Effect of avalglucosidase alfa on disease-specific and general patient-reported outcomes in treatment-naïve adults with late-onset Pompe disease compared with alglucosidase alfa: Meaningful change analyses from the Phase 3 COMET trial.

BACKGROUND: The Phase 3 COMET trial (NCT02782741) comparing avalglucosidase alfa and alglucosidase alfa included health-related quality of life (HRQoL) assessments in treatment-naïve patients with late-onset Pompe disease (LOPD). Here, we further characterize results from disease-specific and general patient-reported outcome (PRO) measures. METHODS: Adults who participated in the COMET trial receiving avalglucosidase alfa or alglucosidase alfa (both 20 mg/kg biweekly) during the 49-week double-blind treatment period were included in the analysis. Proportions of patients exceeding meaningful change thresholds at Week 49 were compared post hoc between treatment groups. PROs and their meaningful change thresholds included: Pompe Disease Severity Scale (PDSS; decrease 1.0-1.5 points), Pompe Disease Impact Scale (PDIS; decrease 1.0-1.5 points), Rasch-built Pompe-specific Activity Scale (R-PAct; change from unable to able to complete activity), 12-item Short Form Health Survey (SF-12; physical component summary [PCS] score: increase ≥6 points, mental component summary [MCS] score: increase ≥7 points), EuroQol 5 Dimension 5 Level (EQ-5D-5L; improvement of ≥1 category), and Patient Global Impression of Change (PGIC; any improvement). RESULTS: The analysis included 99 adult patients (avalglucosidase alfa n = 50; alglucosidase alfa n = 49). Patients who received avalglucosidase alfa had significantly greater odds of achieving a meaningful change versus alglucosidase alfa for the PDSS Shortness of Breath (OR [95% CI] 11.79 [2.24; 62.18]), Fatigue/Pain (6.24 [1.20; 32.54]), Morning Headache (13.98 [1.71; 114.18]), and Overall Fatigue (5.88 [1.37; 25.11]) domains, and were significantly more likely to meet meaningful change thresholds across multiple PDSS domains (all nominal p < 0.05). A numerically greater proportion of patients in the avalglucosidase alfa group were able to complete selected activities of the R-PAct compared with the alglucosidase alfa group. Significantly greater proportions of patients who received avalglucosidase alfa achieved meaningful improvements for EQ-5D-5L usual activities dimension, EQ visual analog scale, and all four PGIC domains. The proportion of patients with improvements in SF-12 PCS and MCS was greater in the avalglucosidase alfa group versus alglucosidase alfa group, but was not significant (p > 0.05). CONCLUSIONS: These analyses show that avalglucosidase alfa improves multiple symptoms and aspects of daily functioning, including breathing and mobility. This supports the clinical relevance of the effects of avalglucosidase alfa on HRQoL for patients with LOPD.

Defining the Minimal Important Change and Meaningful Change Value of the Disease Activity Index for Psoriatic Arthritis: A Chinese Longitudinal Study.

OBJECTIVE: To determine the minimal important change (MIC) and meaningful change value (MCV) of the Disease Activity Index for Psoriatic Arthritis (DAPSA) and the effect size (ES) of DAPSA. METHODS: This was a retrospective cohort study, recruiting 106 patients who agreed to participate in the research from the Department of Dermatology, Xiangya Hospital, between November 1, 2019, and April 1, 2023. An anchor-based method using linear regression analyses was used to determine the MICs and MCVs of the DAPSA. The anchor question assessed whether the patient's well-being had changed since their previous visit, employing a 5-point Likert scale that ranged from "much improved" to "much deteriorated." RESULTS: The overall MIC value was 8.4 (95% CI 0.01-16.75). The MIC improvement was 9.5 (95% CI 0.89-18.14) and MIC deterioration was 1.1 (95% CI -9.81 to 12.05). The overall MCV was 10.5 (95% CI 4.34-16.72). MCV improvement was 11.4 (95% CI 5.95-16.95) and MCV deterioration was 1.1 (95% CI -9.81 to 12.05). The ES was 0.6. CONCLUSION: A change in DAPSA of 8.4 is indicative of an MIC, offering physicians an additional means to contextualize the patient's perception of disease activity during treatment, and a change in DAPSA of 10.5 is likely to be regarded as MCV. These values can enhance the utility of DAPSA in psoriatic arthritis clinical trials.

