Cutting-Edge Technologies for Digital Therapeutics: A Review and Architecture Proposals for Future Directions
Round 1
Reviewer 1 Report
Comments and Suggestions for Authors
The main topic of this research is to describe the basic technologies currently adopted in DTx products through a literature review.
TITLE
The title is unclear. It is not clear whether the article is a review on digital therapeutics or a descriptive article on the design processes of a digital solution for major mental disorder.
INTRODUCTION
The introduction is insufficient. The authors did not state the objectives of the study and the research question. There is a lack of references to the state of the art on the use of information technology for the treatment of major mental disorder. A clear link between digital solutions, covid-19 and major mental disorder is missing.
What was the basis for the classification in Figure 1? Do the authors refer to the definitions of the WHO's Global Observatory for eHealth?
TECHNOLOGIES IN DTX
The authors referred to the systematic review as a type of article. The manuscript totally lacks a repeatable method to find, select and synthesize all available evidence.
The manuscript does not answer a clearly formulated research question and does not explicitly state the methods used to arrive at the answer.
There is no description of the methodology used. The authors quoted articles from the literature in a completely arbitrary manner.
MAJOR DEPRESSIVE DISORDER DTX
How does “System design” fit in with the literature search on digital therapeutics?
A description of the method that was used to design the solution is missing. There is a lack of reference on how the characteristics of the disease and the needs of the patients were taken into account. The proposed design does not describe how the solution integrates with public and private health and care services.
DISCUSSION
The paper would benefit from a short and crisp conclusion.
The article has serious methodological flaws and therefore cannot be accepted.
Author Response
First of all, thank you for suggesting us to submit revised draft of our manuscript entitled, "Cutting-edge technologies for Digital Therapeutics: A system design for Major Depressive Disorder" to Applied Sciences. We also appreciate the time and effort you have dedicated to providing insightful feedback on ways to strengthen our paper. We thought it was a paper that lacked a lot, so our research team revised the entire manuscript to make a better paper. We have incorporated changes that reflect the detailed suggestions you have graciously provided. We also hope that our edits and the responses below satisfactorily address all the issues and concerns you have noted.
Point 1. TITLE - Unclear title of the paper
Response 1: Our research team agrees with the opinion about the unclear title of the paper. The paper's primary goal is to explain the field of digital therapeutics and the major technologies to be considered and to present an ideal overall digital therapeutics architecture when the technologies are combined. In proposing the entire architecture, our team selects major depressive disorder as a suitable field to consider all suggested technologies, so the specific architecture is presented as an example. To clarify the paper's main topic, we edit the title from “Cutting-edge Technologies for digital therapeutics: A system design for Major Depressive Disorder” to “Cutting-edge Technologies for digital therapeutics: A systematic review and future directions.”
Point 2. INTRODUCTION - Insufficient information and objective of the research.
Response 2-1: It is true that we could have been more evident in the objective of our research topic and the connections between digital therapeutics, COVID-19, and major depressive disorder. The paper's primary purpose is added at the end of the Introduction section(page 3). We also mention why the digital therapeutics market is emerging after the COVID-19 pandemic and why the major depressive disorder is selected for our architecture design.
Response 2-2: The purpose of our research team’s inclusion of Figure 1 is to distinguish three frequently mixed words: digital health, digital medicine, and digital therapeutics so that readers can quickly check the differences at once. The definition of digital health was referred to the Food and Drug Administration(FDA) notification. The definition of digital medicine was referred to the Defining Digital Medicine(Elenko, E., et al, 2015) paper published in the Nature biotechnology journal. Finally, the definition of Digital Therapeutics was referred to the definition of an international non-profit organization, Digital Therapy Alliance(DTA).
Point 3. TECHNOLOGIES IN DTX - lacks research question and systematic review methodologies.
Response 3: Our team agrees with the comment that we select systematic research as a type of article but lacks research methodologies. Therefore, our research planning process, including thesis search and research question theorem, is newly added at the beginning of section 2 (page 3). Additionally, we agree with the comment that our paper needs more research questions. However, we suggest mentioning each research question at the beginning of each subsection instead of listing the research questions in a table format.
Point 4. MAJOR DEPRESSIVE DISORDER DTX - lack of system design methods and scalability to public healthcare
Response 4: We agree with the comment about the detailed explanations of methodologies and the considerations in our system design. Therefore, we added core points we considered before the system design, right before the architecture figure (page 10). In addition to the critical points of our system design, we also add the current issue of the major depressive disorder treatment system and how the suggested digital therapeutics system can be a solution.
Point 5. Discussion - need for a concise conclusion.
