Application of the Child Health and Nutrition Research Initiative (CHNRI) methodology to prioritize research to enable the implementation of Ending Cholera: A global roadmap to 2030.

BACKGROUND: The "Ending Cholera: A Global Roadmap to 2030" (Roadmap) was launched in October 2017. Following its launch, it became clear that additional evidence is needed to assist countries in controlling cholera and that a prioritized list of research questions is required to focus the limited resources to address the issues most relevant to the implementation of the Roadmap.
METHODS: A comprehensive list of research questions was developed based on inputs from the Working Groups of the Global Taskforce for Cholera Control and other experts. The Child Health and Nutrition Research Initiative methodology was adapted to identify the relevant assessment criteria and assign weights to each criterion. The assessment criteria were applied to each research question by cholera experts to derive a score based on which they were prioritized.
FINDINGS: The consultation process involved 177 experts and stakeholders representing different constituencies and geographies with research priority scores ranging from 88·8 to 65·7% and resulted in the prioritization of the top 20 research questions across all Roadmap pillars, the top five research questions for each Roadmap pillar, and three discovery research questions. This resulted in 32 non-duplicative research questions that considers both immediate and long-term Roadmap goals.
INTERPRETATION: The transparent, inclusive, and rigorous process to develop a Research Agenda is aimed to secure broad buy-in and serve as a guide for funding agencies and researchers to focus their efforts to fill the evidence gaps plaguing cholera-endemic countries.

Introduction

Cholera is a diarrheal disease that can be treated with rehydration; however, without treatment, cholera can kill within hours. Although cholera has been eliminated from high-income countries for over 150 years, it remains an important public health problem and is endemic mainly in the low- and middle-income countries in sub-Saharan Africa and Asia. Cholera remains a stark marker of inequity and continues to disproportionately affect the poorest and most vulnerable populations around the world and within each affected country. It is currently estimated that cholera affects at least 47 countries and causes 2.9 million cases and 95,000 deaths per year worldwide with large, devastating outbreaks still occurring at regular intervals such as in Zimbabwe 2008, Haiti in 2010, Sierra Leone in 2012, and more recently in Yemen, 2016 [1,2].

In October 2017, the partners of the Global Task Force on Cholera Control (GTFCC) endorsed a call to action to end cholera through the implementation of a new strategy known as “Ending Cholera: A Global Roadmap to 2030” (the Cholera Roadmap). The Cholera Roadmap champions a multi-sector approach focused on cholera hotspots where the populations most affected live and built on the different pillars for cholera control, namely disease surveillance (epidemiology and laboratory confirmation); vaccination with oral cholera vaccines (OCV); water, sanitation, and hygiene (WASH); case management (CM); and community engagement (CE). The Cholera Roadmap aims to achieve a 90% reduction in cholera deaths and cholera elimination in 20 countries by 2030 [2,3].

With the launch of the Cholera Roadmap, it became clear that additional evidence is required on the effectiveness of existing tools and interventions and how to optimise their implementation. However, given the limited resources and competing priorities, it is important to prioritize research to fill the key evidence gaps for optimal implementation of the Cholera Roadmap. A 12-month process was launched to develop a prioritized Research Agenda for the Cholera Roadmap by adapting the Child Health and Nutrition Research Initiative’s (CHNRI) approach, which is reported here [4-9]. The development process was guided by a Steering Committee convened specifically for this purpose.

Methodology

The research prioritization process was conducted in two phases. The first phase consisted of adapting the CHNRI method to achieve alignment with the multi-sector approach of Cholera Roadmap and the second phase utilized the adapted methodology to develop a prioritized list of research questions for inclusion in the Research Agenda.

Phase 1

Phase 1 focused on identifying the relevant research questions for inclusion in the prioritization exercise and adapting the CHNRI methodology by defining the Research Agenda’s context and selecting and weighting the most appropriate prioritization criteria.

