An mHealth App to Promote Adherence to Immunosuppressant Medication and Track Symptoms in Children After Hematopoietic Stem Cell Transplant: Protocol for a Mixed Methods Usability Study

Background In the United States, poor adherence accounts for up to 70% of all medication-related hospital admissions, resulting in $100 billion in health care costs annually. In pediatrics, adherence is largely dependent on caregivers. In a high-risk hematopoietic stem cell transplant (HSCT) population, caregivers are isolated with their child due to infection risk and must manage challenging treatment regimens at home, often with limited time and support. Complex behavioral interventions, typically employed to address adherence, are difficult to deliver and manage in the context of these daily tasks. The most successful adherence interventions, and thus improved clinical outcomes, have included mobile health (mHealth) reminder approaches and a direct measure of adherence. Objective This is a 3-phase project, with this protocol describing phase 2, to determine the usability and feasibility of an mHealth app (BMT4me) designed to promote adherence to immunosuppressant medication and to track symptoms among children who received HSCT. Methods This study uses an iterative convergent mixed methods design to develop and assess the usability and feasibility of an adherence digital health intervention. We will recruit 15 caregivers of pediatric patients receiving HSCT to complete user testing. Qualitative and quantitative data will be integrated to enhance and expand upon study findings. Results Enrollment began in September 2021 and is ongoing. A total of 7 caregivers have enrolled. We anticipate completion by fall 2022. We anticipate high usability scores and a better understanding of unique features within the app that are needed for HSCT families post transplant. To date, usability scores among enrolled participants are greater than 70%. Feedback from qualitative interviews is being used to further adapt the app by adding specific weekly logs, call provider options, and voice to text. Conclusions This protocol describes a mixed methods usability and feasibility study to develop and implement a smartphone app for caregivers of children receiving HSCT. The app was designed to improve immunosuppressant adherence and to track symptoms in the acute phase post discharge. Study findings will inform further refinement of the app and the feasibility of a pilot randomized controlled trial examining efficacy on clinical outcomes. Trial Registration ClinicalTrials.gov NCT04976933; https://clinicaltrials.gov/ct2/show/NCT04976933 International Registered Report Identifier (IRRID) DERR1-10.2196/39098

1 K99 NR019115-01A1 3 NRRC (78) SKEENS, M and mHealth interventions that improve clinical outcomes for children undergoing hematopoietic stem cell transplant (HSCT). The overall goal during the K99 is to gain advanced research training in mHealth interventions, adherence and conducting randomized controlled trials (RCTs) to develop and test a mHealth application for adherence of pediatric HSCT patients in the acute phase post-transplant. Using a behavioral economics approach, the goal of this new mHealth application will be to improve adherence and ultimately clinical outcomes as well as collect information regarding barriers. The research specific aim during the K99 phase is to develop an adherence mHealth application using a mixed methods approach and to evaluate the usability and acceptability of the mHealth application for pediatric HSCT patients in the acute outpatient phase post-transplant. To meet the K99 training objectives, a comprehensive training plan has been developed in concert with an internationally recognized interdisciplinary mentorship team of senior research experts. The overall goal during the R00 phase is to conduct a pilot RCT with 40 caregivers to assess acceptability, feasibility and potential efficacy of the newly developed mHealth app. The research specific aims during the R00 phase are to: 1) evaluate the acceptability of a newly developed mHealth app and the feasibility of enrolling and retaining 40 caregivers of children in the acute outpatient phase post-HSCT and 2) evaluate the potential efficacy of the mHealth app on adherence to immunosuppressants in children who have been discharged home during the acute phase post-HSCT. The results will directly support an R-01 application to conduct a multi-site RCT efficacy trial of the mHealth application on adherence and clinical outcomes in children during the acute phase post-HSCT.

PUBLIC HEALTH RELEVANCE:
In the United States, poor adherence accounts for up to 70% of all medication-related hospital admissions and an estimated 50-80% of pediatric patients are nonadherent. Behavioral economics (BE) suggests that small "nudges" or reminders can produce and sustain behavior change, thus with mobile health (mHealth) access nearly ubiquitous and an estimated 3.7 billion mHealth application downloads in 2017 alone,13 technology has great potential to improve adherence. Nurses could easily deliver these universal mHealth intervention approaches as a frontline approach to family education and care, addressing the critical need to improve adherence and clinical outcomes among children to ultimately prevent morbidity and mortality.

