The Early Detection and Case Management of Skin Diseases With an mHealth App (eSkinHealth): Protocol for a Mixed Methods Pilot Study in Côte d’Ivoire

Background There is a high prevalence of skin diseases sub-Saharan Africa, including skin neglected tropical diseases (NTDs) that could lead to lifelong disabilities and deformities if not diagnosed and treated early. To achieve early detection and early treatment of these skin diseases, we developed a mobile health app, eSkinHealth. Objective This paper outlines a protocol for evaluating the effect of our eSkinHealth app in the early detection and effective management of skin diseases in Côte d’Ivoire. Methods A mixed methods pilot trial will be conducted in Côte d’Ivoire and will consist of 3 phases: (1) the development and improvement of the eSkinHealth app, (2) a pilot trial to evaluate the usability of the eSkinHealth app for local medical staff in Côte d’Ivoire, and (3) a pilot trial to evaluate the effectiveness of early detection and case management of targeted skin NTDs (Buruli ulcer, leprosy, yaws, and lymphatic filariasis) with the eSkinHealth app in Côte d’Ivoire. The pilot study will be implemented as a 2-arm trial with local health care providers and patients with skin NTDs over a 3-month follow-up period. The local health care providers will be assigned to an intervention group receiving the eSkinHealth app to be used in their daily practices or a control group. Training will be provided on the use and implementation of the app and the diagnostic pipeline to the intervention group only, while both groups will receive training on skin diseases. Our primary outcome is to evaluate the early detection and effective management of skin diseases using the eSkinHealth app in Côte d’Ivoire by the number of cases diagnosed and managed. Additionally, we will evaluate the eSkinHealth app with validated questionnaires and in-depth interviews. Procedures of our methods have been reviewed and approved by the Institutional Review Board of the Ministry of Health, Côte d’Ivoire and by Tulane University in 2021. Results This study was funded in 2021. We started the enrollment of patients in February 2022, and data collection is currently underway. We expect the first results to be submitted for publication in 2023. Conclusions Our eSkinHealth app is a field-adapted platform that could provide both direct diagnostic and management assistance to health workers in remote settings. The study will provide evidence for the usability and the effectiveness of the eSkinHealth app to improve the early detection and case management of skin NTDs in Côte d’Ivoire and, furthermore, is expected to contribute to knowledge on mobile health approaches in the control of skin NTDs. Trial Registration ClinicalTrials.gov NCT05300399; https://clinicaltrials.gov/ct2/show/study/NCT05300399 International Registered Report Identifier (IRRID) DERR1-10.2196/39867

ZRG1 IMST-U (55) YOTSU, R weaknesses in dermatological services in LMICs providing a breakthrough to management of skin diseases in this underserved populations, as well as contributing to the dermatology of skin of color worldwide, envisioning Skin Health for All.
PUBLIC HEALTH RELEVANCE: While the prevalence of skin diseases are very high in LMICs, especially in children, dermatological services in LMICs are lacking mainly due to lack of clinical skills, and further, ways to document and store clinical course which is important for individual patient followup do not exist.If there is a field-adapted platform for data collection and sharing for skin conditions allowing clinical decision support for healthcare providers onsite, and remotely through teledermatology, this could serve as a breakthrough to management of skin diseases in this underserved populations.In this project, we will complete the development and optimization of a powerful and comprehensive, but easy-to-use smartphone / tablet application tool that addresses these gaps, envisioning Skin Health for All.

CRITIQUE 1
Significance: 4 Investigator(s): 2 Innovation: 2 Approach: 4 Environment: 2 Overall Impact: The aim of this project is to build a telehealth program to diagnose skin conditions in Côte d' Ivorie.Generally, the application is well written and organized and the roles of each participant are clear.Aim 1 is to develop an mHealth platform to assist with diagnosis and management of skin lesions with an emphasis on dark skin.The next Aim is to create a medical record for longitudinal storage of records to provide better follow up.The third Aim is to formalize the platform for derm telehealth.The innovative idea to gain information about skin disorders in dark skinned people is important.There is some concern about significance because the proposal covers general skin diseases rather than targeting specific areas of concern.In addition, it is unclear if simply providing diagnosis will decrease mortality.There is also not a clear plan for sustainability, particularly in the treatment realm, after the grant is over.The first Aim of the R33 phase is very well described and has measurable endpoints, but the other R33 Aims do not.