The potential research questions were identified through three main sources (i) the GTFCC’s five working groups (ii) stakeholder interviews and survey and (iii) publicly available documents such as the World Health Organization (WHO) research priorities for cholera vaccination. These questions were reviewed, consolidated and classified according to the relevant Roadmap pillar and the CHNRI 4D framework categories i.e., Delivery, Development, Description and Discovery. In some situations, if research questions were relevant to more than one Roadmap pillar, they were classified as “cross-cutting” [5]. The consolidated questions underwent an iterative consultative process with 20 cholera experts to remove duplication and redundancies, standardize the language and format to improve clarity and facilitate scoring of the questions to arrive at a final set of research questions for prioritization. Four hundred and fifty-three research questions were identified by the GTFCC working groups and through the interviews and surveys. These were reviewed by GTFCC working group chairs and key technical experts and consolidated into 124 questions after removal of duplications and non-research statements. These 124 questions underwent further review by 17 cholera experts, and ultimately, 93 were chosen for inclusion in the prioritization process. Thirty-one questions were excluded based on feedback from the experts that sufficient evidence and guidance already existed for those questions. The 31 research questions were flagged to the GTFCC for follow up to determine if systematic reviews and grading of the quality of the evidence was needed to determine the need for additional research to generate primary data. The list of 93 research questions selected for prioritization included 25 (27%), 23 (25%), 19 (20%), 16 (17%), and ten (11%) classified as cross-cutting, epidemiology, surveillance and laboratory, case management, OCV, and WASH pillars, respectively. Given their cross-cutting nature and the importance in all cholera interventions, the ten community engagement questions were all classified into the cross-cutting category. Per the 4D category, the distribution of the 93 questions were split amongst the 4D domains of delivery, development, description, and discovery was 36 (39%), 35 (38%), 19 (20%), and 3 (3%), respectively.

In parallel, stakeholder consultations were held (via online survey and telephone interviews) to select the most important research prioritization criteria. Eight potential criteria were selected for consultation including affordability, ethical answerability, equity, fundability, impact, implementability, relevancy, and sustainability. Inputs were obtained to agree on the definition of each criterion and its weight in the prioritization process as well as on the importance of each criterion independent of the others. Four hundred and nineteen individuals were contacted to either complete an online survey via Qualtrics™ (n = 306) or participate in a 45-minute telephone interview (n = 113). The telephone interviews specifically targeted key senior-level experts and country-level stakeholders who were considered less likely to respond to an online survey and could provide more qualitative feedback that would be difficult to capture in a survey.

Both the interviewees and survey respondents were asked four demographic questions and to rate the eight proposed criteria and their description using a 5-point Likert scale of “not important at all” to “extremely important”. A mean was calculated for each criterion based by applying points of one for “not important at all” to five for “extremely important”, which was used to narrow the number of prioritization criteria. This rating was used to ultimately select 5 prioritization criteria for us in the final prioritization exercise. Further, the respondents were given open-ended questions to describe their rationale for their rating, improve the criteria descriptions, and indicate what they considered were key evidence gaps. All qualitative responses were combined and analyzed through an iterative process with the interviewer to develop key themes. Additional stratified analyses were conducted to evaluate any trends in the responses based on the demographic characteristics. See S1 File for the interview and survey questions.

One hundred and forty-one experts representing 32 countries provided their feedback either through the interviews or the online survey in Phase 1, informing in the definition of the Research Agenda context and selection of five criteria for use in prioritizing the research questions. The definitions of the five selected criteria were revised based on the feedback from the interviews and survey to improve clarity and enable uniform use in the prioritization process. Following the CHNRI guideline, the Research Agenda context was defined as follows (i) Population of interest: all countries and communities where cholera is endemic and/or there is an epidemic risk of cholera (ii) Time scale: present-day to 2030 (iii) Geographic scope of research: global, regional, national, and sub-national levels. Sub-national may include different administrative levels, such as provinces or states, districts, communities or households (iv) Impact of interest: reduction of deaths and burden of cholera where burden may include prevalence and morbidity as well as any economic or social impact of cholera. Additional information may be found in S2 File.

Following the initial analysis which identified 5 prioritization criteria and to finalize the CHNRI approach, a virtual meeting was conducted with a subset of the stakeholders who participated in the interviews and survey to discuss the design of the survey, Research Agenda’s context, and weighting of each criterion. To inform this discussion and determine appropriate weights to each of the five criteria finally selected for the prioritization exercise, a second online survey was sent to 85 stakeholders to “distribute 100 points across the five criteria according to the perceived level of importance, i.e., to allocate higher points to the criterion considered as the most important”. This process enabled the weighting of each criterion based on its importance relative to that of the other criteria. Following the CHNRI approach, the weights were calculated by dividing the mean values allocated to each criterion by 20 or the value if each of the 100 points was distributed equally between the 5 criteria [10]. Of the 85 stakeholders, 40 responded to the second survey. This method allowed the respondents to rank each criterion in respect to other criteria, which was used to set the appropriate weights for each criterion. Table 1 provides an overview of the five criteria and their weights to evaluate the research questions.

Table 1

Five criteria utilized to evaluate research questions.