Meaningful Symptomatic Change in Patients With Myelofibrosis From the SIMPLIFY Studies.

OBJECTIVES: Patients with myelofibrosis develop symptoms due to bone marrow fibrosis, systemic inflammation, and/or organomegaly. Alleviating symptoms improves overall quality of life. Clinical trials have historically defined symptom response as a reduction of at least 50% in Total Symptom Score at week 24 compared with baseline. Whether 50% constitutes a meaningful benefit has not been established. This study determined the meaningful change threshold (MCT) for 2 momelotinib phase III trials, SIMPLIFY-1 and SIMPLIFY-2. METHODS: The absolute and percentage MCT was determined using anchor-based methods applied to the modified Myeloproliferative Neoplasm Symptom Assessment Form v2.0 and Patient Global Impression of Change. MCTs were applied retrospectively to determine responder rates. Generalized estimating equations estimated the treatment-related difference in likelihood of improvement. RESULTS: In SIMPLIFY-1, a Janus kinase inhibitor-naive population, the MCT was 8 points. In SIMPLIFY-2, a previously Janus kinase inhibitor-treated population, the MCT was 6 points. A 32% MCT was determined in both studies, showing that the historic 50% reduction threshold may be a conservative choice. In SIMPLIFY-1, a similar proportion of patients achieved responder status with 24 weeks of momelotinib or ruxolitinib therapy based on the absolute MCT (39% vs 41%, respectively). In SIMPLIFY-2, a significantly greater proportion of patients treated with momelotinib achieved responder states compared with best available therapy based on absolute and percent change MCTs. CONCLUSIONS: This study demonstrates that momelotinib provided clinically meaningful symptom benefit for patients with myelofibrosis and provides insight into the appropriateness of the symptom change threshold used in historical studies.

Meaningful Change Thresholds and Fatigue Severity Points on Patient-Reported Outcomes by the Fatigue Symptoms and Impacts Questionnaire in Patients With Relapsing Multiple Sclerosis.

OBJECTIVES: The Fatigue Symptoms and Impacts Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS) is a new content-valid, concise, and reliable 20-item patient-reported outcome measure to evaluate the symptoms and impacts of fatigue in patients with relapsing forms of multiple sclerosis. Analyses were performed to derive meaningful change thresholds (MCTs) on patient-reported outcomes as measured by FSIQ-RMS and generate receiver operating characteristic (ROC) curves to determine fatigue severity cut points at baseline and change in severity at post-baseline and supplement the anchor-based MCT results. METHODS: Analyses were based on data from the OPTIMUM trial (NCT02425644). An anchor-based approach using uncollapsed changes on the Patient Global Impression of Severity at week 108 were used to determine the MCT for only the FSIQ-RMS Symptoms domain; distribution-based MCT estimations were conducted using baseline FSIQ-RMS Impacts scores. ROC curves with calculation of area under the curve were used to identify the best cut point. RESULTS: Based on the evidence provided by the anchor-based analyses using the Patient Global Impression of Severity as an anchor for the FSIQ-RMS Symptoms domain, meaningful score changes for improvement and deterioration were -6.3 and 6.3, respectively. Meaningful score changes for the FSIQ-RMS Physical, Cognitive/Emotional, and Coping Impacts domains using distribution-based methods were 10.8, 8.4, and 9.8, respectively. These results are supported by the ROC analyses. CONCLUSIONS: Thresholds to support interpretation of the FSIQ-RMS, such as MCTs, can be used to determine and categorize patients who have experienced a meaningful change in their MS-related fatigue (eg, responder analyses) in future clinical research studies.

A Review of Meaningful Change Thresholds for EORTC QLQ-C30 and FACT-G Within Oncology.

