate analyses to assess their potential as confounding factors. We have clarified this approach in both the “Procedures and Examinations” and “Data Analysis”. Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 11 Sep 2025 P. Anthony Halim , Department of Dermatology and Venereology, Faculty of Medicine Universitas Indonesia, Dr. Cipto Mangunkusumo Hospital, Jakarta, 10430, Indonesia 11 Sep 2025 Author Response We thank the reviewer for the constructive feedback on our work. Below, we provide point-by-point responses to each of the concerns raised. 1. Regarding potential confounders and inclusion/exclusion criteria: ... Continue reading We thank the reviewer for the constructive feedback on our work. Below, we provide point-by-point responses to each of the concerns raised. 1. Regarding potential confounders and inclusion/exclusion criteria: Thank you for your thoughtful comment. We agree that addressing potential confounding factors is critical to ensure internal validity. In designing the exclusion criteria (Table 2), we focused on systemic conditions that are known to significantly alter vitamin D metabolism or immune function, including diabetes mellitus, end-stage kidney disease, severe liver dysfunction, malignancy, autoimmune disorders, and systemic infections. To operationalize this, we screen participants using a combination of structured clinical interviews and medical record reviews, including relevant laboratory and radiologic findings when available. We have clarified these procedures in the revised manuscript (“Case and control definitions” section). 2. Regarding methods to ensure wound depth: We appreciate this important point. As stated in the inclusion criteria, eligible wounds must not extend beyond the subcutaneous layer. Wound depth is primarily assessed through clinical inspection of the ulcer base. In cases where slough or necrotic tissue obscures the wound base, we would perform sharp debridement as part of standard clinical practice to allow proper visualization. Patients are eligible for inclusion if, following debridement, the wound bed is confined to the subcutaneous layer. Any wound showing evidence of deeper tissue involvement, such as fascia, tendon, or bone exposure, would be excluded. This has been clarified in the revised manuscript (“Procedures and examinations” section ) to support reproducibility. 3. Regarding other factors that might influence the presence of trophic ulceration: We thank the reviewer for this important observation. We fully agree that trophic ulceration in leprosy is multifactorial. In this study, we collect detailed sociodemographic data (including occupation, education level, and household income) as well as clinical variables (nutritional status, smoking history, disease duration, WHO classification, Ridley-Jopling classification, history of leprosy reactions, presence of peripheral neuropathy, and other deformities). These variables serve as proxies for disease severity, environmental conditions, and lifestyle-related factors. All these factors are incorporated into bivariate and multivariate analyses to assess their potential as confounding factors. We have clarified this approach in both the “Procedures and Examinations” and “Data Analysis”. We thank the reviewer for the constructive feedback on our work. Below, we provide point-by-point responses to each of the concerns raised. 1. Regarding potential confounders and inclusion/exclusion criteria: Thank you for your thoughtful comment. We agree that addressing potential confounding factors is critical to ensure internal validity. In designing the exclusion criteria (Table 2), we focused on systemic conditions that are known to significantly alter vitamin D metabolism or immune function, including diabetes mellitus, end-stage kidney disease, severe liver dysfunction, malignancy, autoimmune disorders, and systemic infections. To operationalize this, we screen participants using a combination of structured clinical interviews and medical record reviews, including relevant laboratory and radiologic findings when available. We have clarified these procedures in the revised manuscript (“Case and control definitions” section). 2. Regarding methods to ensure wound depth: We appreciate this important point. As stated in the inclusion criteria, eligible wounds must not extend beyond the subcutaneous layer. Wound depth is primarily assessed through clinical inspection of the ulcer base. In cases where slough or necrotic tissue obscures the wound base, we would perform sharp debridement as part of standard clinical practice to allow proper visualization. Patients are eligible for inclusion if, following debridement, the wound bed is confined to the subcutaneous layer. Any wound showing evidence of deeper tissue involvement, such as fascia, tendon, or bone exposure, would be excluded. This has been clarified in the revised manuscript (“Procedures and examinations” section ) to support reproducibility. 