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David Cella,1 Ron D Hays2 1Department of Medical Social Sciences, Northwestern University, Chicago, IL, USA; 2Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USACorrespondence: David Cella, Email d-cella@northwestern.eduAbstract: We briefly review the history of measuring perceptions of health and quality of life, followed by an examination of conceptual issues related to terminology that have led to potentially conflicting ontologies. Then, we discuss challenges posed by the lack of consensus on common meaning and the proliferation of measures. Next, we suggest a solution grounded in an ontology adopted by the National Institutes of Health (NIH) funded Patient-Reported Outcomes Measurement Information System (PROMIS) project. We conclude by discussing issues associated with mapping the PROMIS domain framework onto other familiar ontologies and recommend a way forward for PROMIS to provide a sustainable ontological structure to enable coherent common measurement.Keywords: patient-reported outcomes, quality of life, health-related quality of life, ontology, PROMIS®, patient reported outcomes measurement information system

John Devin Peipert,1,* Sherif M Badawy,2,* Sharon H Baik,1 Laura B Oswald,1 Fabio Efficace,3 Sofia F Garcia,1 Daniel K Mroczek,1 Michael Wolf,4 Karen Kaiser ,1 Betina Yanez,1 David Cella1 1Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; 2Division of Hematology, Oncology and Stem Cell Transplant, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA; 3Italian Group for Adult Hematologic Disease (GIMEMA), Health Outcomes Research Unit, Rome, Italy; 4Department of Medicine, Division of General Internal Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA*These authors contributed equally to this workCorrespondence: John Devin Peipert Email john.peipert@northwestern.eduAbstract: Poor medication adherence is associated with reduced drug effectiveness, poor health-related quality of life, increased morbidity and mortality, and increased healthcare utilization and cost. Including the patient’s voice is essential in understanding barriers to adherence. Useful patient-reported adherence measures are brief, inexpensive, non-invasive; can indicate barriers to adherence; and can be incorporated in electronic health records. The NIH Patient-Reported Outcomes Measurement Information System (PROMIS®) includes high-quality, freely available patient-reported measures covering many important constructs in patient-centered research but does not include a medication adherence measure. To fill this gap, we developed the PROMIS Medication Adherence Scale (PMAS) using the rigorous PROMIS instrument development guidelines. To develop the PMAS, we first conducted a review of the reviews, which enabled us to identify content areas relevant to medication adherence behavior. Then, we conducted qualitative research to elicit patients’ views of and experiences with medication adherence. This process identified the following important content areas to guide item writing: extent medication is taken, knowledge of medication regimen, beliefs about medication, remembering to take medication, skipping due to side effects, skipping due to feeling better, and cost of medications. Based on the results of these activities, we wrote items and aimed to retain 1– 2 items per content area. The final item set included 9 total adherence items, which were then refined through intensive comprehension and translatability review, as well as cognitive interviews. Future steps include testing the PMAS’s validity.Keywords: medication adherence, patient-reported outcome, PROMIS

Karen Kaiser,1 Susan E Yount,1 Christa E Martens,1 Kimberly A Webster,1 Sara Shaunfield,1 Amy Sparling,1 John Devin Peipert,1 David Cella,1 Scott T Rottinghaus,2 Bonnie MK Donato,2 Richard Wells,3 Ioannis Tomazos2 1Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; 2Alexion Pharmaceuticals Inc, Boston, MA, USA; 3Sunnybrook Health Sciences Centre, Toronto, ON, CanadaCorrespondence: Karen KaiserDepartment of Medical Social Sciences, Northwestern University Feinberg School of Medicine, 625 N. Michigan Ave. Suite 2700, Chicago, IL 60611, USATel +1 312-503-3521Fax +1 312-503-4800Email k-kaiser@northwestern.eduPurpose: To develop a patient preference questionnaire (PPQ) assessing eculizumab and ravulizumab treatment for paroxysmal nocturnal hemoglobinuria (PNH).Patients and Methods: The development of the PNH-PPQ© was consistent with Food and Drug Administration guidelines for patient-reported outcome measure development, and included 1) a targeted literature review; 2) PNH expert clinician input on treatment preferences; 3) review of existing qualitative data on the PNH treatment and disease experience; 4) concept elicitation interviews with 8 PNH patients who received eculizumab and/or ravulizumab; 5) translatability review; and 6) cognitive debriefing with 5 patients. Interview participants were recruited through a United Kingdom PNH patient advocacy group and a Canadian clinical site involved in clinical trial ALXN1210-PNH-302.Results: Six themes were identified as most relevant to the PNH treatment experience from the concept elicitation interviews: disease symptoms (n=8/8); treatment frequency (n=7/8); quality of life impact of treatment/disease (n=7/8); treatment burden (n=7/8); treatment efficacy (n=5/8); and treatment side effects (n=5/8). An initial list of 88 preference questions was reduced to 11 highly relevant and non-redundant questions reflecting the 6 themes. Cognitive interview participants unanimously agreed that the PNH-PPQ instructions were clear; response options were understandable, easy to use, and provided enough choices; and the questions captured the factors that inform treatment preferences.Discussion: When new drugs have similar efficacy to existing medications, documenting patient preferences is important for confirming patient benefit from the new medication. Understanding what matters most to patients is essential for delivering patient-centered care and may play a particularly significant role in treatment decision making. The availability of such a tool may be especially important as new orphan drugs are developed and patients with rare diseases have more than one treatment option to consider.Conclusion: The PNH-PPQ provides a patient-centered approach for evaluating preferences for the treatment of PNH. The PNH-PPQ has subsequently assessed patient preference in the clinical trial sub-study ALXN1210-PNH-302s.Keywords: paroxysmal nocturnal hemoglobinuria, questionnaire development, ravulizumab, eculizumab, treatment experience