OBJECTIVES: This literature review provides an overview of meaningful change thresholds for the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30) and the Functional Assessment of Cancer Therapy - General (FACT-G) used across hematological cancers and solid tumors (melanoma, lung, bladder, and prostate). METHODS: Embase, MEDLINE, and PubMed were searched to identify relevant oncology publications from 2016 to 2021. Label claims from the US Food and Drug Administration and the European Medicines Agency for 7 recently approved drugs (pembrolizumab, atezolizumab, glasdegib, gilteritinib, tisagenlecleucel, axicabtagene ciloleucel, and daratumumab plus hyaluronidase-fihj) were reviewed. RESULTS: Publications providing guidance on meaningful change thresholds for the QLQ-C30 displayed a growing trend away from broad "legacy" thresholds of 10 points for all QLQ-C30 scales), toward deriving "contemporary" thresholds (eg, subscale specific, population specific). Contemporary publications generally provide guidance on selecting thresholds for specific scales that account for improved or worsening thresholds (eg, QLQ-C30 subscales). This trend was not clear for FACT-G, with less new guidance available. Most clinical trials used in regulatory label submissions have used thresholds of 10 points for the QLQ-C30 subscales and 3 to 7 points for the FACT-G total score. Despite the availability of more recent guidelines, contemporary meaningful change thresholds seem slow to emerge in the published literature and regulatory labels. CONCLUSIONS: Trialists should consider using contemporary thresholds, rather than legacy thresholds, for QLQ-C30 endpoints. Thresholds derived for a similar patient-population should be used where available. Further work is required to provide these across a broader range of cancer sites.

Establishing Meaningful Change Thresholds in Patient-Reported Outcomes Among Patients With Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer in ALTA-1L Trial.

OBJECTIVES: An earlier study from the ALTA-1L trial of patients with anaplastic lymphoma kinase-positive non-small cell lung cancer demonstrated that brigatinib produces superior health-related quality of life (QoL) outcomes over crizotinib. This study aimed to derive meaningful change thresholds (MCTs) for European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 and EORTC QLQ-LC13 to refine the earlier results. METHODS: Patients from the ALTA-1L trial were administered the EORTC QLQ-C30 and EORTC QLQ-LC13 questionnaires. Responses were analyzed using anchor-based analysis, graphical analysis, distribution-based analysis, longitudinal responder analysis, and time to deterioration. RESULTS: The patient-reported outcome population comprised 262 patients who completed the EORTC QLQ-C30 at baseline and at least 1 follow-up timepoint. Both anchors (QLQ-C30 items for overall health and QoL) had correlations >0.40 or < -0.40 with all functioning domains, fatigue, pain, appetite loss, and all dyspnea scores. Within-group analysis for most scales found the derived MCT was consistent with a cutoff of 10 points for classifying individual-patient change, except for 3-item dyspnea. The probability of improvement/remaining stable was significantly greater in the brigatinib group over crizotinib for the EORTC QLQ-C30 emotional functioning, appetite loss, and constipation domains. CONCLUSIONS: This study derived MCTs for EORTC QLQ-C30 and QLQ-LC13 domains that may be applied in future studies and again demonstrated the superiority of brigatinib over crizotinib in health-related QoL outcomes in patients with non-small cell lung cancer.

What does better look like in individuals with severe neurodevelopmental impairments? A qualitative descriptive study on SCN2A-related developmental and epileptic encephalopathy.

PURPOSE: There are limited psychometric data on outcome measures for children with Developmental Epileptic Encephalopathies (DEEs), beyond measuring seizures, and no data to describe meaningful change. This study aimed to explore parent perceptions of important differences in functional abilities that would guide their participation in clinical trials. METHODS: This was a descriptive qualitative study. Semi-structured one-on-one interviews were conducted with 10 families (15 parent participants) with a child with a SCN2A-DEE [8 male, median (range) age 7.5 (4.5-21)] years. Questions and probes sought to understand the child's functioning across four domains: gross motor, fine motor, communication, and activities of daily living. Additional probing questions sought to identify the smallest differences in the child's functioning for each domain that would be important to achieve, if enrolling in a traditional therapy clinical trial or in a gene therapy trial. Data were analyzed with directed content analysis. RESULTS: Expressed meaningful differences appeared to describe smaller developmental steps for children with more limited developmental skills and more complex developmental steps for children with less limited skills and were different for different clinical trial scenarios. Individual meaningful changes were described as important for the child's quality of life and to facilitate day-to-day caring. CONCLUSION: Meaningful change thresholds have not been evaluated in the DEE literature. This study was a preliminary qualitative approach to inform future studies that will aim to determine quantitative values of change, applicable to groups and within-person, to inform interpretation of specific clinical outcome assessments in individuals with a DEE.