Criterion	Weight	Description
Answerability	0·79	Do you think the proposed research is answerable in cholera-affected countries and communities? *Assumes all protocols will be subject to appropriate ethics reviews.
Impact	1·20	Will the research outputs contribute to reducing cholera deaths and burden? *Burden may include morbidity, economic or social impact
Implementability	1·12	Will the proposed research lead to solutions that are implementable (e.g. feasibility of introduction, including acceptability to the cholera-affected communities and scale-up)?
Relevancy	1·06	Will the proposed research contribute to addressing relevant evidence gaps in the cholera-affected countries or communities when implementing the Cholera Roadmap?
Sustainability	0·83	Will the proposed research lead to solutions that are sustainable over time without, or with only limited, external financial or technical support in cholera-affected countries?

Phase 2

An online survey was designed using Qualtrics™ to allow respondents to score the identified research questions using the chosen criteria. The survey asked three demographic questions related to respondent location, organization affiliation, and areas of expertise. The research questions were organized into “blocks” by the Roadmap pillar, including case management, community engagement, OCV, WASH, and cross-cutting (if the research questions were relevant to more than one pillar). The blocks were randomized for each survey participant to allow for the inclusion of partial responses without bias towards one Roadmap pillar. The respondents were given options of “Yes”, “No”, and “Maybe” for questions that they felt they could answer, which were assigned points of one, zero, 0·5, respectively. They also had the option to answer “don’t know” for those question that they felt were outside their area of expertise and knowledge. “Don’t know” responses were excluded from the analysis to calculate research priority scores. See S3 File.

Two hundred and forty-five individuals were sent personalized emails to complete the survey. Further, a link to an anonymous survey was also posted on the GTFCC’s website. The online survey remained open for two months with regular email reminders sent weekly.

All responses were downloaded into Microsoft Excel from the Qualtrics™ software, including any partially completed surveys where a response was provided to at least one research question. The following scores were calculated for each research question:

Unweighted research priority score (RPS): the following formula was used where c is the five criteria evaluating the research question.

Weighted research priority score: the following formula was used, where W is the weight for each criterion and c is the five criteria evaluating the research question. The following weights were applied 0·79, 1·20, 1·12, 1·06, and 0·83 for Answerability, Impact, Implementability, Relevancy, and Sustainability, respectively.

Finally, the average expert agreement (AEA) was calculated as well as stratified analyses were also performed using Microsoft Excel to identify any biases considering the respondents’ identified areas of expertise and respondent location [11]. In addition to the CHNRI approach defined above, the trends of the responses provided were also analysed manually, particularly the “Don’t Know”.

Results

Identified research priorities

One hundred and thirty-eight individuals representing 39 countries scored the 93 research questions as part of Phase 2. Of these, 21 individuals only provided partial responses to some but not all the research questions. These were included in the analysis. Table 2 provides an overview of the demographics of individuals who responded.

Table 2

Demographics of individuals who evaluated the research questions.

	#	%
I. Expertise Respondents were allowed to select up to two areas of expertise
Epidemiology / Surveillance / Laboratory	75	34%
Oral Cholera Vaccine	55	25%
Water, Sanitation, and Hygiene	43	19%
Case Management	22	10%
Community Engagement	21	9%
Other	7	3%
II. Organisation Type
Impl. partner (US Center for Disease Control, International Organizations, United Nations, Civil Society Organisation, and Non-Governmental Organistaion)	58	42%
Academic / Research	46	33%
Donor	15	11%
Government in cholera endemic countries	16	12%
Independent	3	2%
III. Respondent location
Global, includes World Health Organization European and American Regional Offices, excluding Haiti	72	52%
World Health Organization African Regional Office	33	24%
World Health Organization Southeast Asia Regional Office	20	14%
World Health Organization Eastern Mediterranean Regional Office	7	5%
Haiti	2	1%
World Health Organization Western Pacific Regional Offices	4	3%
Total	138

Based on the weighted research priority scores, the top 20 research priorities consisted of nine (45%), five (25%), three (15%), two (10%), and one (5%) for OCV, cross-cutting, WASH, epidemiology /surveillance/ laboratory, and case management (CM) pillars, respectively (Table 3). Fourteen questions (70%) were related to Delivery and six (30%) to Development, whereas no Description or Discovery questions ranked within the top 20. From consultation with the Steering Committee and to ensure linkages to the GTFCC and its working groups and their mandates, the top five research priorities of each Roadmap pillar were also identified as key priorities, which resulted in nine additional priorities not captured in the top 20. Furthermore, given the importance of Discovery related research questions to long-term elimination goals, the three questions were also included among key priorities. The final selection of the 32 priorities (top 20 key priorities plus non-duplicative top five Pillar priorities) resulted in the selection of ten (31%) in the OCV pillar, seven (22%) in the epidemiology, surveillance and laboratory, and five each (16% each) in WASH pillar, cross-cutting, and case management pillars, respectively. Considering the 4D framework, 16 Delivery (50%) and 11 Development (34%) questions accounted for the majority of the priorities selected. The results of the “don’t know” analyses did not reveal any significant effects on the overall analyses.