Tyvin Rich,1,* Fengmin Zhao,2,* Ricardo A Cruciani,3 David Cella,4 Judith Manola,2 Michael J Fisch5 1Hampton University Proton Therapy Institute, Hampton, VA, 2Dana-Farber Cancer Institute, Boston, MA, 3Beth Israel Medical Center, New York, NY, 4Northwestern University Feinberg School of Medicine, Chicago, IL, 5The University of Texas MD Anderson Cancer Center, Houston, TX, USA *These authors contributed equally to this work Context: The biology of fatigue and depression in cancer patients is poorly understood. Hypotheses regarding cytokines and growth factors related to sickness behavior and disruption of circadian signaling have been proposed.Objectives: We prospectively examined proinflammatory cytokines (e.g., sickness behavior model) and epidermal growth factor receptor (EGFR) ligands (e.g., circadian disruption model) in the serum of cancer patients enrolled in a clinical trial testing levocarnitine for fatigue.Methods: Serum samples were collected at baseline and week 4. Cytokine/growth factor analyses were performed with a Luminex analyzer. The Brief Fatigue Index and the Center for Epidemiologic Studies Depression Index were used to measure fatigue and depression severity. The association between cytokine and symptoms was examined using logistic models.Results: Among 101 analyzable patients, all ten cytokines/growth factors examined were highly elevated at baseline and all significantly decreased at week 4 (p

PurposeHuntington disease (HD) is a chronic, debilitating genetic disease that affects physical, emotional, cognitive, and social health. Existing patient-reported outcomes (PROs) of health-related quality of life (HRQOL) used in HD are neither comprehensive, nor do they adequately account for clinically meaningful changes in function. While new PROs examining HRQOL (i.e., Neuro-QoL-Quality of Life in Neurological Disorders and PROMIS-Patient-Reported Outcomes Measurement Information System) offer solutions to many of these shortcomings, they do not include HD-specific content, nor have they been validated in HD. HDQLIFE addresses this by validating 12 PROMIS/Neuro-QoL domains in individuals with HD and by using established PROMIS methodology to develop new, HD-specific content.MethodsNew item pools were developed using cognitive debriefing with individuals with HD, and expert, literacy, and translatability reviews. Existing item banks and new item pools were field tested in 536 individuals with prodromal, early-, or late-stage HD.ResultsModerate to strong relationships between Neuro-QoL/PROMIS measures and generic self-report measures of HRQOL, and moderate relationships between Neuro-QoL/PROMIS and clinician-rated measures of similar constructs supported the validity of Neuro-QoL/PROMIS in individuals with HD. Exploratory and confirmatory factor analysis, item response theory, and differential item functioning analyses were utilized to develop new item banks for Chorea, Speech Difficulties, Swallowing Difficulties, and Concern with Death and Dying, with corresponding six-item short forms. A four-item short form was developed for Meaning and Purpose.ConclusionsHDQLIFE encompasses both validated Neuro-QoL/PROMIS measures, as well as five new scales in order to provide a comprehensive assessment of HRQOL in HD.

Background: Identifying modifiable risk factors of autism spectrum disorders (ASDs) may inform interventions to reduce financial burden. The infant/toddler gut microbiome is one such feature that has been associated with social behaviors, but results vary between cohorts. We aimed to identify consistent overall and sex-specific associations between the early-life gut microbiome and autism-related behaviors. Methods: Utilizing the Environmental influences on Children Health Outcomes (ECHO) consortium of United States (U.S.) pediatric cohorts, we gathered data on 304 participants with fecal metagenomic sequencing between 6-weeks to 2-years postpartum (481 samples). ASD-related social development was assessed with the Social Responsiveness Scale (SRS-2). Linear regression, PERMANOVA, and Microbiome Multivariable Association with Linear Models (MaAsLin2) were adjusted for sociodemographic factors. Stratified models estimated sex-specific effects. Results: Genes encoding pathways for synthesis of short-chain fatty acids were associated with higher SRS-2 scores, indicative of ASDs. Fecal concentrations of butyrate were also positively associated with ASD-related SRS-2 scores, some of which may be explained by formula use. Limitations: The distribution of age at outcome assessment differed in the cohorts included, potentially limiting comparability between cohorts. Stool sample collection methods also differed between cohorts. Our study population reflects the general U.S. population, and thus includes few participants who met the criteria for being at high risk of developing ASD. Conclusions: Our study is among the first multicenter studies in the U.S. to describe prospective microbiome development from infancy in relation to neurodevelopment associated with ASDs. Our work contributes to clarifying which microbial features associate with subsequent diagnosis of neuropsychiatric outcomes. This will allow for future interventional research targeting the microbiome to change neurodevelopmental trajectories. [ABSTRACT FROM AUTHOR]

Background: Global health measures represent an attractive option for researchers and clinicians seeking a brief snapshot of a patient’s overall perspective on his or her health. Because scores on different global health measures are not comparable, comparative effectiveness research (CER) is challenging. Objective: To establish a common reporting metric so that the physical and mental health scores on the Veterans RAND 12-Item Health Survey (VR-12©) can be converted into scores on the corresponding Patient Reported Outcomes Measurement Information System (PROMIS®) Global Health scores. Design: Following a single-sample linking design, participants from an Internet panel completed items from the PROMIS Global Health and VR-12 Health Survey. A common metric was created using analyses based on item response theory (IRT), producing score cross-walk tables for the mental and physical health components of each measure. The linking relationships were evaluated by calculating the standard deviation of differences between the observed and linked PROMIS scores and estimating confidence intervals by sample size. Participants: Participants (N = 2025) were 49 % male and 73 % white; mean age was 46 years. Main Measures: Mental and physical health subscales of the PROMIS Global Health and the VR-12. The mean VR-12 physical component and mental component scores were 45.2 and 46.6, respectively; the mean PROMIS physical and mental health scores were 48.3 and 48.5, respectively. Key Results: We found evidence that the combined set of VR-12 and PROMIS items were relatively unidimensional and that we could proceed with linking. Linking worked better between the physical health than mental health scores using VR-12 item responses (vs. linking based on algorithmic scores). For each of the cross-walks, users can minimize the impact of linking error with modest increases in sample sizes. Conclusions: VR-12 scores can be expressed on the PROMIS Global Health metric to facilitate the evaluation of treatment, including CER. Extending these results to other common measures of global health is encouraged.

Preference-based health index scores provide a single summary score assessing overall health-related quality of life and are useful as an outcome measure in clinical studies, for estimating quality-adjusted life years for economic evaluations, and for monitoring the health of populations. We predicted EuroQoL (EQ-5D) index scores from patient-reported outcomes measurement information system (PROMIS) global items and domain item banks. This was a secondary analysis of health outcome data collected in an internet survey as part of the PROMIS Wave 1 field testing. For this study, we included the 10 global items and the physical function, fatigue, pain impact, anxiety, and depression item banks. Linear regression analyses were used to predict EQ-5D index scores based on the global items and selected domain banks. The regression models using eight of the PROMIS global items (quality of life, physical activities, mental health, emotional problems, social activities, pain, and fatigue and either general health or physical health items) explained 65% of the variance in the EQ-5D. When the PROMIS domain scores were included in a regression model, 57% of the variance was explained in EQ-5D scores. Comparisons of predicted to actual EQ-5D scores by age and gender groups showed that they were similar. EQ-5D preference scores can be predicted accurately from either the PROMIS global items or selected domain banks. Application of the derived regression model allows the estimation of health preference scores from the PROMIS health measures for use in economic evaluations.

Up to 50% of children and adolescents in the United States (U.S.) experience sleep problems. While existing research suggests that perceived stress in caregivers is associated with poorer sleep outcomes in children, research on this relationship is often limited to infant and early childhood populations; therefore, we investigated this association in school-age children and adolescents. We used cross-sectional caregiver-reported surveys and applied item response theory (IRT) followed by meta-analysis to assess the relationship between caregiver perceived stress and child sleep disturbance, and moderation of this relationship by child age and the presence of a child mental or physical health condition. We analyzed data from the National Institutes of Health (NIH) Environmental influences on Child Health Outcomes (ECHO) Program, a collaboration of existing pediatric longitudinal cohort studies that collectively contribute a diverse and large sample size ideal for addressing questions related to children's health and consolidating results across population studies. Participants included caregivers of children ages 8 to 16 years from four ECHO cohorts. Caregiver perceived stress was measured using the Perceived Stress Scale (PSS), and child sleep disturbance was assessed using five sleep-related items from the School-Age version of the Child Behavior Checklist (CBCL). Increases in caregiver perceived stress and child mental or physical health condition were independently associated with greater sleep disturbance among children. The findings reinforce the importance of accounting for, and potentially intervening on, the broader family context and children's mental and physical health in the interest of improving sleep health. Highlights: Existing research suggests caregiver perceived stress is associated with worse child sleep outcomes. Data from eight cohorts in the National Institutes of Health (NIH) Environmental influences on Child Health Outcomes (ECHO) program were used. We combined item-level analysis within each cohort with meta-analysis to aggregate results across cohorts. Higher caregiver perceived stress and child health conditions were independently associated with poorer child sleep. Study findings reinforce the importance of the broader family context in the interest of improving sleep health. [ABSTRACT FROM AUTHOR]