Strengths
• Skin diseases have a high prevalence in Africa and are often underdiagnosed.
• Left untreated, skin disease can lead to morbidity and mortality.
• A telehealth platform for skin health could help remote workers diagnose and manage skin conditions and keep longitudinal records about skin conditions.
• It is intended to collect high-quality photos for a future AI tool.
• The plan to standardize photo analysis of skin lesions on darker skin is an excellent, important Aim, but it is also so broad it that it may be hard to draw conclusions.
• The research plan Is very broad in terms of skin diseases.It is hard to see a substantial impact if the goal is to diagnose any type of skin disorder.
• There is only brief mention of linkage from diagnosis to treatment.How will this app be used to really make a difference?
• The application would be stronger if it provided more information on the benefit of longitudinal photo capture.
• Remote consultation will be very difficult in areas without internet connectivity.
• It is unclear if simply providing a diagnosis would decrease the prevalence of dermatologic conditions since availability of supplies and cost of treatment is also a factor.

Strengths
• Dr. Yotsu is an Assistant Professor at Tulane -MD from Japan (dermatology) and PhD in International Health with training in tropical medicine.
• Co-investigator Dr. Blanton is a physician scientist with expertise in epidemiology and international disease; he holds a current RO1 focusing on schistosomiasis.
• Dr. Vagamon is a Dermatology Professor in Côte d'Ivorie where the research will be conducted.
• Dr. Koffi is also a medical doctor in Côte d'Ivorie working on neglected tropical diseases (NTDs).
• Dr. Aubin is a health economist living and working in Côte d'Ivorie who works on study implementation, a cost-effective analysis for this study, and will liaison with the Ministry of Health (MOH) which helps ensure sustainability.
• Dr. Itoh (Ota) has a doctorate in nursing and specializes in bioinformatics.She has been working with the Principal Investigator (PI) in Côte d'Ivorie.Mr. Takagi is the CEO of the software company which will work to develop the app.

Weaknesses
• Dr. Yotsu has limited publications but several are in high impact journals (PLoS) and focus on skin disease in Côte d'Ivoire.She has several international grants but no history of NIH or other US federal funding.
• The team could likely benefit from a health economist if cost effectiveness analysis would be performed.

Strengths
• There are gaps in knowledge about dermatology in dark skin and this project helps fill that gap.
• The program builds upon work from previous grants that developed an "eSkinHealth" app to diagnose, monitor and provide clinical decision support in LMICs.

Weaknesses
• The project would develop a novel scoring system for skin wounds but it unclear how creating a record of progression over time would impact morbidity and mortality from disease.ZRG1 IMST-U (55) YOTSU, R

Strengths
• Regarding Aim 1, the app is already built and this project provides its clinical validation.
• The first Aim will improve the app based on user input obtained through in-depth interviews.
• Optimizing health care worker (HCW) photos will help in creating a machine learning tool in the future to assist with diagnosis.
• The endpoint of 70% of trained personnel using the app at month 23 is measurable and is a good measure of feasibility.
• The final Aim is to develop a training package that would be used in the larger study.
• The R33 is focused on Buruli ulcer, leprosy, yaws and lymphatic filariasis, which is logical based on experience of the team and potential for impact.
• The qualitative impact evaluation is well thought out and described.

Weaknesses
• The Aim dealing with accurate wound scoring needs to have more detail about specific interventions that would change depending on what the wound looks like on follow-up.What measures would be provided?Are these practical in an LMIC?Are there any data that this is the case?
• There is not much information given on the 32 trainees and how generalizable this data would be for future scale up and sustainability.
• The endpoint of 100% high quality photos is not adequate for a successful training program.
• The proposal states that dermatologists from Kings College of London will serve in a voluntary capacity for remote diagnosis.The letter of support indicates overall support of the project but should specifically clarify their willingness to participate.
• The wound app Aim evaluation is weak -it is not powered and does not include costeffectiveness analysis language although it mentions this will be done.There are also no measurable endpoints.This Aim is not crucial to the overall application and it may be considered a separate project and could be omitted.
• The image optimization would benefit from some deliverables that could make it easy to use for personnel who did not participate in the formal training.It also lacks measurable endpoints.