Table 3

Priorities for the Cholera Roadmap Research Agenda (n = 32).

4D	Pillar	RQ	Weighted RPS	AEA
Delivery	OCV	What are the optimal oral cholera vaccine schedules (number of doses and dosing intervals) to enhance immune response and clinical effectiveness in children 1 to 5 years of age?	88.8%	80.7%
Delivery	OCV	What are potential delivery strategies to optimise oral cholera vaccine coverage in hard-to-reach populations (including during humanitarian emergencies and areas of insecurity)?	87.4%	75.9%
Delivery	OCV; WASH	Is there additional benefit to adding WASH packages, for example household WASH kits, to an oral cholera vaccine campaign?	87.1%	77.2%
Delivery	OCV	What is the optimal number of doses of oral cholera vaccine to be used for follow up campaigns in communities previously vaccinated with a 2-dose schedule?	86.9%	76.4%
Delivery	OCV	Can the impact of oral cholera vaccine on disease transmission, morbidity and mortality be maximized by targeting specific populations and/or targeted delivery strategies?	86.8%	78.0%
Delivery	CM	What are the barriers and enablers for integrating cholera treatment into community case management by community health workers?	86.8%	74.7%
Delivery	WASH	What levels of coverage for relevant water, sanitation, and hygiene interventions is required in cholera hotspots to control and ultimately eliminate the risk of cholera?	86.3%	74.9%
Delivery	OCV	What impact does the timing of oral cholera vaccine use have on outbreak prevention and control?	86.2%	73.9%
Development	Epi / Sur / Lab	What is the impact of early diagnosis of cholera using a rapid diagnostic test at the point of care in a community setting compared to testing only in health facilities?	86.1%	74.6%
Delivery	OCV	How can the use of oral cholera vaccine in the controlled temperature chain (i.e. outside the cold chain) be leveraged to maximize the coverage or impact of vaccination in a field setting?	85.9%	75.2%
Delivery	All	What is the incremental benefit of implementing a comprehensive interventions package (including water, sanitation, and hygiene, antibiotics, oral cholera vaccine, oral rehydration therapy) to reduce cholera mortality during an epidemic?	85.7%	74.3%
Delivery	OCV	What is the effectiveness and impact of different vaccination strategies for rapid response to cholera outbreaks (e.g., ring vaccination, case-area targeted interventions, etc)?	85.3%	74.1%
Development	OCV; WASH	What is the most cost-effective package of water, sanitation, and hygiene and oral cholera vaccine in different situations, based on transmission dynamics in cholera hotspots?	85.2%	73.7%
Development	WASH	What are the most essential (or what is the minimum set of) infection, prevention, and control (IPC) interventions in cholera treatment facilities and oral rehydration points to reduce risk of transmission within these facilities?	84.9%	74.2%
Delivery	OCV	Are there immunisation strategies other than repeated mass campaigns that will be effective in preventing endemic or epidemic cholera?	84.9%	71.4%
Delivery	All	What is the role and added value of CORTs (community outreach response teams) in enhancing case investigation and outbreak detection?	84.6%	71.2%
Development	OCV	Can oral cholera vaccine be co-administered safely and without interference with other vaccines during mass campaigns or during routine immunization visits (measles containing vaccines, yellow fever, typhoid, meningitis, pneumococcal conjugate vaccine)?	84.3%	72.0%
Delivery	WASH; CE	What are effective strategies to scale up the use of household water treatment in controlling cholera outbreaks?	84.1%	70.9%
Development	Epi / Sur / Lab	How can we improve and fine-tune hotspot definition and identification at a district and sub-district level, such as micro-hotspots, including incorporating a population-based approach?	84.1%	72.1%
Development	WASH	Is improved access to safe water (e.g., water points and distribution networks) effective in controlling and preventing cholera outbreaks?	84.0%	74.1%
Development	CM	What effect does treatment with antibiotics have on cholera transmission?	83.3%	71.0%
Development	CM	What is the optimal treatment schedule for antibiotic prophylaxis given to household contacts of cholera patients and does this have an effect on the magnitude, transmission and secondary attack rate of cholera outbreaks?	80.5%	69.7%
Description	CM	What are the common cholera treatment complications in vulnerable populations (for example: pregnant women, the elderly, those with severe acute malnutrition)?	80.2%	66.5%
Development	CM	Would ReSoMal formulated with higher sodium, or standard oral rehydration solution containing high potassium, result in lower mortality or morbidity, compared to the standard WHO rehydration solution, in children with severe acute malnutrition?	80.1%	65.7%
Development	Epi / Sur / Lab	What are the optimal design(s) of surveillance systems (e.g., indicator-based, event-based, community-based, environmental, sentinel site surveillance) to monitor progress of the Cholera Roadmap?	83.8%	71.0%
Development	Epi / Sur / Lab	What are the optimal surveillance tools (e.g., laboratory methods, case definitions, etc.) to monitor progress of the Cholera Roadmap?	82.8%	69.6%
Description	Epi / Sur / Lab	How can combined epidemiological and genomic analysis of V. cholerae be used to better understand transmission dynamics and inform epidemiological models?	81.2%	67.6%
Delivery	WASH	How can "design thinking" be used to improve the delivery / uptake of water, sanitation, and hygiene interventions? Design thinking focuses on understanding the needs of the people who will use the intervention and working with them to improve it.	83.0%	67.4%
Delivery	WASH	What are the factors / determinants that lead to sustainable investments in water, sanitation, and hygiene at country level?	80.3%	65.9%
Discovery	Epi / Sur / Lab	Research and development of novel and innovative diagnostic tests to accelerate the achievement of the Cholera Roadmap goals.	80.8%	65.9%
Discovery	OCV	Research and development of new or improved vaccines to contribute to accelerate the achievement of the Cholera Roadmap goals.	79.5%	64.7%
Discovery	Epi / Sur / Lab	Research to contribute to the collection of genomic data to create a global V. cholerae sequences database to map long-range transmission routes.	72.8%	55.7%