Effect of present state bias on minimal important change estimates: a simulation study.

PURPOSE: The minimal important change (MIC) in a patient-reported outcome measure is often estimated using patient-reported transition ratings as anchor. However, transition ratings are often more heavily weighted by the follow-up state than by the baseline state, a phenomenon known as "present state bias" (PSB). It is unknown if and how PSB affects the estimation of MICs using various methods. METHODS: We simulated 3240 samples in which the true MIC was simulated as the mean of individual MICs, and PSB was created by basing transition ratings on a "weighted change", differentially weighting baseline and follow-up states. In each sample we estimated MICs based on the following methods: mean change (MC), receiver operating characteristic (ROC) analysis, predictive modeling (PM), adjusted predictive modeling (APM), longitudinal item response theory (LIRT), and longitudinal confirmatory factor analysis (LCFA). The latter two MICs were estimated with and without constraints on the transition item slope parameters (LIRT) or factor loadings (LCFA). RESULTS: PSB did not affect MIC estimates based on MC, ROC, and PM but these methods were biased by other factors. PSB caused imprecision in the MIC estimates based on APM, LIRT and LCFA with constraints, if the degree of PSB was substantial. However, the unconstrained LIRT- and LCFA-based MICs recovered the true MIC without bias and with high precision, independent of the degree of PSB. CONCLUSION: We recommend the unconstrained LIRT- and LCFA-based MIC methods to estimate anchor-based MICs, irrespective of the degree of PSB. The APM-method is a feasible alternative if PSB is limited.

Estimating anchor-based minimal important change using longitudinal confirmatory factor analysis.

PURPOSE: The minimal important change (MIC) is defined as the smallest within-individual change in a patient-reported outcome measure (PROM) that patients on average perceive as important. We describe a method to estimate this value based on longitudinal confirmatory factor analysis (LCFA). The method is evaluated and compared with a recently published method based on longitudinal item response theory (LIRT) in simulated and real data. We also examined the effect of sample size on bias and precision of the estimate. METHODS: We simulated 108 samples with various characteristics in which the true MIC was simulated as the mean of individual MICs, and estimated MICs based on LCFA and LIRT. Additionally, both MICs were estimated in existing PROMIS Pain Behavior data from 909 patients. In another set of 3888 simulated samples with sample sizes of 125, 250, 500, and 1000, we estimated LCFA-based MICs. RESULTS: The MIC was equally well recovered with the LCFA-method as using the LIRT-method, but the LCFA analyses were more than 50 times faster. In the Pain Behavior data (with higher scores indicating more pain behavior), an LCFA-based MIC for improvement was estimated to be 2.85 points (on a simple sum scale ranging 14-42), whereas the LIRT-based MIC was estimated to be 2.60. The sample size simulations showed that smaller sample sizes decreased the precision of the LCFA-based MIC and increased the risk of model non-convergence. CONCLUSION: The MIC can accurately be estimated using LCFA, but sample sizes need to be preferably greater than 125.

'A Meaningful Difference, but Not Ultimately the Difference I Would Want': A Mixed-Methods Approach to Explore and Benchmark Clinically Meaningful Changes in Aphasia Recovery.

