Bryce B. Reeve, Ph.D. - US grants

DESCRIPTION (provided by applicant): The overall objectives of this project are to validate the PROM IS pediatric item banks in 4 pediatric chronic illnesses, and to link pediatric and adult item banks. We developed 9 pediatric item banks during the first PROMIS grant cycle and have performed cross-sectional testing in children with several chronic illnesses. The proposed work is the natural next step toward integration of PROMIS scales into clinical research. We propose longitudinal studies in children with asthma, cancer, nephrotic syndrome, and sickle cell disease. Each study follows children through a clinical transition known to affect health-related quality of life, and each study will examine the responsiveness of the PROMIS instruments and estimate the minimum important difference (MID) for children. As part of these studies, we have proposed to test a new method for establishing MID and to compare that method with traditional distributional and anchor-based methods. The second overall objective is to link PROMIS pediatric item banks with PROMIS adult item banks. We designed most of the pediatric banks to measure the same underlying trait as their counterpart adult banks (e.g., fatigue), but used the concepts and language of children. We will administer pediatric and adult short forms to adolescents with chronic illnesses with a cross-sectional data collection. For this objective, we will use factor analysis and structural equation modeling to establish the empirical relationships between the pediatric and adult item banks and domains, and, to the extent supported by those relationships, use item response theory to link the pediatric and adult item banks. This study will enable researchers to have comparable scores between children and adults participating in the same study and enable longitudinal studies that follow children into adulthood. PUBLIC HEALTH RELEVANCE: Performing longitudinal validity studies in 4 chronic illnesses will prepare PROMIS for use in future clinical research. By linking the pediatric and adult item banks, we will accelerate research on diseases that affect both children and adults and enable researchers to study trajectory of health-related quality of life from childhood to adulthood.

DESCRIPTION (provided by applicant): Using innovative qualitative and quantitative methodologies, the Patient-Reported Outcomes Measurement Information System® (PROMIS®) initiative has developed high quality and clinically relevant patient-reported outcomes measures to be used to evaluate the impact of both disease and interventions on patients' lives. This study will add new knowledge of the reliability, validity, and responsiveness of PROMIS measures through an extensive psychometric evaluation within a population-based cohort of men with prostate cancer participating in a prospective comparative effectiveness research (CER) study. This includes a test of measurement equivalence across race, education, and age groups, as well as mode of administration of the PROMIS measures: via phone interviewer versus computer self-administered questionnaire. This evaluation will also include recently developed PROMIS domains including Sexual Function, Psychosocial Illness Impact, Sleep Related Impairment, and Gastro-Intestinal Symptoms - which are relevant for prostate cancer patients. In response to an Institute of Medicine report that indicated CER of prostate cancer treatments as a top 100 priority, the University of North Carolina was awarded a grant from the Agency for Healthcare Research Quality to conduct a prospective study. The North Carolina Prostate cancer Comparative Effectiveness & Survivorship Study is a population-based cohort of 1,400 prostate cancer patients with diverse race, education and age levels. Participants provide patient-reported data through phone interviews on their health-related quality of life (HRQOL) pretreatment, and at 3, 12, and 24 months post-treatment. These time points are critical as multiple studies have documented that many symptoms (i.e., sex, urinary, and bowel dysfunction; also fatigue, depression, anxiety) increase significantly from pretreatment to post-treatment, and then partially recover by 12 and 24 months. This trend provides an excellent opportunity to evaluate the responsiveness and to estimate minimally important differences of the PROMIS measures. The specific aims include: Aim 1: Evaluate the measurement properties of the PROMIS measures using item response theory models and other psychometric methods. Aim 2: Evaluate the ability of PROMIS measures to detect differences in health-related quality of life across age groups, race groups, treatment types, and comorbidity status. Aim 3: Evaluate the responsiveness of the PROMIS measures relative to legacy measures to detect clinically meaningful changes from baseline (pretreatment) through two years post-treatment. Aim 4: Test for measurement equivalence for the PROMIS measures for key prostate cancer subgroups including race, education, and age. Aim 5: Evaluate measurement equivalence across assessment modes of phone interview and computer self-administered survey. The multi-disciplinary team has extensive experience in psychometrics and prostate cancer care and research. Study results will significantly inform both the use of PROMIS in prostate cancer and provide key validation data on the PROMIS measures. PUBLIC HEALTH STATEMENT: Using innovative qualitative and quantitative methodologies, the NIH Patient-Reported Outcomes Measurement Information System(r) (PROMIS(r)) initiative has developed high quality and clinically relevant patient-reported measures to be used to evaluate the impact of both disease and interventions on patients' lives. This study will add new knowledge of the reliability, validity, and responsiveness of PROMIS measures through an extensive psychometric evaluation within a population-based cohort of men with prostate cancer participating in a prospective comparative effectiveness research (CER) study. Study results will provide key validation data on the PROMIS measures and will inform the adoption of PROMIS measures in prostate cancer CER and outcomes research.