3. Regarding other factors that might influence the presence of trophic ulceration: We thank the reviewer for this important observation. We fully agree that trophic ulceration in leprosy is multifactorial. In this study, we collect detailed sociodemographic data (including occupation, education level, and household income) as well as clinical variables (nutritional status, smoking history, disease duration, WHO classification, Ridley-Jopling classification, history of leprosy reactions, presence of peripheral neuropathy, and other deformities). These variables serve as proxies for disease severity, environmental conditions, and lifestyle-related factors. All these factors are incorporated into bivariate and multivariate analyses to assess their potential as confounding factors. We have clarified this approach in both the “Procedures and Examinations” and “Data Analysis”. Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Comments on this article Comments (0) Version 3 VERSION 3 PUBLISHED 09 Jan 2025 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 3 Version 3 (revision) 23 Oct 25 read Version 2 (revision) 05 Sep 25 read Version 1 09 Jan 25 read Khairuddin Djawad , Hasanuddin University (Ringgold ID: 64739), Makassar, Indonesia; Wahidin Sudirohusodo General Hospital, Makassar, Indonesia Ravindra Turankar , The Leprosy Mission Trust India, New Delhi, India ANABELL ALVARADO NAVARRO , Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Mexico Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 NAVARRO A. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 25 Nov 2025 | for Version 3 ANABELL ALVARADO NAVARRO , Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Mexico 0 Views copyright © 2025 NAVARRO A. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The article addresses a health problem that has been considered a disease of little interest for study. In addition, the authors responded to comments and suggestions made by other reviewers, so, in my opinion, the manuscript is complete and scientifically sound. However, it is not clear to me why the results have not been included, given that the protocol mentions that the study subjects were recruited in September 2024. However, the results are not reported. In addition, several sections are written in the future tense. . Is the rationale for, and objectives of, the study clearly described? Yes Is the study design appropriate for the research question? Yes Are sufficient details of the methods provided to allow replication by others? Yes Are the datasets clearly presented in a useable and accessible format? No Competing Interests No competing interests were disclosed. Reviewer Expertise autoimmunity, immunogenetics, inflammation, immunology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (0) NAVARRO AA. Peer Review Report For: Comparison of serum vitamin D level and vitamin D receptor gene FokI polymorphism in leprosy patients with and without trophic ulcers: protocol for a case-control study [version 1; peer review: 1 approved with reservations] . F1000Research 2025, 14 :57 ( https://doi.org/10.5256/f1000research.189764.r427045) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-57/v3#referee-response-427045 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Turankar R. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 07 Oct 2025 | for Version 2 Ravindra Turankar , Stanley Browne Research Laboratory, The Leprosy Mission Trust India, New Delhi, New Delhi, India 0 Views copyright © 2025 Turankar R. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions COMMENTS ON THE STUDY PROTOCOL ENTITLED, "Comparison of serum vitamin D level and vitamin D receptor gene FokI polymorphism in leprosy patients with and without trophic ulcers: protocol for a case-control study". This is a well-designed and relevant protocol that explores vitamin D status and the VDR FokI polymorphism in leprosy patients with and without trophic ulcers. The study addresses a significant gap with potential implications for clinical management and public health. I have a few points for clarification and improvement. The following points are being made as follows: Major Comments: Confounders: The multifaceted factors leading to ulceration in leprosy encompass neuropathy, deformities, nutrition, footwear, and sun exposure. It is crucial to specify the methods used to measure and control these variables during analysis to guarantee the reliability of the study outcomes. Vitamin D and Seasonality: Since vitamin D levels fluctuate considerably with seasons and sunlight exposure, it is crucial to determine whether participant recruitment was evenly distributed throughout different seasons or if this variability might introduce bias into the study. Laboratory Methods : While PCR-RFLP is a viable method for analyzing the VDR FokI polymorphism, it may be less precise than sequencing or TaqMan assays. Please explain why this approach was chosen, considering factors such as cost, feasibility, and resource availability in local laboratories. Sample Size Assumptions: The assumed odds ratio for the FokI polymorphism effect (around 3.9) might be an overly optimistic estimate. Performing a sensitivity analysis with different effect sizes could support the justification for the chosen sample size. Ulcer Documentation: Using PUSH scoring and photography for ulcer documentation is suitable; however, it's important to specify measures like staff training, double scoring, or adjudication to minimize inter-observer variability. Ethical Safeguards: Since the study involves collecting patient photographs, it is essential to outline the methods for anonymization, secure storage, and obtaining informed consent for possible publication, ensuring compliance with ethical research standards. Minor Points Include the total planned sample size in the abstract. Add an exploratory objective concerning potential gene–environment interaction (vitamin D and VDR polymorphism). Explain how missing data will be managed. Incorporate a flow diagram of participant recruitment to enhance clarity. Clearly specify which covariates will be adjusted for in the multivariate analysis. Indicate if correction for multiple testing will be used for genetic model comparisons. Clearly state limitations, such as the single-centre design, the inability of a case-control study to establish causality, and the potential for residual confounding. These points aim to enhance the clarity, reliability, and ethical standards of the study protocol, ensuring it makes a substantial contribution to the field. Are sufficient details of the methods provided to allow replication by others? Partly – The methods are thorough overall, but some areas need more clarification to ensure full reproducibility. These include details on controlling confounders, inter-observer reliability in ulcer grading, the rationale for choosing PCR-RFLP over other genotyping techniques, and how seasonal variation in vitamin D was managed. Are the datasets clearly presented in a useable and accessible format? ❌ Not applicable – This is a study protocol; no datasets are presented yet. Is the rationale for, and objectives of, the study clearly described? Yes Is the study design appropriate for the research question? Yes Are sufficient details of the methods provided to allow replication by others? Partly Are the datasets clearly presented in a useable and accessible format? Not applicable Competing Interests No competing interests were disclosed. Reviewer Expertise Dr. Ravindra P. Turankar is a researcher in leprosy and neglected tropical diseases, with expertise in Mycobacterium leprae transmission, host susceptibility, and environmental surveillance. His work spans molecular diagnostics, CRISPR-based tools, cytokine profiling, and One Health approaches. He emphasizes community engagement, WASH interventions, and AI-powered surveillance to advance early diagnosis, disability prevention, and climate-resilient strategies for leprosy elimination. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (1) Author Response 23 Oct 2025 P. Anthony Halim, Department of Dermatology and Venereology, Faculty of Medicine Universitas Indonesia, Dr. Cipto Mangunkusumo Hospital, Jakarta, 10430, Indonesia We thank the reviewer for the thoughtful and encouraging comments regarding the significance and methodological design of our study. Below, we respond to each of the points raised. Major Comments 1. Confounders: Reviewer comment: “The multifaceted factors leading to ulceration in leprosy encompass neuropathy, deformities, nutrition, footwear, and sun exposure. It is crucial to specify the methods used to measure and control these variables during analysis to guarantee the reliability of the study outcomes.” Response: We have expanded the “Procedures and examinations” section to provide detailed descriptions of how each of the relevant factors is assessed, including structured history taking, Semmes-Weinstein monofilament testing for neuropathy, physical examination for deformities, BMI classification for nutritional status, and sun exposure estimation. Footwear habits are not formally assessed, but are indirectly represented by socioeconomic status and presence of deformities. Given that this study is conducted in an urban setting, regular footwear use is generally expected among participants. These variables will also be incorporated into bivariate and multivariate analyses as described in the “Data analysis” section. 2. Vitamin D and Seasonality: Reviewer comment: “Since vitamin D levels fluctuate considerably with seasons and sunlight exposure, it is crucial to determine whether participant recruitment was evenly distributed throughout different seasons or if this variability might introduce bias into the study.” Response: We acknowledge the important influence of seasonality on vitamin D levels. To minimize this variability, participant recruitment was planned and completed during the Indonesian dry season (March to September 2024), which provides stable sun exposure. This has been explicitly stated in the Abstract and the “Subject recruitment” section. 3. Laboratory Methods (PCR-RFLP vs. Other Genotyping Methods): Reviewer comment: “ While PCR-RFLP is a viable method for analyzing the VDR FokI polymorphism, it may be less precise than sequencing or TaqMan assays. Please explain why this approach was chosen, considering factors such as cost, feasibility, and resource availability in local laboratories.” Response: We agree with the reviewer that PCR-RFLP may offer lower precision than newer genotyping techniques. However, the FokI polymorphism is a well-characterized variant with a simple restriction site, and PCR-RFLP remains a well-accepted method in these settings. As we are analyzing only one SNP, the higher-throughput capacity of TaqMan or next-generation sequencing is not required for this study. Additionally, PCR-RFLP was chosen based on cost-effectiveness and existing laboratory capacity. This rationale has been included in the “Discussion” section. 4. Sample Size Assumptions: Reviewer comment: “The assumed odds ratio for the FokI polymorphism effect (around 3.9) might be an overly optimistic estimate. Performing a sensitivity analysis with different effect sizes could support the justification for the chosen sample size.” Response: We acknowledge that the assumed odds ratio of 3.9 for FokI polymorphism may be optimistic, as it is based on preliminary data in a different leprosy population. The “ Sample size ” section now includes a statement acknowledging this assumption and its limitations. A note has also been added to the “Discussion” section to encourage cautious interpretation and future validation in larger studies. 5. Ulcer Documentation and Inter-Rater Reliability: Reviewer comment: “ Using PUSH scoring and photography for ulcer documentation is suitable; however, it's important to specify measures like staff training, double scoring, or adjudication to minimize inter-observer variability.” Response: All ulcer scoring is conducted by the first author (a senior dermatology resident), directly supervised by two consultant dermatologists to ensure consistency. The use of the validated PUSH tool, as well as ulcer photography for retrospective verification, has been clarified in the “Procedures and examinations” section. 6. Ethical Safeguards for Photographs: Reviewer comment: “Since the study involves collecting patient photographs, it is essential to outline the methods for anonymization, secure storage, and obtaining informed consent for possible publication, ensuring compliance with ethical research standards.” Response: Thank you for highlighting this. Clinical photographs are taken only following written consent. Photographs primarily involve distal extremities where the ulcers are located, which limit the likelihood of revealing identifiable features. In cases where identifying marks such as tattoos or moles are visible, they will be digitally blurred. All images are stored in an encrypted, password-protected USB flash drive accessible only to the study investigators. These details have been added to the “Ethics and Consent” section. Minor Points Planned sample size added to Abstract. Exploratory gene-environment interaction (vitamin D and FokI genotype) is now mentioned as an exploratory analysis in the Objectives section. Missing data: As this is a prospective study, we anticipate complete data collection. However, if missing data arise, complete-case analysis or multiple imputation will be used if necessary. This has been added to the “Data Analysis” section. Flow diagram of participant recruitment will be developed during study conduct and included in the final results publication. This has now been mentioned in the manuscript. Specify covariates for multivariate analysis: All collected sociodemographic and clinical variables may be included in the multivariate model if their bivariate p-value is <0.25, as outlined in the “Data Analysis” section. Correction for multiple testing in genetic model comparisons: As only one SNP ( FokI ) is analyzed, correction for multiple testing is not deemed necessary, as now clarified in the “Data analysis” section State limitations (single-centre, causality, residual confounding): Limitations regarding the single-centre setting, observational design, potential residual confounding, and potentially optimistic effect size for FokI polymorphism analysis have been added to the Discussion section. View more View less Competing Interests None. reply Respond Report a concern Turankar R. Peer Review Report For: Comparison of serum vitamin D level and vitamin D receptor gene FokI polymorphism in leprosy patients with and without trophic ulcers: protocol for a case-control study [version 1; peer review: 1 approved with reservations] . F1000Research 2025, 14 :57 ( https://doi.org/10.5256/f1000research.187546.r415296) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-57/v2#referee-response-415296 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Djawad K. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 29 Jul 2025 | for Version 1 Khairuddin Djawad , dermatovenereologi, Hasanuddin University (Ringgold ID: 64739), Makassar, South Sulawesi, Indonesia; Wahidin Sudirohusodo General Hospital, Makassar, Indonesia 0 Views copyright © 2025 Djawad K. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions This research has novel value regarding the polymorphism of the fokI gene in ulcers and non-ulcers in leprosy sufferers, but it is necessary to exclude possible confounding factors such as the possibility of other systemic diseases accompanying leprosy such as osteophorosis, cardiovascular disease, other chronic infectious diseases, etc. Information is also needed on what tests you use to exclude the disease. This examination needs to be disclosed so that this research can be repeated by other researchers. How do you ensure that the wound does not pass through the subcutis? What tests do you use? However, what needs to be taken into account is that wounds in leprosy patients are closely related to factors such as the severity of the leprosy, the patient's environment and the patient's lifestyle which have not been taken into account in this research protocol. Is the rationale for, and objectives of, the study clearly described? Yes Is the study design appropriate for the research question? Yes Are sufficient details of the methods provided to allow replication by others? Yes Are the datasets clearly presented in a useable and accessible format? Yes Competing Interests No competing interests were disclosed. Reviewer Expertise dermatologyst I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (1) Author Response 11 Sep 2025 P. Anthony Halim, Department of Dermatology and Venereology, Faculty of Medicine Universitas Indonesia, Dr. Cipto Mangunkusumo Hospital, Jakarta, 10430, Indonesia We thank the reviewer for the constructive feedback on our work. Below, we provide point-by-point responses to each of the concerns raised. 1. Regarding potential confounders and inclusion/exclusion criteria: Thank you for your thoughtful comment. We agree that addressing potential confounding factors is critical to ensure internal validity. In designing the exclusion criteria (Table 2), we focused on systemic conditions that are known to significantly alter vitamin D metabolism or immune function, including diabetes mellitus, end-stage kidney disease, severe liver dysfunction, malignancy, autoimmune disorders, and systemic infections. To operationalize this, we screen participants using a combination of structured clinical interviews and medical record reviews, including relevant laboratory and radiologic findings when available. We have clarified these procedures in the revised manuscript (“Case and control definitions” section). 2. Regarding methods to ensure wound depth: We appreciate this important point. As stated in the inclusion criteria, eligible wounds must not extend beyond the subcutaneous layer. Wound depth is primarily assessed through clinical inspection of the ulcer base. In cases where slough or necrotic tissue obscures the wound base, we would perform sharp debridement as part of standard clinical practice to allow proper visualization. Patients are eligible for inclusion if, following debridement, the wound bed is confined to the subcutaneous layer. Any wound showing evidence of deeper tissue involvement, such as fascia, tendon, or bone exposure, would be excluded. This has been clarified in the revised manuscript (“Procedures and examinations” section ) to support reproducibility. 3. Regarding other factors that might influence the presence of trophic ulceration: We thank the reviewer for this important observation. We fully agree that trophic ulceration in leprosy is multifactorial. In this study, we collect detailed sociodemographic data (including occupation, education level, and household income) as well as clinical variables (nutritional status, smoking history, disease duration, WHO classification, Ridley-Jopling classification, history of leprosy reactions, presence of peripheral neuropathy, and other deformities). These variables serve as proxies for disease severity, environmental conditions, and lifestyle-related factors. All these factors are incorporated into bivariate and multivariate analyses to assess their potential as confounding factors. We have clarified this approach in both the “Procedures and Examinations” and “Data Analysis”. View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Djawad K. Peer Review Report For: Comparison of serum vitamin D level and vitamin D receptor gene FokI polymorphism in leprosy patients with and without trophic ulcers: protocol for a case-control study [version 1; peer review: 1 approved with reservations] . F1000Research 2025, 14 :57 ( https://doi.org/10.5256/f1000research.173385.r392598) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-57/v1#referee-response-392598 Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. 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