CRITIQUE 1
Candidate: 1 Career Development Plan/Career Goals /Plan to Provide Mentoring: 3 Research Plan: 2 Mentor(s), Co-Mentor(s), Consultant(s), Collaborator(s): 1 Environment and Institutional Commitment to the Candidate: 1 Overall Impact: Resubmission application from a post-doc fellow completing her first year at the Research Institute at Nationwide Children's Hospital (NCH). The application has multiple strengths. The candidate has substantial clinical grounding, strong foundational training, and clinical trial experience that result in excellent potential for development as an independent clinician-scientist. The mentorship team is well-matched to the candidate's research and development goals, and the career development plan includes a variety of valuable training activities. The proposed research is sufficiently justified and of appropriate scope for the candidate's stage of development. Design, procedures, and analysis plans for both the K99 usability study and R00 pilot RCT are largely sound, with minor weaknesses that should be easily addressed by the candidate prior to implementation. NCH and the Ohio State University provide numerous resources that will support the candidate in successfully achieving her research goals and transition to independence. Some weaknesses persist from the previous submission, specifically (1) minimal description of how new knowledge in behavioral theory and mHealth interventions obtained during the K99 phase will be incorporated into app development, and (2) lack of hands on experiential training for conduct of multi-site behavioral intervention trials before the independent R00 phase. Overall, the application proposes valuable career development for a 1 K99 NR019115-01A1 4 NRRC (78) SKEENS, M candidate with high potential and good likelihood to transition to independence despite identified weaknesses.

Strengths
• Good foundational training and relevant clinical trial experiences.
• 20 years of clinical experience in pediatric oncology.
• Excellent record of productivity for the candidate's career stage (20+ publications, 6 first authored).
• Has successfully competed for 3 foundation small grants that are supporting her current app development work.
• Referee letters indicate strong potential to become a productive independent clinician-scientist.
• Very good likelihood that the candidate can achieve an independent faculty position within the K99 period.
• Track record of collaborative trials with the Children's Oncology Group indicates the candidate has the ability to organize and manage the proposed clinical studies.

Strengths
• Builds on clinical trial and dissertation research examining adherence to immunosuppressants in pediatric HSCT patients.
• Addresses gaps in the candidate's training specific to behavioral health theories, mHealth interventions, and mixed methods research.
• Career development plan includes didactic and experiential learning activities and takes advantage of numerous professional development workshops and seminars available.
• K99 includes careful oversight with progress evaluations by mentors (quarterly) and a scholarship oversight committee (twice yearly) to gauge and support the candidate's transition to independence.
• Includes plans to search for a faculty position and identifies target institutions with large pediatric HSCT programs.

Weaknesses
• While the candidate makes a case that training is needed beyond her experience conducting cooperative group treatment trials, there is no plan for mentored experiential training in the implementation / conduct of "investigator-initiated multi-site behavioral clinical trials" before the independent R00 phase.
• While the addition of the NIH mHealth Institute in Year 1 is a substantial improvement to the career development plan, adherence conferences added to address noted weaknesses occur after the K99 phase. • Minimal description of the app development process (K99 aim 1). How will new knowledge of behavioral health theory and mHealth obtained during the K99 training be incorporated into the app?
• Identifies 2-3 manuscripts per year as a benchmark, but specific topics are not described.

Strengths
• Good scientific basis, sound design and analysis plans for K99 usability and R00 feasibility and acceptability pilot RCT.
• Development of the app prototype is already in progress with input from provider stakeholders.
• Identifies potential problems and reasonable alternative strategies.
• If the intervention is demonstrated as feasible and acceptable, the candidate will be wellpositioned from a subsequent multi-site R01 efficacy trial.