DESCRIPTION (provided by applicant): The objective of this competing renewal application for the Cancer Care Quality Training Program (CCQTP) is to train additional clinician and non-clinician scientists to work collaboratively in multidisciplinary research teams to improve cancer care quality. The need for an expanded scientific workforce engaged in cancer care quality research is evident. Poor quality cancer care in the forms of overuse, underuse, and misuse exists for all major forms of cancer and occurs across the cancer care continuum. Moreover, significant variations in cancer care quality have been found across practice sites, geographic regions, and patient populations. Given the complexity of cancer itself, and the multidisciplinary nature of cancer care, efforts to improve cancer care quality within the constraints of a single discipline or specialty are likely to produce partial solutions or limited effects. In the past fie years, opportunities for improving cancer care quality through multidisciplinary research have substantially increased. To respond to these opportunities, we must increase the scientific workforce engaged in cancer care quality research and train this workforce to function effectively in multidisciplinary research teams. Over the next five years, the CCQTP will train 10 clinician and non-clinician scientists who have not only the passion to improve cancer care quality, but also the knowledge, skills, and experience to do so in multidisciplinary research teams. To accomplish this goal, the CCQTP will recruit outstanding pre-doctoral and post-doctoral candidates from diverse disciplines and provide them with a specialized curriculum and hands-on research experience that leverages the faculty and research resources that are uniquely available at UNC-Chapel Hill. In its first four years of operation, the CCQTP has received far more applications than available positions. Four post-doctoral fellows and six pre-doctoral fellows have participated in the specialized curriculum and engaged in mentored research projects in cancer care quality. Consistent with the program's multidisciplinary focus, fellows have come from a variety of disciplines and specialties, including social work, health behavior, decision science, health economics, nursing, sociology/organization studies, and health services research. Of the four post-doctoral fellows, two have completed their training and are now employed in academic settings. Of the six pre-doctoral fellows, one has completed her training with a doctoral degree in Year 2 and two others will complete their training with doctoral degrees in late Year 4. One of these two will move into a post-doctoral fellowship, while the other will be employed in an industry setting. CCQTP fellows have been productive scholars. In Years 1-4, fellows and their mentors collaborated on 28 publications, 14 of which the program participant served as first author. In Years 6-10, the CCQTP will add a multidisciplinary seminar in comparative effectiveness research to the specialized curriculum and connect fellows with newly developed data resources, training opportunities, and intramural (pilot) funding programs available at UNC-Chapel Hill to support cancer care quality research.