Strengths
• Tulane has an excellent global health program and record of successful research.
• The National Buruli Ulcer control program is part of the Ministry of Health and has a history of international collaboration and support from WHO.
• Hope Commission International is an NGO that has headquarters in the US.
• The three sites in Côte d'Ivoire are in close proximity and can easily collaborate.
• The PI has a long history of collaboration with the Japanese partners.
• No comment provided by reviewer.

Strengths
• The milestones listed are reasonable.

Weaknesses
• There is no timepoint given for IRB submission and approval, which could upend the project.
• There is not a plan for scale up and sustainability (particularly in terms of supplies) when the project is complete.

Strengths
• No comment provided by reviewer.

Weaknesses
• Timeline is ambitious.There are many goals and a very large number of subjects that may not be feasible in this time period.

Protections for Human Subjects:
Acceptable Risks and/or Adequate Protections

Budget and Period of Support:
Recommended budget modifications or possible overlap identified: • The budget goes all to Tulane.There are fees to cover the work of the local doctors, field workers, medications and IRB.The request is appropriate but there is a minor concern that there is no subcontract with the involved LMIC.

CRITIQUE 2
Significance: 3 Investigator(s): 3 Innovation: 4 Approach: 4 Environment: 4 Overall Impact: The team proposes to use an existing mHealth platform (eSkinHealth) to provide 1) diagnostic aid and telemedical diagnosis of skin disease in Africa, 2) electronic storage of images, 3) organization of clinical/skin image findings.The approach is thoughtful with clear success criteria for the R21 to R33 transition and implementation science-based evaluation.Innovation is primarily in the implementation of technology, rather than the technology itself.More detail for who the precise user of the mHealth device is, and how this integrates into the existing primary health care infrastructure, would be helpful.

Strengths
• Pediatric skin disease is an important problem in sub-Saharan Africa.
• There are no telederm platforms adapted for use in LMICs.
• Maintaining photo/clinic records is a challenge for care delivery.ZRG1 IMST-U (55) YOTSU, R • App is currently in preliminary testing in country.

Weaknesses
• No comment provided by reviewer.

Strengths
• Team has relevant experience.

Weaknesses
• No comment provided by reviewer.

Strengths
• This mHealth approach could be useful for its intended purpose.
• Focusing on app performance in darker skin pigmentation is an important innovation for global impact.
• Innovation is not primarily in the technology (combining telemedicine + electronic health records) but in the implementation.Successful demonstration could generalize to other specialties.

Weaknesses
• How does this integrate with other medical care needs in the LMIC setting (e.g., acute diarrheal illness, malaria, etc.)?

Strengths
• Aim 1 -thoughtful user-centered approach to evaluating usability • Aim 2 -Delphi approach to developing wound scoring system • R33 evaluation could be quite impactful.
• Well described implementation science approach

Weaknesses
• Aim 1 -measurement of usability is not clear prior to the milestones section.What does >68 mean system usability mean?How does it relate to "effectiveness, efficiency, and overall ease of use"?
• It is not clearly described how the app improves diagnosis of Buruli ulcer (or any diagnosis).
• QR code-based patient ID relies on patients not losing the QR code.Is there a backup?
• Vague details on how the tele-dermatology would work in practice.
• High probability of ongoing work if successful.

Weaknesses
• No comment provided by reviewer.

Strengths
• Clear milestones with quantifiable criteria for success of R21.

Weaknesses
• Need to better define exactly how the usability metric is calculated in Aim 1.
• 100% high image quality is a high bar -is this realistic?

Strengths
• Timeline makes sense.

Weaknesses
• No comment provided by reviewer.