S1 Table provides the full list and scores for the 93 research questions, including the AEA scores.

Results stratified by the expertise and geographical location

Stratified analyses were conducted considering the respondents’ areas of expertise and location. Several differences were observed in the prioritization of the research questions in the stratified analyses. Differences were observed in prioritization based on the area of expertise of the scorer. For example, the CM experts ranked more CM questions (n = 13) as high importance and WASH experts placing a higher priority on cross-cutting questions (n = 16) (Fig 1). In addition, when considering the respondent’s geographical location, individuals based in cholera-endemic countries placed a higher priority on cross-cutting questions (n = 16) and less priority on OCV research questions (n = eight) compared to those at the global level (n = nine and n = 12, for cross-cutting and OCV research questions, respectively) (Fig 2). There were also differences in responses based on geographic regions with respondents in Africa placing a higher priority on cross-cutting questions compared to Asia, which placed a higher emphasis on CM questions (Fig 3). In comparison, there were no significant differences in the 4D categorization of prioritized questions with Delivery and Development questions continuing to be prioritized over Discovery and Description.

Fig 1

Breakout of the top 32 priorities by Roadmap pillar and respondent expertise.

Fig 2

Breakout of the top 32 priorities by perspective.

Fig 3

Breakout of the top 32 priorities by geographic region.

Discussion

The 32 questions provide a fairly balanced set of priorities across all of the Roadmap pillars that considers immediate and long-term goals. There was a higher selection of OCV-related questions, which may be related to potential sampling e.g., a high number of stakeholders were involved in OCV-related activities or interpretation bias e.g., OCV tends to provide more concrete impact compared to the other Roadmap pillars. Further, the identified priorities lean heavily towards Delivery and Development research questions as opposed to Description and Discovery, implying a high perceived need to address immediate barriers to implementing the Roadmap interventions. Although the Discovery questions scored lower, they were ultimately included in the final list of priorities based on expert judgement. Even though the Discovery questions may not have outputs prior to the 2030 Roadmap goals, it was felt that the immediate availability of funding could accelerate the availability of innovative solutions that are likely to have an impact on the longer-term goals for cholera control, especially achieving and sustaining elimination.