Response 5: We agree with the comment that the short and concise conclusion about the entire paper will be helpful for readers of the research. Therefore, we changed the title of section 4 to “Conclusion and Discussion” and then added an overall summary and concluding sentences in the third paragraph (page 12).
Author Response File: 
Author Response.pdf
Reviewer 2 Report
1. The article provides a comprehensive overview of various DTx; however, the explanation could be more concise and clear. It would greatly enhance the reader's understanding if the information was presented in a table format, categorizing each DTx and its respective medical use case.
2. Section 2.2.1 provides a brief introduction to machine learning. To improve the article's comprehensiveness, it would be beneficial to include specific examples of how machine learning is applied in DTx. This would help readers better understand the practical applications of the cutting-edge technology.
3. As a review article on cutting-edge technology, the scope of this discussion could be further expanded. Virtual reality technology has vast potential applications in DTx, and it would greatly enhance the comprehensiveness of the article if this topic were addressed.
4. Section 2.4 provides a detailed introduction to the advantages of recommendation systems. However, as a review article, it is also important to discuss the challenges that recommendation systems face, such as ensuring patient privacy protection. Addressing these issues would provide a more well-rounded view of the topic.
5. Section 2.1.1 provides only a brief introduction to two methods for removing sensitive information and their corresponding experimental results. As a review article, it would be helpful to compare the differences between different methods in practical applications or provide recommendations based on real-world scenarios. This would greatly enhance the relevance and utility of the article for readers.
The Quality of English Language can be improved.
Author Response
First of all, thank you for suggesting us to submit revised draft of our manuscript entitled, "Cutting-edge technologies for Digital Therapeutics: A system design for Major Depressive Disorder" to Applied Sciences. We also appreciate the time and effort you have dedicated to providing insightful feedback on ways to strengthen our paper. Thus, it is with great pleasure that we resubmit our article for further consideration. We have incorporated changes that reflect the detailed suggestions you have graciously provided. We also hope that our edits and the responses we provide below satisfactorily address all the issues and concerns you have noted.
Point 1. Table format summary for clearer information.
Response 1: It is true that the clear table about the digital therapeutics products and technologies would help the readers. While writing this paper, we wanted to discuss the technologies used in digital therapeutics and write what parts should be strengthened to become advanced digital therapeutics. Therefore, we check the digital therapeutics products currently being serviced in each country and the technical aspects used in the products. However, almost all digital therapeutic products were written about something other than the technology used in the product in their papers or articles. Accordingly, it was impossible to provide a clear table, so they could not add the details.
Point 2. Specific examples of machine learning in DTx
Response 2: It is true that the machine learning section lacks detailed examples or applications of the algorithms in the digital therapeutics field. Therefore, our team added the representative research examples, medical imaging, and the purpose of those researches at the end of section 2.2.1. (page 6)
Point 3. Virtual Reality technology in DTx
Response 3: In addition to the development of mobile hardware technologies such as smartphones, virtual reality technologies mentioned by the reviewer have recently been widely distributed. This virtual reality technology can also be applied to digital treatments. With the kind comment, our research team added it to the data collection part of section 2.1 (page 4) to explain data collection through VR devices and applications to DTx.
Point 4. Privacy protection in recommendation system.
Response 4: We agree that the recommendation system has the advantage of providing personalized treatment, but it also has concerns about personal health information violation. When designing the digital therapeutics architecture, our research team also recognized the possibility of information infringement in advance and suggested federated learning to protect personal data. Therefore, by adding this point at the end of section 2.4 (page 9), we explain that federated learning can also be used for AI model generation and recommendation systems.
Point 5. Sensitive information removing methods comparison.
Response 5: Our research discussed how to process sensitive personal information because user data must be reliably managed by international regulations such as HIPAA and GDPR. It is true that the necessity of explaining the actual application in the medical field, we added it to the end of section 2.1.1. (page 5) Differences between de-identification methods used in actual medical data analysis, data variables to which the algorithm is applied, and algorithms applied according to the data were added.
Author Response File: Author Response.pdf
Round 2
Reviewer 1 Report
TITLE
The title indicates that the article is a systematic review, but in practice it is not. A systematic review, unlike other types of review, involves a research method designed to reduce bias. The methods are repeatable and the approach is formal and systematic.
It is suggested to read the following article, and then completely revise the drafting of the review following the steps needed to implement a systematic review:
Cochrane Handbook for Systematic Reviews of Interventions, 2008, p. 6
INTRODUCTION
The article must be divided into the following paragraphs: Introduction; Materials and methods; Results; Discussion; Conclusion.