DESCRIPTION: Over 60% of children diagnosed with cancer will participate in a clinical trial; the great majority of these children will experience multiple treatment-related adverse events that require intense supportive care. The Federal Government mandates for safety monitoring that all trials report adverse events (AEs); defined by the National Cancer Institute (NCI) as any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medical treatment. The standard practice in oncology trials is for the clinician to grade all AEs using the standard NCI lexicon of the Common Terminology Criteria for Adverse Events (CTCAE), but multiple studies in adult cancer populations found that clinicians underreport the number and severity of symptoms compared to what patients report. More than a third of the 790 AEs on the CTCAE have some subjective aspect to its identification, requiring patient-report to assure accuracy of the AE documentation. Given the known toxicity of cancer treatments on children's lives, the child's perspectives in grading subjective AEs must be integrated into AE reporting. Without including the child's AE reports, the risk/benefit ratio of cancer treatments wil not be accurately established. In a small number of studies comparing child, parent and clinician symptom ratings, clinicians were poor and caregivers only slightly better at recognizing the symptoms the children were experiencing. This new study with 6 Children's Oncology Group (COG) sites extends our team's current research with pediatric clinicians that identified 62 subjective AEs from the CTCAE that 7- to 20- year olds in cancer treatment could be expected to validly rate, and which could serve as the basis for designing a pediatric patient-report CTCAE (PRO-CTCAE) measure. This 5-year study includes 3 aims. In Aim 1, we will design both English and Spanish versions of a pediatric and caregiver-proxy version of the PRO- CTCAE by translating the 62 subjective AEs into child-friendly terms and create companion interview questions that are comprehensible to children and their caregiver-proxies. In Aim 2, we will use cognitive interviewing methods to evaluate how well children and caregiver-proxies understand and respond to the PRO-CTCAE questions. Strata will represent different cancer types and different age ranges. Aim 3 is a longitudinal study to evaluate the reliability, validity and responsiveness of the PRO-CTCAE measures with newly diagnosed children in cancer treatment, stratified by age and cancer types. We will also assess concordance of AE ratings by caregiver-proxies, clinicians and children over time and changing clinical conditions. This study constitutes a first step towards our long term research goal of documenting the differences in care management and outcomes when the PRO-CTCAE is incorporated into cancer clinical trials.

PROJECT 1 SUMMARY Clinical measures of disease used in research and healthcare delivery settings do not fully capture the effects of chronic diseases and their treatment burden on children and adolescents. If identified, such factors could be directly addressed through focused comprehensive care of the child and her/his family. Advancing the availability and usefulness of patient reported assessment tools to inform research and clinical care aligns with the federal priority for improving treatment through rigorous comparative effectiveness research and is integral to precision medicine, an enterprise predicated on robust actionable phenotypic patient descriptions. To more fully capture youth's experiences and perspectives, the Patient-Reported Outcomes Measurement Information System® (PROMIS®) Pediatric measures were designed and have undergone extensive psychometric evaluation; however, these instruments continue to be underutilized by the research and clinical communities. The proposed project involves longitudinal clinical validation of PROMIS Pediatric measures undertaken with a large diverse sample of 1500 children/adolescents with rheumatic disease, cancer or inflammatory bowel disease and their parent/caregiver proxies. Participants are engaged through large, extant, multisite clinical and public health research platforms. Participants will provide time series reports using PROMIS measures for validation research. The first objective of this research is to evaluate the responsiveness of the PROMIS Pediatric measures to detect change in health related quality of life (HRQOL) over time and its association with clinical anchors and patient-reported symptom toxicities. Through time series analysis of prospectively engaged pediatric cohorts, we will ascertain whether PROMIS Pediatric measures of psychological stress, depression, anxiety, mobility, fatigue, and pain interference are responsive to prospectively observed changes in treatment and disease activity. The second objective is to evaluate whether PROMIS Pediatric measures of depression and anxiety are associated with subsequent measures of health status including physical and social health, disease-specific outcomes and substance use, after adjusting for relevant measures of baseline health status using a retrospective cohort study of prospectively collected data. The primary exposures of interest will be measured by PROMIS Pediatric depression and anxiety domains. Outcomes will be assessed at one or more subsequent time points to ascertain whether depression and anxiety increase the risk of subsequent disease relapse and other negative health outcomes. Finally, the third objective of this study is to determine the association between steps taken (pedometer data) and PROMIS Pediatric measures of physical activity and function-mobility with exploratory analyses of associations among daily steps, pain interference, fatigue, and depression. Findings from the research project will provide a rich and rigorously evaluated set of pediatric measures for widespread use in clinical research and care to improve efforts to address the full needs of children and adolescents with serious chronic medical conditions.