Protections for Human Subjects:
Acceptable Risks and/or Adequate Protections Data and Safety Monitoring Plan (Applicable for Clinical Trials Only):

Acceptable
Inclusion Plans: • Sex/Gender: Distribution justified scientifically • Race/Ethnicity: Distribution justified scientifically Overall Impact: This is an initial application to use an app called eSkinHealth, a smartphone or tablet app that logs and provides longitudinal follow up around the development of ulcerative skin disease in the Ivory Coast.The investigators focus on Buruli ulcers, which may cause significant morbidity and is classified as a neglected tropical disease.Part of the issue is that there is high prevalence of disease in sub-Saharan Africa yet understanding of diagnosis and follow up is hampered by the lack of dermatologists who manage this disease, and supporting tools that permit longitudinal follow up for patients suffering from Buruli ulcers.In this proposal, the investigators will use the eSkinHealth app that was previously developed and piloted and adapt it through structured user feedback from key stakeholders.The R21 phase will also develop best practice guidelines and a scoring system for wound assessment and finally develop a photo system to store images of wounds for teaching purposes as well as follow up.The milestones governing the transition to the R33 phase are well defined.The R33 phase itself is rather ambitious; two clinical trials are planned in eight randomized health care regions.If successful, this proposal will have high impact on the management and infrastructure around ulcerative skin disease and wounds in the Ivory Coast.The project team is very strong having had collaborations and involvement of investigators and the Ministry of Health in the Ivory Coast.The study site is also ideal to investigate the use of the app given the high prevalence of Buruli ulcers in this region.There are minor weaknesses around the ability to provide true teledermatology services post study, and the sustainability of the app developed.There are also several concerns in terms of human subjects about data safety and consent, especially of children who may be enrolled in the study.Despite these issues, the research methods overall are sound, and impact is likely to be moderate to high.

Significance:
• The prevalence of skin disease in sub-Saharan Africa is high, and there is a lack of specialists to help diagnose these diseases, which lead to significant morbidity.
• Diagnosis of skin disease can be supported through low intensity use of mHealth applications to take photos of lesions and telemedicine to foster treatment guidance.
• Understanding the epidemiology of skin disease in Africa is difficult given the lack of infrastructure to support image storage and longitudinal follow up; this proposal seeks to address these important barriers.

Weaknesses
• With increased teledermatology and mHealth tools to diagnose skin disease, especially Buruli ulcers, it is unclear if there is capacity to conduct the intensive months-long wound care that may be required in these cases.

Strengths
• The PI has expertise in diagnosis of tropic skin diseases and has close collaborators in the Ivory Coast, which will be the prime site for research activities.
• Study investigators in the Ivory Coast have developed clinical infrastructure for managing skin related NTDs.Additionally, there is development of mHealth infrastructure in the Ivory Coast to enable outreach to manage NTDs and connect with international experts.

Weaknesses
• No comment provided by reviewer.

Strengths
• Deployment of a tablet-based teledermatology system in sub-Saharan Africa is innovative and seeks to address a fundamental challenge in the diagnosis and treatment of skin disease.
• Obtaining photos of dark-skinned individuals may help advance teaching surrounding skin disease in Africa.This strategy, if successful, will enhance the mHealth capacity of the Ivory Coast.
• Longitudinal assessment of skin disease through an app that can be used online and offline as a dermatology electronic health record is innovative.
• Access to the app by patients is by a QR code given to patients -they can then have a provider scan this QR code and obtain access to longitudinal wound images.

Weaknesses
• Unclear how this app would facilitate linkage to dermatology care.

Strengths
• Approach in the R21 phase is built around an app that has been developed previously.Several algorithms exist to guide clinicians through management of wounds and other skin diseases.
1 R21 TW011860-01 12 ZRG1 IMST-U (55) YOTSU, R • R21 development phase uses the modified information systems framework to improve the existing app, integrating user feedback from physicians, nurses, health workers and patients.
• The R33 phase is grounded in the realist evaluative approach and seeks to understand the effects of screening, referral and teledermatology to manage specific ulcerative skin disease.