Weaknesses
• Limited innovation -content is limited to medication reminders and dosing log. Are there plans to further develop self-management support for caregivers in future iterations?
• The primary outcome of the pilot RCT appears to change throughout the application (feasibility & acceptability vs preliminary efficacy/adherence). Limitations in using a pilot study to estimate effect size should be noted (for example, see https://www.nccih.nih.gov/grants/pilot-studiescommon-uses-and-misuses).
• The power analysis section notes plan to use a different control condition in the subsequent R01 (enhanced usual care or attention control). It would be valuable to assess feasibility of the planned control group in the R00 pilot study.
• Excluding the control group from interviews at the end of the study misses an opportunity to assess study feasibility and capture information about other steps taken to facilitate adherence when caregivers learn they will not receive the medication reminder app.
• No analysis plans for comparison of Medication Level Variability Index (MLVI) to other adherence measures (exploratory aim).
• If the caregiver is the person using the app and administering the medication, what is the rationale for excluding children with developmental delay?

Strengths
• Primary mentor (Dr. Cynthia Gerhardt) is a pediatric psychologist with expertise in behavioral theories and mixed methods research in children with cancer. Has ongoing behavioral intervention research that could support the candidate's training. Good track record of funding & dissemination.
• Two distance co-mentors provide expertise related to adherence in pediatric oncology: a senior nurse scientist at UAB (Landier) and a pediatric psychologist at Cincinnati Children's Hospital (Pai).
• Three collaborators at OSU bring complementary expertise in medical informatics and mHealth patient engagement (Lin), biostatistics (Rausch) and behavioral economics (Stevens). • A pediatric psychology consultant at Mount Sinai School of Medicine (Dr. Shemesh) will provide guidance in use and interpretation of the adherence biomarker, Medication Level Variability Index.
• All members of the mentorship team have active research; several have extensive experience mentoring trainees and junior faculty.
• There is a clear plan for frequent individual and quarterly group meetings; letters of support commit to the planned mentorship and meetings.

Weaknesses
• None. • NCH indicates at least the minimum required 75% protected time, funding to support research expenses beyond the K99/R00 award, and consideration of a faculty position following completion of the K99 phase.

Strengths
• Feasible time frame presuming the candidate stays at Nationwide Children's Hospital or transitions to an institution with a similarly sized HSCT program.
• Adequate recruitment and retention plans.

Protections for Human Subjects: Acceptable Risks and Adequate Protections
• Risks to both the caregiver and child are addressed in human subjects' protection.

Inclusion Plans
• Sex/Gender: Distribution justified scientifically • Race/Ethnicity: Distribution justified scientifically • Inclusion/Exclusion Based on Age: Distribution not justified scientifically • The age range of 2-12 years is for the children only; does not include the caregivers.

Biohazards: Not Applicable (No Biohazards)
Resubmission: Responsive to weaknesses previously noted in the research strategy, plan for K99 to R00 transition, and the candidate's use of resources at NCH. However, limitations noted in the app design phase / development process and RCT training remain concerns.

Training in the Responsible Conduct of Research: Acceptable
Comments on Format (Required): • Includes online and face-to-face, lecture and discussion.
Comments on Subject Matter (Required): • Includes NIH recommended subject matter.
Comments on Faculty Participation (Required; not applicable for mid-and senior-career awards): • Mentors are involved in informal RCR training.
Comments on Frequency (Required): • Ongoing throughout training.

Resource Sharing Plans: Not Applicable (No Relevant Resources)
Budget and Period of Support: Recommend as Requested Overall Impact: This is a resubmission of a K99/R00 application from Dr. Skeens, a post-doctoral fellow at Wexner Research Institute, Nationwide Children's Hospital (RINCH). Dr. Skeens has 20 years of clinical experience in pediatric oncology/transplant units. Her proposed research builds on her dissertation and is on strategies to increase medication adherence for children undergoing hematopoietic stem cell transplant (HSCT). She is an excellent candidate, with a number of publications and recent foundation grant funding. Overall, it appears Dr. Skeens was responsive to the majority of the previous reviewer's comments. For her training plan, some areas that might need to be included are identified. For the proposed research, there are still some questions, for example, about the proposed app and data collected. She has a large mentoring team, with needed skills, although as noted before a team of 7 seems large, and the lack of onsite nurse mentor is noted. RINCH appears to have the resources needed for Dr. Skeens' success. • Clinical experience as an RN for 4 years and then as a NP for 12 years in the bone marrow transplant (BMT) unit and 5 years on the Embryonal Tumor Team at Nationwide Children's Hospital in Columbus OH.
• Research focus area is caring for children with cancer and blood disorders and their families. Dissertation was on adherence to immunosuppressants in pediatric stem cell transplant patients. Proposed study is on strategies to increase medication adherence for children undergoing hematopoietic stem cell transplant (HSCT).
• Member of a number of professional organizations such as Children's Oncology Group, Bone Marrow foundation, Association of Pediatric Hematology Oncology Nurses.
• Honors include Nursing Leadership Award for Children's Oncology Group.
• 16 publications from 2012-present, one dissertation paper published, second under revision.
• Currently PI on a Daisy Foundation grant and Oncology Nurses Foundation.
• Dr. Skeens provided a letter listing additional publications since grant submission, one from 2019 and 4 since March 2020.
• Letters of support for Dr. Skeens are extremely strong, including one from the Chief Scientific Officer at RINCH.