? DESCRIPTION (provided by applicant): PROMIS(r) measures have been developed to provide a systematic, domain-based approach to the assessment of patient-reported outcomes (PROs) across the lifespan and disease groups; however, these instruments continue to be underutilized by the research community, including pediatric disease investigators. This PEPR proposal leverages three existing infrastructures of the Childhood Arthritis and Rheumatology Research Alliance (CARRA), Cancer Pediatric PRO Research Network, and the Crohn's and Colitis Foundation of America Partners Kids and Teens Internet Cohort to further study legacy and newly developed PROMIS measures with the goal to enhance and promote their use by pediatric researchers and clinicians. There continues to be compelling need for PRO measures that parallel disease activity, identify high-risk patients, and reflect health outcomes important o patients and families. In addition, more robust understanding of relationships between patient factors and disease burden will promote successful care approaches and improved physical and mental health and social well-being. Two research projects are proposed for our multicenter longitudinal study of approximately 1500 children with rheumatic disease, cancer, and inflammatory bowel disease. The first research project addressed the need for clinical validation of PROMIS Pediatric measures including the following 3 aims: Aim 1. Evaluate the responsiveness of the PROMIS Pediatric measures to measure change in health over time and its association with clinical anchors and patient-reported symptom toxicities. Aim 2. Evaluate whether PROMIS measures of depression and anxiety are associated with subsequent measures of health status including physical and social functioning, substance use, and disease specific outcomes; Aim 3. Determine the association between steps taken (pedometer data) and PROMIS Pediatric measures in order to explore the use of pedometry data to augment PROs in research and clinical care. The second research project addresses the need to enhance the meaningfulness and usefulness of PROMIS measures and includes the following 3 aims: Aim 4. Identify unobserved subgroups of children with rheumatic disease, cancer, or IBD with respect to physical and mental health using latent profile analysis and latent transition analysis, and examine demographic and clinical characteristics associated with the subgroup classification and transition over time; Aim 5. Estimate a clinically minimally important difference (MID) in change in PROMIS Pediatric scores from the child's perspective and compare with the previously generated estimate of an MID of 3 points from qualitative scale-judgment methods; and Aim 6. Identify clinical cut scores along the PROMIS Pediatric metric associated with varying levels of symptom severity and functional status using standard setting methods with adolescents, parents, and clinicians. The Center's Data Management and Administrative Cores include experienced clinicians, behavioral scientists, statisticians, psychometricians, and information technology experts to facilitate, coordinate, and synergize these research studies.

DESCRIPTION: Over 60% of children diagnosed with cancer will participate in a clinical trial; the great majority of these children will experience multiple treatment-related adverse events that require intense supportive care. The Federal Government mandates for safety monitoring that all trials report adverse events (AEs); defined by the National Cancer Institute (NCI) as any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medical treatment. The standard practice in oncology trials is for the clinician to grade all AEs using the standard NCI lexicon of the Common Terminology Criteria for Adverse Events (CTCAE), but multiple studies in adult cancer populations found that clinicians underreport the number and severity of symptoms compared to what patients report. More than a third of the 790 AEs on the CTCAE have some subjective aspect to its identification, requiring patient-report to assure accuracy of the AE documentation. Given the known toxicity of cancer treatments on children's lives, the child's perspectives in grading subjective AEs must be integrated into AE reporting. Without including the child's AE reports, the risk/benefit ratio of cancer treatments wil not be accurately established. In a small number of studies comparing child, parent and clinician symptom ratings, clinicians were poor and caregivers only slightly better at recognizing the symptoms the children were experiencing. This new study with 6 Children's Oncology Group (COG) sites extends our team's current research with pediatric clinicians that identified 62 subjective AEs from the CTCAE that 7- to 20- year olds in cancer treatment could be expected to validly rate, and which could serve as the basis for designing a pediatric patient-report CTCAE (PRO-CTCAE) measure. This 5-year study includes 3 aims. In Aim 1, we will design both English and Spanish versions of a pediatric and caregiver-proxy version of the PRO- CTCAE by translating the 62 subjective AEs into child-friendly terms and create companion interview questions that are comprehensible to children and their caregiver-proxies. In Aim 2, we will use cognitive interviewing methods to evaluate how well children and caregiver-proxies understand and respond to the PRO-CTCAE questions. Strata will represent different cancer types and different age ranges. Aim 3 is a longitudinal study to evaluate the reliability, validity and responsiveness of the PRO-CTCAE measures with newly diagnosed children in cancer treatment, stratified by age and cancer types. We will also assess concordance of AE ratings by caregiver-proxies, clinicians and children over time and changing clinical conditions. This study constitutes a first step towards our long term research goal of documenting the differences in care management and outcomes when the PRO-CTCAE is incorporated into cancer clinical trials.

ABSTRACT Opioid misuse is common among adolescents and has been associated with devastating morbidity and mortality. Clinical practices of opioid prescribing in the acute hospital setting may be an important source of opioid exposure and contributor to longer-term opioid use disorder in children, particularly when coupled with the physiologic vulnerability of the pediatric brain. Investment in the development of opioid-sparing drugs during management of acute pain in children is an important step toward combatting the opioid crisis. A current barrier to the development of opioid-sparing drugs in children is the lack of standardized, high-quality clinical outcome assessments (COAs) and endpoints for use in clinical trials. To address this need, Dr. Kanecia Zimmerman (Pediatric Critical Care Physician) and Dr. Bryce Reeve (Psychometrician) will leverage existing infrastructure of the NIH-funded Pediatric Trials Network (PTN) and the Duke Center for Health Measurement (CHM). This partnership capitalizes on strong expertise in pediatric drug development, design and successful execution of pediatric clinical trials, evaluation of analgesic safety and efficacy in children, and identification and validation of high-quality COAs. Drs. Zimmerman and Reeve (co-PIs) will lead a team of uniquely-qualified investigators in the identification of a core set of high quality COAs and endpoints for use in the evaluation of opioid-sparing drugs in children, ages 2 to 18 years. Specifically, the research team will accomplish the following goals: 1) conduct formative research to identify important outcomes for pediatric opioid-sparing drug trials that matter most to patients, caregivers, and clinicians; 2) identify existing COAs for each outcome and determine each COA?s strengths and limitations for use in pediatric trials; and 3) gather further qualitative and quantitative evidence for the psychometric properties and fit-for-purpose of clinician-, observer-, and patient- reported COAs. The recommended core set of COAs will be administered together in a longitudinal study among a diverse sample of children with acute pain from a range of conditions to evaluate the COAs performance. With oversight and input from a diverse and well-rounded external technical advisory committee, completion of these goals will help ease the burden of investment in pediatric drug development and facilitate patient-centered opioid-sparing trials during the critical period of childhood. All recommended set of COAs, endpoints, and supporting documents will be made available to the public through the PTN and CHM websites and distributed to pediatric research networks and investigators.

Abstract Pain is the most common symptom leading patients to consult a physician in the United States, and its negative effects on quality of life can be substantial. Chronic pain is associated with both direct (e.g., health care) and indirect costs (e.g., lost wages, disability days) that have been estimated to range from $560-635 billion annually. Although considerable progress has been made in understanding the pathophysiologic mechanisms of pain, the most widely prescribed medications for acute and chronic pain ? non-steroidal anti-inflammatory drugs (NSAIDs) and opioid analgesics ? have major drawbacks, including modest efficacy and significant risks that can limit long-term use. Consequently, there is a compelling public health need for the development of pain treatments with improved efficacy and safety. Millions of Americans also suffer from addiction or receive anesthesia for surgical procedures, and although there are efficacious treatments available in each of these additional therapeutic areas, many existing interventions have only modest efficacy or have incompletely characterized safety risks. The primary objective of the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership is to identify, prioritize, sponsor, coordinate, and promote innovative activities that will expedite the discovery and development of improved analgesic, anesthetic, and addiction treatments for the benefit of the public health. The major activities of the ACTTION partnership include conducting systematic reviews, consensus meetings, and methodologically-focused research studies as well as developing and qualifying novel clinical outcome assessments and biomarkers, with the aim of increasing the assay sensitivity and informativeness of clinical trials. The knowledge gained from these efforts will accelerate the development of novel medications and other treatments for pain, anesthesia, and addiction that are more effective and safer than existing treatments.