Weaknesses
• The R21 phase assesses the usability of the app in a 3-month trial period, but without specific skin conditions, it is unclear how often the app would be used by different stakeholders.
• Unclear how many in depth interviews are conducted in the R21 phase.
• The applicants report that dermatologists from King's College London and International Foundation for Dermatology will support the teledermatology component of this app, but it is unclear how the dermatologists will be recruited and the number of dermatologists needed to sustain the teledermatology capabilities to support community health worker (CHW) screening patients in the Ivory Coast.
• The goals of the R33 phase are ambitious -to conduct two separate clinical trials during the three years of the R33.It is unclear if patients are recruited out of the same clinics as the Aim 1 clinical trial (R33 phase), or whether there would be bias for CHWs who have used the app in one study but may not be using it in the second.

Strengths
• Strong facilities at Tulane and especially at the IRFCI and other participating Cote d'Ivorie sites suggest an adequate institutional environment to conduct the proposed work.
• On site facilities in the Ivory Coast have the infrastructure required to conduct clinical trials.

Weaknesses
• No indication of strategies to conduct outreach in communities within the Ivory Coast.

Strengths
• There are strong and detailed milestones for transition to R33 phase.Quantified measures with benchmarks for passage to the R33 are well defined.
• Milestones detail long term impact of modules developed in the R21 phase that will be used both in the R33 phase and can be applied outside of the context of the grant.

Weaknesses
• No comment provided by reviewer.

Strengths
• Structured timeline with key tasks for success in both R21 and R33 phase are described. Weaknesses • It is not evident how long and if local ethics approval will be required for each of the randomly selected health areas in the R33 phase.
• The R21 timeline does not describe plans for integrating findings in the three Aims to refine the eSkinHealth app prior to deployment in the R33 phase.

Protections for Human Subjects:
Unacceptable Risks and/or Inadequate Protections • Children are included in the study but no discussion of how children would be consented.The reviewers noticed that the applicants did not include the research resource sharing plans in their application.NIH considers the sharing of unique research resources developed through NIH-sponsored research an important means to enhance the value and further the advancement of research.When resources have been developed with NIH funds and the associated research findings published or provided to NIH, it is important that the results be made readily available for research purposes to qualified individuals within the scientific community.

COMMITTEE BUDGET RECOMMENDATIONS:
The budget was recommended as requested.
NIH has modified its policy regarding the receipt of resubmissions (amended applications).See Guide Notice NOT-OD-18-197 at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-18-197.html.The impact/priority score is calculated after discussion of an application by averaging the overall scores (1-9) given by all voting reviewers on the committee and multiplying by 10.The criterion scores are submitted prior to the meeting by the individual reviewers assigned to an application, and are not discussed specifically at the review meeting or calculated into the overall impact score.Some applications also receive a percentile ranking.For details on the review process, see http://grants.nih.gov/grants/peer_review_process.htm#scoring.

•
No discussion surrounding potential data breaches and use of photos to identify study participants.What happens if there are facial lesions or photos inadvertently include identifying information (e.g.facial features)?Ulcerative skin disease is a significant problem in the Ivory Coast, and development of the proposed mHealth intervention will be of high value.No resource sharing plan described in proposal.
• Sex/Gender: Distribution justified scientifically • Race/Ethnicity: Distribution justified scientifically • For NIH-Defined Phase III trials, Plans for valid design and analysis: Not applicable • Inclusion/Exclusion Based on Age: Distribution justified scientifically Justified •

WERE PREPARED BY THE SCIENTIFIC REVIEW OFFICER TO SUMMARIZE THE OUTCOME OF DISCUSSIONS OF THE REVIEW COMMITTEE, OR REVIEWERS' WRITTEN CRITIQUES, ON THE FOLLOWING ISSUES: PROTECTION OF HUMAN SUBJECTS: UNACCEPTABLE Reviewer
3 notes that children are included in the study but there is no discussion as how children would be consented.In addition, there is no consideration of potential data breaches and use of photos to identify study participants.What happens if there are facial lesions or photos inadvertently include identifying information?
INCLUSION OF WOMEN PLAN: ACCEPTABLE INCLUSION OF MINORITIES PLAN: ACCEPTABLE INCLUSION ACROSS THE LIFESPAN PLAN: ACCEPTABLE SCIENTIFIC REVIEW OFFICER'S NOTE: