When better is the enemy of good: two cautionary tales of conceptual validity versus parsimony in clinical psychometric research.

This paper presents an empirical challenge to the assumption that an item-response theory analysis always yields a better measure of a clinical construct. We summarize results from two measurement development studies that showed that such an analysis lost important content reflecting the conceptual model ("conceptual validity"). The cost of parsimony may thus be too high. Conceptual models that form the foundation of QOL measurement reflect the patient's experience. This experience may include concepts and items that are psychometrically "redundant" but capture distinct features of the concept. Good measurement is likely a balance between relying on IRT's quantitative metrics and recognizing the importance of conceptual validity and clinical utility.

Development and validation of the HDSIM™ assessment system: a measure of hemorrhoid disease symptom impact.

BACKGROUND: Hemorrhoid disease (HD) affects 10 million people in the US at any given time, and 50% of the US population will develop symptomatic hemorrhoids during their lifetime. Approximately 60% of people with hemorrhoids experience symptoms. Despite its prevalence and impact on quality of life, the existing patient-reported outcome measures of HD have not been validated using standard psychometric methods. The present study thus aimed to develop the Hemorrhoid Disease Symptom Impact Measure™ (HDSIM™) assessment system, a patient-reported measure of HD symptoms and impact for use in HD clinical research. METHODS: On the basis of results from qualitative cognitive interviews, we generated the conceptual model and item pool. A cross-sectional web-based survey (n = 1066) was done, including a randomly selected retest subsample (n = 100) 1-2 weeks later. The survey sample was selected to be evenly distributed across mild, moderate, and severe levels of disease and to be nationally representative of the general United States population in terms of race, gender, and region. Existing disease-specific measures of symptoms and generic measures of quality of life and well-being were compared to the new tool for construct validation. RESULTS: The HDSIM system includes 38 items representing six conceptual-model-driven subscales, aligning with the conceptual model: Symptoms at Worst, Symptoms at Best, Bowel Health Impact, Life Impact, Mental Health Impact, and Manageability. Psychometric analyses documented that the subscales had excellent internal consistency reliability, cross-sectional construct validity (i.e., convergent and divergent validity, known groups validity), test-retest stability, and longitudinal construct validity (i.e., responsiveness). CONCLUSION: The HDSIM system is fit for purpose in hemorrhoid disease clinical trials research. Since measures are validated in an iterative manner over many studies and over time, the present study results should be considered preliminary.

Fatigue Item Response among Hemoglobin-Normalized Patients with Paroxysmal Nocturnal Hemoglobinuria: PEGASUS Trial Results at 16 and 48 Weeks.

Background. A common symptom of paroxysmal nocturnal hemoglobinuria (PNH) is fatigue, which in some patients can be severe. Eculizumab (Ecu) has proven efficacy in controlling intravascular hemolysis, but commonly results in persistent anemia and fatigue. Pegcetacoplan's (Peg) efficacy was documented in the PEGASUS phase III clinical trial, showing improved hemoglobin (Hb) and patient-reported fatigue. This post-hoc analysis sought to describe this fatigue improvement related to Hb normalization using the Functional Assessment of Chronic Illness Therapy-Fatigue subscale (FACIT-F)'s individual questions to speak more directly to patients' experience and clinicians' day-to-day practice. Methods. The PEGASUS trial compared Peg with Ecu in patients who remained anemic on Ecu over 16 weeks (n = 41 and 39, for Peg and Ecu, respectively), after which all patients received Peg open label for 32 weeks ("Peg" vs. "Ecu-to-Peg" at Week 48). Hb normalization was defined as ≥12-16 g/dL for females and ≥13.6-18 g/dL for males. The FACIT-F assessed fatigue. Using the complete-case data set, Cohen's d summarized the effect sizes of the mean FACIT-F item change for both study arms from the baseline to week 16 (n = 36 and 37, for Peg and Ecu, respectively) and from the baseline to week 48 (n = 30 and 29, for Peg and Ecu-to-Peg, respectively), and for Hb-normalized patients in each study arm from the baseline to week 16 (n = 14 and 0, for Peg and Ecu, respectively) and from the baseline to week 48 (n = 10 and 12, for Peg and Ecu-to-Peg, respectively). Results. The FACIT-F scores for both arms were worse at the baseline compared to later in the trial. Peg patients reported improvements on all fatigue items at Week 16, but Ecu patients reported improvement in only one item. At Week 48, the improvement in fatigue was maintained in Peg patients, and Ecu-to-Peg patients' fatigue improved on all FACIT-F items. Hb normalization was achieved in 14 Peg patients but no Ecu patients at Week 16, and in 10 Peg and 12 Ecu-to-Peg patients, respectively, at week 48. The FACIT-F single items showing the largest change overall, and particularly in Hb-normalized patients across the study arms, were related to symptoms and social limitations. Conclusions. Peg patients reported lasting improvements in fatigue. Patients who were anemic on Ecu reported sustained improvements in fatigue with Peg treatment. Patients who had Hb normalization generally had large, clinically important improvements in fatigue items.