Weaknesses
• Minor confusion over current funding. A third grant is mentioned and on the biosketch it appears to be an America Nurses Credentialing Center grant, though no dates listed. Later there is a statement about an OSU CTSS grant, but not listed on the biosketch.
• Has added training requested by previous reviewers.

Weaknesses
• Would expect inclusion of more conferences to attend across all 5 years.
• Since the app is developed on behavioral economics theory thought there might be training focused on behavioral economics and adherence.
• In order to develop skills in app development, may need more than just workshops. For example, may want to take a course on Human Factors which are often offered in engineering.
• Not clear what training in RCTs will occur.
• NIH Methodologies Boot Camp, listed for mixed methods, is not always about mixed methods.
(This year it's on AI). Might explore a course at OSU CON on mixed methods.

Strengths
• K99 is to develop and explore usability and acceptability of an app targeting adherence to immunosuppressant therapy in children post HSCT.
• R00 is also to test acceptability of the app and to evaluate the efficacy of the app.
• Provides an overview that highlights lack of research in adherence in this group of children; notes 52-73% adherence rates.

Weaknesses
• In background, it states that with data obtained from the app, families identified at greater risk for non-adherence could be referred. It isn't clear what the data is that will be used from the app to identify non-adherence. There may be an opportunity to develop a predictive model, but the app appears to only remind the caregiver. Is it the barrier component that might be predictive? Would be helpful to describe how barrier data is collected and coded. It doesn't appear that the app will have med adherence measures as part of it or MLVI; these appear to be separate.
• The app will include reminders, track adherence (not clear if this means parents document that they have given the medication), and capture barriers. Innovation highlights measure of adherence, but these appear to be separate measures and not part of the app.
• App is in development, would be helpful to know the role of Dr. Skeens in this process beyond providing content.
• For the Medication Adherence Measure, it would be helpful to know the number of items, psychometrics, and how long this takes to complete. It is noted in the potential problems that weekly assessments may be burdensome.
• In the R00 phase, assume the table of study measures are the same for both groups, except for the System Usability Scale and the Caregiver Satisfaction which seem to be only for the app group, although not clear.
• Under potential problems, there is a reference to recruitment of non-adherent families being difficult. It doesn't appear there was a plan to enroll nonadherent families, just families in general.

Strengths
• Dr. Skeens has an interdisciplinary team with a range of expertise. • Scholarship Oversight Committee will provide direction to the mentoring team. Includes mentors, external nurse oncology researcher, a local MD (Cripe) in pediatric oncology and another psychologist.

Weaknesses
• As noted, before, a mentoring team of 7 seems excessive. For example, both Drs. Gerhardt and Pai seem to have similar areas of expertise for mentoring Dr. Skeens.
• Not clear what the difference is among the groups: Collaborators vs consultant; mentoring team vs oversight committee.
• As noted, only one nurse scientist who is not at RINCH seems to be a concern for career development during the K99 component, although Dr. Landier is a leading expert in pediatric adherence research and nursing.
• Only meeting monthly with most of the mentoring team. May need more time.

Strengths
• Research Institute, Nationwide Children's Hospital (RINCH) appears to have the resources needed for his project.
• Per mentor Gerhardt, Dr. Skeens will have at least 75% release time (actually 80%) to devote to the K99 and the R00, although R00 component in theory may not occur at RINCH.

Weaknesses
• Not clear how many children have a HSCT each year at NCH. A previous reviewer noted 50 per year. If this is accurate, although number in each phase are decreased, may still be a concern. However, R00 may not occur at NCH.

Strengths
• A table provides the overview of the timeline.

Weaknesses
• Per note of previous reviewer, there may still be concerns about enough potential subjects for the two studies.

Protections for Human Subjects: Acceptable Risks and Adequate Protections
• Caregivers (primarily parents) are subjects in both K99 and R00. However, data will be obtained about children, so they also appear to be subjects.

Data and Safety Monitoring Plan (Applicable for Clinical Trials Only): Acceptable
• The R00 is a clinical trial. Dr. Skeens outlines a DSMP and will defer to the IRB on the potential need for a DSMB.

Training in the Responsible Conduct of Research: Acceptable
Comments on Format (Required): • Online, small groups, in-person discussions.

Comments on Subject Matter (Required):
• Includes NIH required topics.
Comments on Faculty Participation (Required; not applicable for mid-and senior-career awards): • Members of mentoring team are included.

Comments on Duration (Required):
• At least 8 hours per week.

Comments on Frequency (Required):
• Weekly throughout. Overall Impact: This is a K99/R00 resubmission by Dr. Skeens. The PI has covered the majority of the reviewers' recommendations. While this is a very ambitious proposal that will require rigor in maintaining the research timeline, the PI has proposed a convincing argument and support of this proposal. This is a very strong proposal from the well-qualified PI with strong clinical background in pediatric oncology. The team is highly skilled in their respective areas that will aptly support the PI in 1 K99 NR019115-01A1 12 NRRC (78) SKEENS, M the needed training activities and research plan. Overall, it was a pleasure to read Dr. Skeens' resubmission.

Strengths
• Post-doctoral fellowship at the Abigail Wexner Research Institute at Nationwide Children's Hospital in Columbus, OH.
• Awarded -Vanderbilt Centennial Fellow and 2 doctoral scholarships from Oncology Nursing Society and American Cancer Society.
• 20 years clinical experience in pediatric oncology and HSCT.
• While in doctoral studies she published 9 manuscripts; 3 as first author.
• She is site PI for a multi-site study that is examining at the effectiveness and feasibility of 2 parent education discharge strategies for parents of children newly diagnosed with CA and is co-investigator on other institutional trials examining supportive care for pediatrics with HSCT and late effects in pediatric oncology.
• PhD in nursing science, clinical research track from Vanderbilt University.
• Independent study in qualitative research and investigated an adherence biomarker (MLV1) and association with post-HSCT.
• She participated in the Patient-Centered Pediatric Research Program for clinical research fellows at NCH.
• She has published 3 papers since last reviewed; given 5 presentations; and has 5 papers under review.
• She secured new funding from Oncology Nurses Foundation to develop an adherence mobile health app for pediatric stem cell transplant patients using focus groups of parents and health care providers; and in addition, two other sources of funding.
• Has established collaboration with Dr. Lin in the development of an mHealth app; attended NIH on MHealth Institute and 2 adherence conferences to enhance her learning objective training in app design; she has also been working with Dr. Gerhardt since last summer on the proposed app.
• To complete the R00 research she is planning on applying to: CHLA, Texas, Seattle Children's, and Cincinnati Children's.
• She aims to build a program of research to develop and evaluate interventions that improve adherence and ultimately clinical outcome.
• Since last summer, the PI has been working with Dr. Gerhardt.

Strengths
• The mentored K99 phase training has been designed to provide the PI with training in several areas that appropriate and well-justified for the candidate's current stage of scientific and 1 K99 NR019115-01A1 13 NRRC (78) SKEENS, M professional development and proposed research career goals. The stated training gaps are in health behavior theories for medication adherence; mixed method approaches and the assessment of adherence; the use of innovative eHealth/mHealth technologies in pediatric adherence; and advanced training in design, implementation and analysis of biobehavioral RCTs.
• The plan is to meet with Drs. Gerhardt, Landier and Pai will evaluate the progress on a quarterly basis which seems worthwhile and a goal to ensure the PI is progressing adequately and appropriate for guiding the applicant towards a successful transition to the independent phase of the award.
• Table 1 outlining the career development has been improved and clarifies any previous questions; very succinct.
• This is a very ambitious career development proposed which if executed correctly and rigorously will potentially contribute substantially to the scientific and professional development of the PI and facilitate her successful transition to independence.
• The timeline planned for transition to the independent phase of the award appropriate for the candidate's current stage of scientific and professional development is appropriate for the K99 phase of the award.
• PI attended to career training recommendations by the reviewers.

Weaknesses
• Training in RCTs was not addressed.
• App development was partially addressed in the resubmission but not adequately to understand what she did to develop the app; how was she involved; what parts did she develop and more of her training was needed in this area.

Strengths
• The proposed K99 phase research is highly significant and scientifically sound with a novel population of study.
• Adequate prior research that will serve as key support for the proposed research; the PI also added further documentation in this version of the proposal.
• The scientific and technical merits of her previous work leading to the K99 research is appropriate for developing the research skills outlined in the career development plan and appropriate for developing a successful R00 research program.
• The R00 phase research is clear, significant, scientifically sound and a logical extension of the K99 phase research.
• Fidelity measures were stated appropriately in the R00 phase research -the PI will monitor the ensure intervention fidelity; methodological procedures include fidelity processes as well.
• Study approach was also improved with clearly outlining the study sample, measures and procedures.
• Clinical outcome measures were addressed in R00 phase research.
• Potential problems and alternative strategies are adequately addressed. • Seems like the app is being developed now. Has the PI been involved in developing the app?

Weaknesses
• Why is it that another type of reminder device is required for parents? Is there something more sophisticated that would be more useful? Is this device truly any more novel than another reminder device?

Strengths
• Primary mentor, Dr. Cynthia Gerhardt, is a pediatric psychologist and has 20 years of conducting research; she is on 10 grants and 3 as PI and 1 MPI.
• The candidate has organized a team of co-mentors and collaborators: Landier is an expert in adherence in pediatric leukemia and conducts longitudinal, multi-site trials as well as qualitative and mixed methods; Dr. Pai is an expert in pediatric HSCT adherence and psychosocial adjustment as well as intervention development and the conduct of behavioral RCTs. The PIs collaborators include Dr. Lin will provide training on mHealth technologies; Stevens is an expert in the design and analysis of clinical trials; Dr. Shemesh is a consultant who provide consultation on the MLVI methodology and the development of multi-site RCTs for adherence.
• For each mentor, collaborator and consultant, meeting time have been provided and seem reasonable.
• Has identified members on the Scholarship Oversight Committee. Letter of support from Dr. Cripe.

Weaknesses
• While the team is quite large; how does the PI intend to manage such a large mentoring team? Is everyone necessary?

Strengths
• Strong environment and an appropriate fit for the PI.
• PI enhanced this section of the proposal and addressed reviewers' concerns.
• Strong institutional commitment and letters of support from mentors, collaborators, consultant and from members of the Scientific Advisory Committee.

Weaknesses
• None. Resubmission: PI has addressed major concerns from the reviewers; perhaps, the only item that seems somewhat concerning may be the timeline for recruitment in R00, however, there is confidence since the PI with mentors will entertain necessary alternatives so that the PI does not get delayed.

Training in the Responsible Conduct of Research: Acceptable
Comments on Format (Required): • In person, online, lecture and mentorship.
Comments on Subject Matter (Required): • NIH topics.
Comments on Faculty Participation (Required; not applicable for mid-and senior-career awards): • Mentors will participate in informational RCR discussions.
Comments on Frequency (Required): • CITI once during award period; RCR certification annually; didactic sessions weekly. Footnotes for 1 K99 NR019115-01A1; PI Name: Skeens, Micah 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. Notice of NIH Policy to All Applicants: Meeting rosters are provided for information purposes only. Applicant investigators and institutional officials must not communicate directly with study section members about an application before or after the review. Failure to observe this policy will create a serious breach of integrity in the peer review process, and may lead to actions outlined in NOT-OD-14-073 at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-14-073.html and NOT-OD-15-106 at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-106.html, including removal of the application from immediate review.