The stratified analyses clearly demonstrated differences in opinion between the different stakeholder groups, based on their areas of expertise and geographical location. The respondents tended to give higher scores to research questions in their own areas of expertise compared to other areas, which may be driven by their knowledge of the specific Roadmap pillar. If this exercise were repeated, additional efforts should be made to ensure that each Roadmap pillar was equally represented among those participating in the prioritization exercise. When considering the respondent’s geographical location, there was a clear divergence in perceptions of the key priorities from those based at the global level compared to those based in cholera-endemic countries. Those located in cholera-endemic countries prioritized more cross-cutting questions compared to those based at the global level. In addition, differences were observed between respondent in different geographical locations. For example, the respondents located in Africa placed a higher priority on cross-cutting questions compared to Asia, which placed a higher emphasis on CM questions. This may reflect the different needs based on the country’s current progress towards cholera control and prevention efforts. Further, this reflects the importance of ensuring open dialogue between all relevant stakeholders including the governments where the research priorities will be evaluated to ensure the utilization of research outputs and alignment with ongoing government programmes. Finally, regardless of the stratified analysis, there was general agreement amongst the respondents in all stakeholder groups that the top ten key research questions were very important but less agreement on those ranked questions ranked as 11–32. This indicates that there is more convergence in opinion for the highest priority questions per the AEA, while the lower scores were driven more by a difference in opinion between the different stakeholder groups, rather than a convergence in opinion that these do not represent important evidence gaps. While the stratified analyses provide interesting perspectives on the goals of various stakeholders, the number of individuals for some of the stratified groups, including CE, CM, stakeholders located in Asia and Africa was lower than the threshold of 45 experts required to achieve an optimal collective opinion by CHNRI method [6,12]. Thus there is a risk of bias here because of a small group of respondents whose view of priorities may be influenced by their own knowledge and experience [13,14].

The CHNRI approach was selected amongst other options to identify the cholera research priorities as it is systematic, consultative, transparent, and reproducible [13,15-18]. It incorporates the consideration of values of a wider group of stakeholders. It reduces the impact of self-interest when deriving the initial research question list. Individual ranking reduces any undue individual influence on the process and outcome. In this exercise it allowed the engagement of 177 individuals in identifying research questions, selecting the key criteria and relevant weights to evaluate the research questions, and evaluating the research questions. The process has its limitations also—it is long and sometimes complex, which can affect response rates [19]. If care is not taken to include the government officials in identifying their problems, it may neglect considering the existing government priorities [17]. Finally, it is challenging to obtain the right mix of stakeholders depending upon the area to be explored [14].

In addition to some of the potential biases indicated in the stratified analysis, the other limitation of this work was the suboptimal representation from individuals working for the governments of cholera-endemic countries in identifying their problems and scoring the research questions. Due to COVID pandemic, several face-to-face meetings planned with the government representatives from the cholera-endemic countries were cancelled and their input into the process was affected. Effort was made to involve them through telephone calls, but it was difficult to get time from many of them because they were involved in the response to the COVID pandemic. Second, a systematic literature review was not conducted to identify research gaps. The research questions were largely collected from the GTFCC working groups and supplemented via interviews and consultations, which resulted in a different number of research questions across the Roadmap pillars that were collected via different methodologies and had different levels of specificity. While efforts were made to standardize the questions, the questions could have been further refined and standardized.

Key strengths of this work included the extensive consultations with stakeholders operating in cholera-endemic countries across different areas of responsibility including policy and decision-makers, donors, and operational leads. This allowed the ability to identify research priorities that are most important for the successful implementation of the Cholera Roadmap.

List of 93 research questions and their scores.

(DOCX)

Click here for additional data file.

Interview and survey questionnaire used to adapt CHNRI approach and identify research questions.

(DOCX)

Click here for additional data file.

Phase 1 results.

(DOCX)

Click here for additional data file.

Guidance document accompanying prioritization survey to evaluate research. Questions.

(DOCX)

Click here for additional data file.

24 Nov 2021

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Reviewer #1: This paper presents a research priority setting exercise, using the CHNRI method, to support the Global Roadmap to 2030 for cholera. This paper contains important research priorities and novel adaptations of the CHNRI method. Congratulations to the authors on the manuscript.

I have several questions about the exercise:

- What method did the experts use to further cut down the RQs into a list of 93? Were all the RQs removed answerable through a systematic review or already had sufficient evidence? For those that were answerable through a review, what is the rationale for eliminating systematic reviews (as if called for, they may summarise evidence in a way that is actionable/could lead to policy changes)? Is the exercise intending to look at primary data collection?

- What was the rationale for choosing different methods to weight the criteria in the first and second round? I understand the first round was intended to eliminate criteria through low weights. How did the weights differ with both methods? Was there any lack of engagement doing this exercise twice?

- The discussion states that scorers were more likely to score RQs in their area of expertise higher. Do you have any recommendations for countering this in future (perhaps by either aiming to achieve fairly equal representation across areas of expertise, or only having RQs scored by experts in that area)?

- Were there any partial scores for the list of RQs (e.g., someone started and stopped scoring)? If so, were these included in the RPS? Was there a threshold to the proportion of RQs scored in order to be included?

- What is the rationale for not including Average Expert Agreement?