Mental health after lumbar spine surgery: cognitive appraisal processes and outcome in a longitudinal cohort study.

BACKGROUND CONTEXT: A not uncommon finding following spine surgery is that many patients do not achieve mental health improvement up to population norms for their age cohort, despite improvement in pain and functioning. PURPOSE: This study examined how patients who were categorized as depressed versus not depressed think about health-related quality of life as assessed by cognitive-appraisal processes. It examined cross-sectional and longitudinal differences over 12 months post-surgery. DESIGN: Prospective longitudinal cohort study with data collected at pre-surgery and at ∼3- and ∼12-months post-surgery from August 2013 to August 2023. PATIENT SAMPLE: We included 173 adults undergoing lumbar spine surgery for degenerative spinal conditions at an academic medical center. The study sample was 47% female, with a mean age of 61 (SD=15.0), and a median level of education of college graduate. OUTCOME MEASURES: Depression was defined as a Mental Component Score (MCS)≤38 on the Rand-36, building on studies that equated MCS scores with significant depression as assessed by clinically validated depression scales. The Quality-of-Life Appraisal Profile assessed the cognitive-appraisal domains of Experience Sampling and Standards of Comparison. METHODS: The analysis focused on two comparisons: cross-sectionally comparing those who were not depressed (n=82) to those who were depressed (n=77) at baseline; and comparing longitudinal trajectories among those depressed before surgery and improved (n=54) versus did not improve (n=23). T-tests characterized group differences in appraisal endorsement; analysis of variance evaluated appraisal items in terms of explained variance; and Pearson correlation coefficients assessed direction of association in predicting mental health. RESULTS: There were pre-surgical and longitudinal differences in both cognitive appraisal domains. Before surgery, depressed patients were less likely than non-depressed patients to endorse emphasizing the positive; more likely to focus on worst moments, recent flare-ups, their spinal condition, and the future; and more likely to compare themselves to high aspirations (eg, perfect health). Over time, among those who were depressed before surgery, those who improved focused decreasingly on worst moments and on the time before their spinal condition, and increasingly on emphasizing the positive and balancing the positives/negatives. Appraisal explained more variance in mental health among those who did not improve as compared to those who did, at all timepoints. All appraisal items were more highly correlated with mental health among those who remained depressed as compared to those who improved, particularly over time. CONCLUSIONS: Endorsement of cognitive appraisal processes was different for depressed versus non-depressed spine-surgery patients before surgery and distinguished those who were depressed before surgery and improved versus those who did not improve. These findings suggest that targeted interventions could be beneficial for addressing mental health concerns during the spine surgery recovery trajectory. These interventions might use appraisal measures to identify patients likely to remain depressed after surgery, and then focus on helping these patients shift their focus and standards of comparison.

Reserve-building as a buffer for depression among individuals living with disability: a longitudinal study of current activities related to brain health.

Aims: This study examined whether reserve-building activities are associated with attenuated reported depression among people who were disabled from work due to a medical condition as compared to employed, retired, and unemployed participants. Methods: This secondary analysis included 771 individuals who provided data at three time points: baseline (late Spring 2020), follow-up 1 (Spring 2021), and follow-up 2 (Fall 2021). The DeltaQuest Reserve-Building Measure assessed current activities related to brain health. An analysis of variance and Pearson correlation coefficients assessed group differences in reserve-building activity scores. Classification and regression tree (CART) modeling investigated factors associated with higher and lower reported depression by employment group. The random effects (RE) models tested two buffering hypotheses: (1) comparing all groups to the employed group and (2) examining within-group effects. Results: Engaging in outdoor activities, exercise, and religious/spiritual activities was associated with reduced depression over time in the overall sample. While disabled participants endorsed lower levels of being Active in the World, Outdoor activities, and Exercise and higher levels of Inner Life and Passive Media Consumption than the other employment groups, more reserve-building activities distinguished depression levels in the disabled group's CART models compared to the others. Among the disabled, unemployed, and retired participants, engaging in any reserve-building activities was also associated with lower depression scores, which was distinct from the employed participants. In the RE models that used the employed group as the reference category, only the disabled group's level of depression was buffered by engaging in creative activities. In the within-group RE models, the disabled group's engagement in Religious/Spiritual, Outdoors, and Games was associated with substantially reduced within-group depression, which was different from the other employment groups. In contrast, reserve-building activities were not implicated at all as buffers for employed participants. Conclusion: This study revealed a beneficial effect of reserve-building activities on buffering depression over time during the COVID-19 pandemic, particularly for disabled people. It documented that even if such individuals engaged in lesser amounts of such activities as compared to other employment groups, the buffering effect was substantial. Given the low-cost and accessible nature of reserve-building activities, it would be worthwhile to encourage such activities for disabled individuals.

Functional Status Correlates of Change and Stability in Appraisal after Spine Surgery: Earlier versus Later Effects.

Spine surgery generally yields a notable improvement in patients' health state, and there is variability in measured patient outcomes after spine surgery. The present work aimed to describe for clinicians how appraisal underlies their patients' experience of healthcare interventions. This prospective longitudinal cohort study (n = 156) included adults undergoing spine surgery for degenerative spinal conditions. The analysis was a descriptive illustration of the relationship between change in the spine-related disability using the Oswestry Disability Index and change in cognitive-appraisal processes using the Quality-of-Life Appraisal Profilev2-Short Form, early versus later during the recovery trajectory (i.e., between baseline and 3 months post-surgery; and between 3 and 12 months post-surgery). Cognitive-appraisal processes related to Sampling of Experience showed greater change soon after surgery, whereas Standards of Comparison appraisals changed more later in the recovery trajectory. Different appraisal processes were emphasized by patients who reported worsening of the spine-related disability, as compared to those who reported no change or improvement. These findings suggest that changes in appraisal differ depending on the individual's experience of the impact of spine surgery. Appraisal processes thus reflect an ongoing dynamic in adaptation to changing function.

Individual differences in the long-term impact of the pandemic: moderators of COVID-related hardship, worry, and social support.

PURPOSE: Understanding people's response to the pandemic needs to consider individual differences in priorities and concerns. The present study sought to understand how individual differences in cognitive-appraisal processes might moderate the impact of three COVID-specific factors-hardship, worry, and social support-on reported depression. METHODS: This longitudinal study of the psychosocial impact of the COVID-19 pandemic included 771 people with data at three timepoints over 15.5 months. Participants were recruited from panels of chronically ill or general population samples. Depression was measured by an item response theory validated depression index created using items from existing measures that reflected similar content to the Patient Health Questionnaire-8. COVID-specific factors of hardship, worry, and social support were assessed with items compiled by the National Institutes of Health. The Quality of Life Appraisal Profilev2 Short-Form assessed cognitive appraisal processes. A series of random effects models examined whether appraisal moderated the effects of hardship, worry, and social support on depression over time. RESULTS: Over time the association between low social support and depression was greater (p = 0.0181). Emphasizing the negative was associated with exacerbated depression, in particular for those with low social support (p = 0.0007). Focusing on demands and habituation was associated with exacerbated depression unless one experienced greater hardship (p = 0.0074). There was a stronger positive connection between recent changes and depression for those people with higher worry scores early in the pandemic as compared to later, but a stronger positive correlation for those with lower worry scores later in the pandemic (p = 0.0015). Increased endorsement of standards of comparison, emphasizing the negative, problem goals, and health goals was associated with worse depression scores (all p < 0.0001). People who were younger, disabled, or had greater difficulty paying bills also reported worse depression (p < 0.0001, 0.0001, and 0.002, respectively). CONCLUSION: At the aggregate level, COVID-specific stressors changed over the course of the pandemic, whereas depression and social-support resources seemed stable. However, deeper analysis revealed substantial individual differences. Cognitive-appraisal processes showed considerable variability across individuals and moderated the impact of COVID-specific stressors and resources over time. Future work is needed to investigate whether coaching individuals away from maladaptive cognitive-appraisal processes can reduce depression and lead to better overall well-being.

Depression trajectories during the COVID-19 pandemic: a secondary analysis of the impact of cognitive-appraisal processes.

PURPOSE: This study characterized depression trajectories during the COVID pandemic and investigated how appraisal and changes in appraisal over time related to these depression trajectories. METHODS: This longitudinal study of the psychosocial impact of the COVID-19 pandemic included 771 people with data at three timepoints over 15.5 months. The depression index was validated using item-response-theory methods and receiver-operating-characteristic curve analysis. The Quality of Life (QOL) Appraisal Profilev2 Short-Form assessed cognitive-appraisal processes. Sequence analysis characterized depression-trajectory groups, and random effects models examined appraisal main effects, appraisal-by-group, and appraisal-by-group-by-time interactions. RESULTS: Sequence analysis generated six trajectory groups: Stably Well (n = 241), Stably Depressed (n = 299), Worsening (n = 79), Improving (n = 83), Fluctuating Pattern 1 (No-Yes-No; n = 41), and Fluctuating Pattern 2 (Yes-No-Yes; n = 28). While all groups engaged in negative appraisal processes when they were depressed, the Stably Depressed group consistently focused on negative aspects of their life. Response-shift effects were revealed such that there were differences in the appraisal-depression relationship over time for standards of comparison and recent changes for the Stably Depressed, and in health goals for those Getting Better. CONCLUSION: The present work is, to our knowledge, the first study of response-shift effects in depression. During these first 15.5 pandemic months, group differences highlighted the connection between negative appraisals and depression, and response-shift effects in these relationships over time. Egregious life circumstances may play a lesser role for the Stably Depressed but a greater role for people who have transient periods of depression as well as for those with improving trajectories (i.e., endogenous vs. reactive depression). How one thinks about QOL is intrinsically linked to mental health, with clear clinical implications.

Cognitive Processes during Recovery: Moving toward Personalized Spine Surgery Outcomes.

This paper focuses on a novel application of personalized medicine: the ways one thinks about health (i.e., appraisal processes) as relevant predictors of spine-surgery response. This prospective longitudinal cohort study (n = 235) investigated how appraisal processes relate to outcomes of spinal decompression and/or fusion surgery, from pre-surgery through one-year post-surgery. Patient-reported outcomes assessed spine-specific disability (Oswestry Disability Index (ODI)), mental health functioning (Rand-36 Mental Component Score (MCS)), and cognitive appraisal processes (how people recall past experiences and to whom they compare themselves). Analysis of Variance examined the appraisal-outcomes association in separate models at pre-surgery, 3 months, and 12 months. We found that appraisal processes explained less variance at pre-surgery than later and were differentially relevant to health outcomes at different times in the spine-surgery recovery trajectory. For the ODI, recall of the seriousness of their condition was most prominent early in recovery, and comparing themselves to positive standards was most prominent later. For the MCS, not focusing on the negative aspects of their condition and/or on how others see them was associated with steady improvement and higher scores at 12 months. Appraisal processes are relevant to both spine-specific disability and mental-health functioning. Such processes are modifiable objects of attention for personalizing spine-surgery outcomes.

Race-related differences in the economic, healthcare-access, and psychological impact of COVID-19: personal resources associated with resilience.

BACKGROUND: The impact of the coronavirus disease 2019 (COVID) is worse among those with fewer financial resources, in jobs not amenable to remote work, and in denser living conditions. People of color are more likely to be among these vulnerable groups. Although race itself is a social construction and not based on underlying genetic/biological differences, this study investigated race/ethnicity differences in the negative repercussions of COVID and in the benefits of psychological and social resources. METHODS: This cross-sectional, web-based study (n = 4817) was administered to a heterogeneous United States sample in Spring/Summer 2020. Information was gathered on the following COVID-specific variables: Infection Status, Coping with Lockdown, Social Support, Post-traumatic Growth, Interpersonal Conflict, Worry about Self, Financial Impact on Family, Lack of Money, Inadequate Access to Healthcare, and Housing Instability. Resilience was operationalized as the ability to maintain a sense of wellness in the face of the pandemic, using the DeltaQuest Wellness measure. Multivariate linear regression (adjusting for demographics) and propensity-matched cohort analysis (matched on demographics) evaluated the impact of COVID-specific variables on Wellness in separate models for Whites and Non-Whites. FINDINGS: Both sets of models retained the same COVID-specific variables and explained about half of the variance in wellness. Coping with Lockdown, Social Support, and Post-traumatic Growth were associated with higher levels of Wellness in both Whites and Non-Whites, while Interpersonal Conflict and Worry about Self were associated with lower levels of Wellness. While these associations are similar, Non-Whites reported worse levels of some positive resources (e.g., social support) and more challenging levels of negative stressors (e.g., interpersonal, worry, financial). Non-Whites also reported much higher levels of post-traumatic growth. CONCLUSION: COVID was a source of worry and even conflict, but also unlocked people's resources in use of health-enhancing behavioral strategies, social support, and renewed gratitude for sources of personal meaning and value. The similar relationships between Whites and Non-Whites on wellness and COVID-specific stressors across racial groups underscore that race is a social construction, not a biological fact. Focusing on a renewed appreciation for sources of personal meaning, and particularly faith, seemed to buffer much of the COVID-related stress for Non-Whites.

Interplay of disability, caregiver impact, and out-of-pocket expenditures in Duchenne muscular dystrophy: a cohort study.

BACKGROUND: Providing caregiving support to people with Duchenne muscular dystrophy (DMD) is challenging, beginning in early childhood, and continuing through the progression of multidimensional disability. This study addressed the interplay between caregiver impact, out-of-pocket expenditures, and DMD disability. To examine these interconnections, we investigated the association between caregiver impact domains and out-of-pocket expenditures; and the presence of clusters in caregivers on the basis of DMD-related disability domains in the patients for whom they provided caregiving support. METHODS: This web-based study recruited 566 DMD caregivers (140 males, 426 females; mean age 41.6 years, SD 8.8, range 21-72), examining caregiver impact using the DMD Caregiver Impact Measure, PROMIS-derived parent-proxy (PPP) measures of their child's disability, and items tapping out-of-pocket expenditures related to home and vehicle accommodations and assistive devices. T-tests compared caregiver impact scores by out-of-pocket expenditures incurred. Latent Profile Analyses (LPA) were conducted to generate impact profiles related to child's disability as reported by caregiver proxies. RESULTS: Higher out-of-pocket expenditures were generally associated with worse impact on the subscales, but several expenditures (e.g., kitchen, bathroom, scooter) were associated with lower impact. LPA indicated that the four-group solution provided the best relative fit and yielded good profile separation (entropy = 0.91). Caregivers with lowest impact reported the highest mobility, cognitive, and upper extremity functioning of their DMD care recipients, whereas the highest caregiver impact was driven by their care recipient's negative affect and fatigue. The upper-middle impact group showed great variability in proxy-disability domains, whereas the lower-middle group had similar levels of disability across domains. Profiles were represented across all child ages. CONCLUSION: Out-of-pocket expenditures were often associated with worse caregiver impact, but some associated with milder impact (i.e., bathroom or kitchen modification, investing in a ceiling lift or medical scooter). While their son's level of disability and age were related to impact on the DMD caregiver, the domains giving rise to highest caregiver impact were not the most visible aspects of disability, such as mobility, but rather negative affect and fatigue. Other contextual attributes are likely implicated, and will be addressed in the companion paper.

Drivers of caregiver impact in Duchenne muscular dystrophy: a cohort study.

BACKGROUND: In our companion paper, we addressed the interplay between caregiver impact, out-of-pocket expenditures, and Duchenne Muscular Dystrophy (DMD) disability. We found that DMD caregiver impact could be characterized by four Latent Profile Analysis impact profiles: lowest, lower middle, upper middle, and highest impact. The impact on caregivers was often but not always worse with greater out-of-pocket expenditures. Further, while the lowest-, lower-middle, and highest-impact profiles reflected low, moderate and high disability-related caregiver burden, respectively, the upper-middle profile group was quite variable in level of disability across domains. To better understand the four caregiver-impact profiles, we examine how a comprehensive set of psychosocial factors differentiate the four profile groups. METHODS: Psychosocial factors assessed included demographic characteristics, quality of life (QOL), stress, cognitive appraisal, reserve-building, and general and COVID-specific resilience. Linear modeling examined relationships between impact profiles and psychosocial factors. We used effect size rather than p-value as the criterion for determining relevance of the broad range of characteristics examined. RESULTS: Multivariate analyses implicated stress and environmental mastery, appraisal sampling of experience, COVID-specific variables, appraisal standards of comparison, appraisal goals, demographics, appraisal combinatory algorithm, reserve-building, and resilience, in order of prominence (average eta2 = 0.29, 0.29, 0.16, 0.15, 0.09, 0.07, 0.07, 0.06, 0.05, and 0.02, respectively). On the whole, comparisons of highest-versus-lowest impact profiles revealed more and larger differences than comparisons of upper-middle versus lower-middle impact profiles. Life stress, goals, and reserve-building activities had a smaller differentiating effect in the middle groups. CONCLUSION: A more comprehensive 'story' about DMD caregiver impact involves life stress, environmental mastery, COVID-specific variables, and cognitive and behavioral factors. Implications are discussed for coaching interventions to support DMD caregivers.

Measuring Duchenne muscular dystrophy impact: development of a proxy-reported measure derived from PROMIS item banks.

BACKGROUND: Person-reported outcomes measurement development for rare diseases has lagged behind that of more common diseases. In studies of caregivers of patients with rare diseases, one relies on proxy report to characterize this disability. It is important to measure the child's disability accurately and comprehensively because it affects caregiver burden. We aimed to create a condition-specific caregiver proxy-report measure for Duchenne Muscular Dystrophy (DMD) in order to understand the impact of DMD on the caregiver. Drawing on relevant item banks from the Patient-Reported Outcome Measurement Information System (PROMIS), we sought to confirm their reliability and validity in the target sample of DMD caregivers. METHODS: This web-based study recruited DMD caregivers via Rare Patient Voice, patient-advocacy groups, and word of mouth. Recruitment was stratified by age of the caregiver's child with DMD, which broadly represents stages of DMD progression: 2-7, 8-12, 13-17, and > 18. Telephone interviews with DMD parent-caregivers pretested possible measures for content validity. The web-based study utilized an algorithm to categorize respondents' ambulatory status for tailored administration of PROMIS Parent-Proxy items as well as some new items developed based on caregiver interviews. Item response theory analyses were implemented. RESULTS: The study sample included 521 DMD caregivers representing equally the four age strata. The proxy-report measure included the following domains: fatigue impact, strength impact, cognitive function, upper extremity function, positive affect, negative affect, sleep-device symptoms, and mobility. The first five domains had strong psychometric characteristics (unidimensionality; acceptable model fit; strong standardized factor loadings; high marginal reliability). Negative Affect, covering anger, anxiety, depressive symptoms, and psychological stress, fit a bifactor model with good model fit, high marginal reliability, and strong factor loadings. The Sleep-device symptoms domain was not unidimensional, and the mobility domain did not have a simple structure due to residual correlations among items at opposite end of the mobility-disability continuum. These two domain scores were retained as clinimetric indices (i.e., uncalibrated scales), to achieve the overall goal of having a content-valid DMD-specific measure across all stages of disease severity. CONCLUSIONS: The present study derived a DMD-specific proxy-report measure from PROMIS item banks and supplemental items that could potentially be utilized in caregiver research across all stages of the care recipient's DMD. Future research will focus on assessing the responsiveness and validity of the measure over time and its comparison to DMD patient self-report.

Norm-based comparison of the quality-of-life impact of ravulizumab and eculizumab in paroxysmal nocturnal hemoglobinuria.

AIMS: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and life-threatening intravascular hematologic disorder with significant morbidity and premature mortality. Clinical trials (NCT02946463 and NCT03056040) comparing ravulizumab with eculizumab for PNH have supported the non-inferiority of the former and similar safety and tolerability. This secondary analysis compared PNH trial participants after 26 weeks on either treatment (n = 438) to a general-population sample (GenPop) (n = 15,386) and investigated response-shift effects. METHODS: Multivariate analysis of covariance (MANCOVA) investigated function and symptom scores on the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 of people with PNH as compared to GenPop, after covariate adjustment. Risk-factor groups were created based on clinical indicators known to be associated with worse PNH outcomes, and separate MANCOVAs were computed for lower- and higher-risk-factor groups. Differential item functioning (DIF) analyses examined whether item response varied systematically (1) by treatment, (2) compared to GenPop, and (3) over time, the latter two suggesting and reflecting response-shift effects, respectively. DIF analyses examined 24 items from scales with at least two items. Recalibration response shift was operationalized as uniform DIF over time, reflecting the idea that, for a given group, the difficulty of endorsing an item changes over time, after adjusting for the total subscale score. Reprioritization response shift was operationalized as non-uniform DIF over time, i.e., the relative difficulty of endorsing an item over time changes across the total domain score. RESULTS: Across PNH risk-factor levels, people who had been on either treatment for 26 weeks reported better-than-expected functioning and lower symptom burden compared to GenPop. Ravulizumab generally showed larger effect sizes. Results were similar for lower and higher PNH risk factors, with slightly stronger effects in the former. DIF analyses revealed no treatment DIF, but did uncover group DIF (9 items with uniform DIF, and 11 with non-uniform) and DIF over time (7 items with uniform DIF, and 3 with non-uniform). CONCLUSIONS: This study revealed that people with PNH on ravulizumab or eculizumab for 26 weeks reported QOL levels better than those of the general population. Significant effects of DIF by group and DIF over time support recalibration and reprioritization response-shift effects. These findings suggest that the treatments enabled adaptive changes.

No impact of Asian ethnicity on EORTC QLQ-C30 scores: Group differences and differential item functioning in paroxysmal nocturnal hemoglobinuria.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening terminal-complement-mediated disease resulting in intravascular hemolysis and thrombosis with significant morbidity and premature mortality. There exists no disease-specific quality-of-life (QOL) measure for PNH. Its QOL effects resemble those of hematologic cancers, which supports the use of cancer-specific QOL measures in PNH clinical trials. The European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 has published norms for many European and North American countries, but not for Asian countries. We investigated differences by Asian ethnicity in scores and item function on the EORTC QLQ-C30. METHODS: This secondary analysis focused on two non-inferiority PNH trials (301 and 302) comparing eculizumab and ravulizumab (n = 441). Analysis of covariance examined the main effect of Asian ethnicity on baseline EORTC QLQ-C30 scores, after adjusting for propensity scores encompassing trial, demographic and clinical factors. Mixed modeling of longitudinal data compared subscale scores in Asian vs. non-Asian patients, after propensity adjustment. Differential item function (DIF) was examined using ordinal regression models at baseline and longitudinally, to predict item score from total score, ethnicity, and their interaction to test for uniform DIF (significant main effect for Asian) and non-uniform DIF (significant Asian-by-total-score interaction). RESULTS: Of the 15 baseline domains, Asian patients scored slightly better on role and emotional functioning and slightly worse on constipation and diarrhea (0.22 < Cohen's d < 0.36). In longitudinal models, Asians reported slightly higher appetite loss, diarrhea, and financial difficulties than non-Asians (R2 increment < 0.0005). There was negligible uniform and non-uniform DIF, i.e., R2 0 to 0.018, far below Zumbo's (1999) criterion of 0.13. On average there were larger differences from norms for Asians (mean = 0.05, sd = 0.44) than non-Asians (mean = -0.07, sd = 0.36), but the size and direction of the differences varied considerably by domain, age, and gender. CONCLUSION: When compared to norms, Asian patients showed no systematic biases. DIF results supported this finding. We conclude that Asian ethnicity does not impact interpretation of EORTC QLQ-C30 scores.