The research methodology leaves too much room for individual assessment regarding the eligibility of the selected studies. Inclusion and exclusion criteria are not clearly defined. Systematic reviews typically answer the research question by synthesising all available evidence and assessing its quality. Synthesising means bringing different information together to tell a single, cohesive story. Synthesis can be narrative (qualitative), quantitative or both. The method by which synthesis is carried out must be described in detail.
Some characteristics, or features, of systematic reviews are:
- Clearly stated set of objectives with pre-defined eligibility criteria
- Explicit, reproducible methodology
- A systematic search that attempts to identify ALL STUDIES that would meet the eligibility criteria
- Assesses the validity of the findings, for example assessing the risk of bias
- Systematic presentation and synthesis of the findings of the included studies.
The concept expressed by the authors in Response 2-2 must be better explained in the article to help the reader understand Figure 1.
RESULTS
Based on the above considerations, the results of the review are heavily biased. It appears that the articles included in the review were arbitrarily chosen by the authors, instead of being the result of a process supported by a methodology.
DISCUSSION
The authors' commentary on the digital therapeutics emerging from the review should be included in the “discussion” paragraph.
CONCLUSION
The article should end with a “conclusion” paragraph
Authors should consider withdrawing the article and repeating the systematic literature review, clearly defining the research objectives and adopting an explicit, reproducible methodology.
Author Response
First, we appreciate your suggestions and ideas for the second revision. Our research team gathered to discuss the part you reviewed in the second revision, and we will reflect on the following amendments and submit our opinions.
1. TITLE
Based on the comments you gave us at the first revision, we changed the title of this study to “Cutting-edge Technologies for Digital Therapeutics: A systematic review and future directions.” However, with the overall review of the paper, we decided that it would be good to change the title of the manuscript to "Cutting-edge Technologies for Digital Therapeutics: A review and architecture proposals for future direction."
2. INTRODUCTION
Our research team agrees with the review that it does not fit in the field of conventional systematic review in its research design and structure. Therefore, we also reviewed the “Cochrane Handbook for Systematic Reviews of Interventions” you kindly suggested through the revision. However, it is true that we conducted a comprehensive review of research based on current issues in digital therapeutics and technology-enhanced direction suggestions.
Although the direction of the research is a systematic review, it was concluded in a similar structure to the general review study. This is due to the need for more references to our proposed research question. Since the advent of the digital therapeutics’ definition, various companies and research teams have developed and conducted clinical trials on each innovative solution for various diseases. Several studies have been done to evaluate clinical efficacy, but there needs to be more explanation for the technical aspects that they are applying. This is also connected to why and how we set the research question of this study.
Digital therapeutics solutions with different forms and structures for each disease should be implemented with technical supplementation such as data preprocessing and AI-enhanced analysis. However, research still needs to be done to fill out the empty explanations on technological support. Therefore, we agree that there are areas for improvement of our research as a systematic review regarding the design, but the study will help the growth of the digital therapeutics field in the future.
3. RESULTS
We appreciate for pointing out the possibility of bias in the result section. However, as mentioned earlier, we reviewed digital therapeutics studies and decided it was necessary to organize applicable technologies, so we conducted this study. Also, since previous studies do not explain the technology, we have divided digital therapeutics architecture into sub-disciplinary areas, then find articles to cover the latest or most appropriate technologies in each field and support our argument. Therefore, some articles describe technologies in each field rather than references to digital therapeutics.
4. DISCUSSION
We agree with the comment about the “Discussion” section. Therefore, the discussion section has been modified to emphasize the study's necessity, core results, and importance. In addition, the relevance to the previous studies or the overall summary of the research results was moved to a concussion section.
5. CONCLUSION
We agree with the comment that the “conclusion” section should be added at the end of the research. Therefore, we have summarized the main findings and perspectives of the study by adding a conclusion section. Our team hope that this will be a part of highlighting the core content of the study and its importance to potential readers.
Author Response File: Author Response.pdf
Reviewer 2 Report
I noticed that the problems that I pointed out before had been properly addressed. I have no further suggestions for revision.
I suggest the authors make a thoroughly proofreading to ensure that there are no errors or irregularities in the paper.
Author Response
Our research team was able to improve the completeness of the paper based on the good points and suggestions that you pointed out. We appreciate the detailed revision that you have made. In addition, through the second revision of another reviewer, the title of the manuscript, discussion, and conclusion parts were revised, as shown in the manuscript below. Please check if there is anything different from the direction of our research or that needs to be fixed. Thank you.
Author Response File: Author Response.pdf
Round 3
Reviewer 1 Report
The authors revised the article as requested.