Some minor comments:

- On line 139-140, should 'research' be capitalised before Agenda (or both lowercase?)

- On line 265, CHNRI acronym has a typo

- It would be useful to spell out all acronyms in their first instance (e.g., OCV, CM, etc.) for readers who are unfamiliar with the acronyms.

Reviewer #2: The authors have tried to create a prioritized list of research questions to focus the limited resources and address the issues most relevant to the implementation of the Roadmap, for funding agencies and researchers to focus their efforts to fill the evidence gaps plaguing cholera-endemic countries. Intense work has been put in through various methods in achieving the research questions, however there are number of limitations and few methods lack clarity.

Most importantly the prevalence of cholera infection and the severity (mortality) due to this infection in low resource countries needs to be mentioned.

While seasonal episode of cholera is most seen, the intervention should focus accordingly. The population that is most affected must be described and strategies to curtail the infection needs to be explicitly explained.

Information on whether the vaccination has helped in reducing the infection rate and the severity must be discussed before implementing to the general population.

As one of the factors mentioned is malnutrition, access to health care facilities and good nutrition, WASH, it is also important to align with the government programs and policies laid for the communicable diseases specific to the country. This is important since the countries selected are a mixed bag with different facilities and opportunities.

There are number of abbreviated terms that needs expansion when used for the first time in the text. Eg: GTFCC’s, OCV

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Reviewer #1: Yes: Kerri Wazny

Reviewer #2: No

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7 Jan 2022

7 January 2021

Jai K Das

Academic editor PLOS ONE

Dear Dr. Das,

We thank you and the reviewers for the informative and helpful assessment of our manuscript. Because of the positive nature of the review, and at your request, we are submitting a revised manuscript. The following is a detailed list of the revisions and/or our responses.

We believe that our responses to the helpful advice from the reviewers and subsequent edits have improved the manuscript substantially. We hope that you will now deem it acceptable for publication. We look forward to your further consideration. Please do not hesitate to contact me with any further questions.

Sincerely,

Melissa Ko, on behalf of the authors

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This paper presents a research priority setting exercise, using the CHNRI method, to support the Global Roadmap to 2030 for cholera. This paper contains important research priorities and novel adaptations of the CHNRI method. Congratulations to the authors on the manuscript.

I have several questions about the exercise:

- What method did the experts use to further cut down the RQs into a list of 93? Were all the RQs removed answerable through a systematic review or already had sufficient evidence? For those that were answerable through a review, what is the rationale for eliminating systematic reviews (as if called for, they may summarise evidence in a way that is actionable/could lead to policy changes)? Is the exercise intending to look at primary data collection?

The research questions were reduced to 93 based on the feedback of 17 world renowned cholera experts who indicated that the research questions already had a sufficient level of evidence and/or guidance. The 31 research questions that were removed were also flagged for the GTFCC to follow up with to determine if the research question was fully addressed with the available data or whether a systematic review of the available data is required to address the knowledge gap. Please see the revisions in lines 123-129.

A primary goal of the Research Agenda was to prioritize the research questions that require the generation of primary data to fill existing evidence gaps. As these 31 research questions were deemed to either have sufficient evidence and / or available guidance they were eliminated from the prioritization process but, as we agree with the reviewer that systematic reviews can be very valuable for summarizing evidence in a way that is actionable and can lead to change, we highlighted these research questions as “knowledge” rather than evidence gaps to the GTFCC and its partners for them highlighted as actionable for GTFCC and its partners to follow up on by either communicating the knowledge, developing relevant guidance/technical notes, and determining if additional systematic review should be conducted.

- What was the rationale for choosing different methods to weight the criteria in the first and second round? I understand the first round was intended to eliminate criteria through low weights. How did the weights differ with both methods? Was there any lack of engagement doing this exercise twice?

The first method focused on rating eight potential criteria (selected on prior CHNRI exercises) that could be used to prioritize the research questions using a Likert scale. The respondents were asked to rate the criteria independently of each other and, as the reviewer notes, this was helpful for eliminating criteria that were deemed less important or relevant for cholera research by the respondents. The first method also allowed respondents to give feedback on the definitions of their preferred prioritization criteria, which we used to refine the definitions for the prioritization exercise to maximize clarity and universal understanding. Following method 1, a set of 5 criteria were selected with some revisions for the prioritization exercise. The second method focused on asking the respondents to rank each of the criteria against the other criteria. The ranking based on relative importance of each criterion allowed for the generation of weights to generate the priority score for each research question. There were slight differences between the two methods. For example” implementability” rated highest, followed by the “impact” in the first method. However, in the second method the ranking of “implementability” and “impact” were reversed. However, the definitions underwent some revisions between the two methods and the definitions for the criteria were not identical between the two rounds. We had about a 50% response rate for both methods.

Please see lines 140-142, 163-164, 173-176 for further revisions.

-The discussion states that scorers were more likely to score RQs in their area of expertise higher. Do you have any recommendations for countering this in future (perhaps by either aiming to achieve fairly equal representation across areas of expertise, or only having RQs scored by experts in that area)?

Yes, if this exercise were repeated it would be imperative to ensure there is an equal representation of expertise across the different Roadmap pillars. Due to the multi-sectoral approach of the Roadmap and since some individuals may have practical and extremely relevant experiences across multiple pillars but may not identify themselves as an expert in each pillar, we did not want to limit the respondents’ opportunities to prioritize any research questions.

Line 335-337 have been revised to reflect this information.

- Were there any partial scores for the list of RQs (e.g., someone started and stopped scoring)? If so, were these included in the RPS? Was there a threshold to the proportion of RQs scored in order to be included?

Yes, partial scores were included if they responded to at least one assessment of a research question, please refer to lines 224-226 and 235-237 for the methodology. Note this information was already included so there are no revisions.

There were 21 partial responses recorded and included in the RPS, this has been revised as part of lines 258-259.

- What is the rationale for not including Average Expert Agreement?

The average expert agreement was originally included as part of the supplementary table 4, we did not include it in the main body of the article because there was little discrimination between the AEAs for the research question. However, based on this comment we have edited to include it in Table 3 starting on line 283.

Some minor comments:

- On line 139-140, should 'research' be capitalised before Agenda (or both lowercase?)

Correct, we have edited this

- On line 265, CHNRI acronym has a typo

Correct, we have edited this

- It would be useful to spell out all acronyms in their first instance (e.g., OCV, CM, etc.) for readers who are unfamiliar with the acronyms.

The acronyms have been checked and defined the first time that they are used, generally in lines 87-89.

Reviewer #2: The authors have tried to create a prioritized list of research questions to focus the limited resources and address the issues most relevant to the implementation of the Roadmap, for funding agencies and researchers to focus their efforts to fill the evidence gaps plaguing cholera-endemic countries. Intense work has been put in through various methods in achieving the research questions, however there are number of limitations and few methods lack clarity.

Most importantly the prevalence of cholera infection and the severity (mortality) due to this infection in low resource countries needs to be mentioned.

This has been updated to reflect the current situation of cholera in lines 78-81 as well as the estimated number of deaths and cases.

While seasonal episode of cholera is most seen, the intervention should focus accordingly. The population that is most affected must be described and strategies to curtail the infection needs to be explicitly explained.

Please find relevant edits in lines 84-89.

Information on whether the vaccination has helped in reducing the infection rate and the severity must be discussed before implementing to the general population.

The manuscript reports on an exercise to prioritize research questions to fill critical evidence gaps on interventions to control cholera. While vaccination is one of the interventions, the research questions also include other pillars. The manuscript does not make any recommendations for vaccination. Policy recommendations on the use of cholera vaccines have been made by WHO at the global level and for use at country levels by the respective national policy-making bodies. Hence, we did not feel that a discussion on the impact of one of several interventions for cholera control are relevant to this paper.

As one of the factors mentioned is malnutrition, access to health care facilities and good nutrition, WASH, it is also important to align with the government programs and policies laid for the communicable diseases specific to the country. This is important since the countries selected are a mixed bag with different facilities and opportunities.

This is an important point that was raised by a few interviews and discussions. We have edited to highlight the importance of open dialogue with countries to ensure full utilization and alignment to government programmes.

Please see revised lines 345-348.

There are number of abbreviated terms that needs expansion when used for the first time in the text. Eg: GTFCC’s, OCV

These have been checked for and edited, see lines 78-81.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

21 Feb 2022

Application of the Child Health and Nutrition Research Initiative (CHNRI) methodology to prioritize research to enable the implementation of Ending Cholera: a global roadmap to 2030.

PONE-D-21-25214R1

Dear Dr. Ko,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Jai K Das

Academic Editor

PLOS ONE

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #2: The comments raised by the reviewer has been addressed satisfactorily. There are couple of suggestion made based on the limitation identified due to methodological / logistic issues and also enhanced due to the COVID-19 pandemic. Additional information with face-to-face interviews in a subgroup on evaluating the COVID pandemic situation will be useful. It is important to revisit the work relevant to this area through a systematic literature review to help the reader in identifying research gaps. The questionnaire and other tools used should be periodically validated and standardized for accuracy.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Kerri Wazny

Reviewer #2: No