INTRODUCTION: Outcome measurement instruments (OMIs) are used to gauge the effects of treatment. In post-stroke aphasia rehabilitation, benchmarks for meaningful change are needed to support the interpretation of patient outcomes. This study is part of a research programme to establish minimal important change (MIC) values (the smallest change above which patients perceive themselves as importantly changed) for core OMIs. As a first step in this process, the views of people with aphasia and clinicians were explored, and consensus was sought on a threshold for clinically meaningful change. METHODS: Sequential mixed-methods design was employed. Participants included people with post-stroke aphasia and speech pathologists. People with aphasia were purposively sampled based on time post-stroke, age and gender, whereas speech pathologists were sampled according to their work setting (hospital or community). Each participant attended a focus group followed by a consensus workshop with a survey component. Within the focus groups, experiences and methods for measuring meaningful change during aphasia recovery were explored. Qualitative data were transcribed and analysed using reflexive thematic analysis. In the consensus workshop, participants voted on thresholds for meaningful change in core outcome constructs of language, communication, emotional well-being and quality of life, using a six-point rating scale (much worse, slightly worse, no change, slightly improved, much improved and completely recovered). Consensus was defined a priori as 70% agreement. Voting results were reported using descriptive statistics. RESULTS: Five people with aphasia (n = 4, > 6 months after stroke; n = 5, < 65 years; n = 3, males) and eight speech pathologists (n = 4, hospital setting; n = 4, community setting) participated in one of four focus groups (duration: 92-112 min). Four themes were identified describing meaningful change as follows: (1) different for every single person; (2) small continuous improvements; (3) measured by progress towards personally relevant goals; and (4) influenced by personal factors. 'Slightly improved' was agreed as the threshold of MIC on the anchor-rating scale (75%-92%) within 6 months of stroke, whereas after 6 months there was a trend towards supporting 'much improved' (36%-66%). CONCLUSION: Our mixed-methods research with people with aphasia and speech pathologists provides novel evidence to inform the definition of MIC in aphasia rehabilitation. Future research will aim to establish MIC values for core OMIs. PATIENT OR PUBLIC CONTRIBUTION: This work is the result of engagement between people with lived experience of post-stroke aphasia, including people with aphasia, family members, clinicians and researchers. Engagement across the research cycle was sought to ensure that the research tasks were acceptable and easily understood by participants and that the outcomes of the study were relevant to the aphasia community. This engagement included the co-development of a plain English summary of the results. Advisors were remunerated in accordance with Health Consumers Queensland guidelines. Interview guides for clinicians were piloted by speech pathologists working in aphasia rehabilitation.

Care partner-informed meaningful change thresholds for the Clinical Dementia Rating-Sum of Boxes for trials of early Alzheimer's disease.

INTRODUCTION: Consensus definitions of meaningful within-patient change (MWPC) on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) are needed. Existing estimates use clinician-rated anchors in clinically diagnosed Alzheimer's disease (AD) populations. Incorporating the care partner perspective offers important insights, and evaluating biomarker-confirmed cohorts aligns estimates with ongoing trials. METHODS: Anchor-based analyses were conducted to evaluate MWPC on the CDR-SB in early AD (Tauriel; NCT03289143) using Caregiver Global Impression of Change in memory or daily activities. RESULTS: Across time points and anchors, mean CDR-SB changes associated with the "somewhat worse" category ranged from 1.50 to 2.12 in early AD, 1.07 to 2.06 in mild cognitive impairment-AD, and 1.79 to 2.25 in mild AD. DISCUSSION: The proposed ranges are appropriate to define meaningful progression on the CDR-SB in similar cohorts and support the interpretation of treatment benefit through MWPC analyses. Thresholds should be calibrated to the context of use; lower/higher thresholds may be applicable in studies of earlier/later disease over shorter/longer durations. HIGHLIGHTS: Within-patient CDR-SB change thresholds are provided using caregiver-rated anchors. 1.5 to 2.5 points may be an appropriate range in early AD trials of similar durations. Cumulative distribution function plots illustrate the benefit of a given treatment. When selecting thresholds, the target population and study design should be considered.

Likely change indexes improve estimates of individual change on patient-reported outcomes.

PURPOSE: Individual change on a patient-reported outcome (PRO) measure can be assessed by statistical significance and meaningfulness to patients. We explored the relationship between these two criteria by varying the confidence levels of the coefficient of repeatability (CR) on the Patient-Reported Outcomes Measurement Information System (R) Physical Function (PF) 10a (PF10a) measure. METHODS: In a sample of 1129 adult cancer patients, we estimated individual-change thresholds on the PF10a from baseline to 6 weeks later with the CR at 50%, 68%, and 95% confidence. We also assessed agreement with group- and individual-level thresholds from anchor-based methods [mean change and receiver operating characteristic (ROC) curve] using a PF-specific patient global impression of change (PGIC). RESULTS: CRs at 50%, 68%, and 95% confidence were 3, 4, and 7 raw score points, respectively. The ROC- and mean-change-based thresholds for deterioration were -4 and -6; for improvement they were both 2. Kappas for agreement between anchor-based thresholds and CRs for deterioration ranged between κ = 0.65 and 1.00, while for improvement, they ranged between 0.35 and 0.83. Agreement between the PGIC and all CRs always fell below "good" (κ < 0.40) for deterioration (0.30-0.33) and were lower for improvement (0.16-0.28). CONCLUSIONS: In comparison to the CR at 95% confidence, CRs at 50% and 68% confidence (considered likely change indexes) have the advantage of maximizing the proportion of patients appropriately classified as changed according to statistical significance and meaningfulness.

How strong should my anchor be for estimating group and individual level meaningful change? A simulation study assessing anchor correlation strength and the impact of sample size, distribution of change scores and methodology on establishing a true meaningful change threshold.

PURPOSE: Treatment benefit as assessed using clinical outcome assessments (COAs), is a key endpoint in many clinical trials at both the individual and group level. Anchor-based methods can aid interpretation of COA change scores beyond statistical significance, and help derive a meaningful change threshold (MCT). However, evidence-based guidance on the selection of appropriately related anchors is lacking. METHODS: A simulation was conducted which varied sample size, change score variability and anchor correlation strength to assess the impact of these variables on recovering the simulated MCT for interpreting individual and group-level results. To assess MCTs derived at the individual-level (i.e. responder definitions; RDs), Receiver Operating Characteristic (ROC) curves and Predictive Modelling (PM) analyses were conducted. To assess MCTs for interpreting change at the group-level, the mean change method was conducted. RESULTS: Sample sizes, change score variability and magnitude of anchor correlation affected accuracy of the estimated MCT. For individual-level RDs, ROC curves were less accurate than PM methods at recovering the true MCT. For both methods, smaller samples led to higher variability in the returned MCT, but higher variability still using ROC. Anchors with weaker correlations with COA change scores had increased variability in the estimated MCT. An anchor correlation of around 0.50-0.60 identified a true MCT cut-point under certain conditions using ROC. However, anchor correlations as low as 0.30 were appropriate when using PM under certain conditions. For interpreting group-level results, the MCT derived using the mean change method was consistently underestimated regardless of the anchor correlation. CONCLUSION: Sample size and change score variability influence the necessary anchor correlation strength when recovering individual-level RDs. Often, this needs to be higher than the commonly accepted threshold of 0.30. Stronger correlations than 0.30 are required when using the mean change method. Results can assist researchers selecting and assessing the quality of anchors.

Measuring individual true change with PROMIS using IRT-based plausible values.

AIMS: A primary advantage of IRT-based patient-reported outcome measures such as PROMIS short forms and computer-adaptive tests is that each estimate of the latent trait comes with a standard error. Such measurement error needs to be acknowledged, in particular when monitoring individual patients over time. In this study, we use plausible values to account for measurement error and analyze the probability of true within-individual change. METHODS: We use a longitudinal, observational study of stable and exacerbated COPD patients (N = 185), providing PROMIS Physical Function and Fatigue T-scores over 3 months. At each measurement, we imputed 1000 plausible values from the scores' posterior distribution. These were then used to calculate probability of true change using a pre-specified threshold such as minimally important difference supported by the literature, or [Formula: see text] > 0. We demonstrate assessment of change in individuals and in groups, across different measures (Short Forms and CATs), and at various levels of confidence. RESULTS: Using plausible value imputation and with 95% certainty, 47.5% of participants in the exacerbated group reported less fatigue, compared with 26.5% of participants in the stable group. Comparison of Short Forms and CATs suggests that CATs have better ability to detect change compared to short forms. We also illustrate this method using an individual's probability of change at different time points. CONCLUSION: Plausible values offer a flexible way to include measurement error in analysis of individuals and on sample level. Assessment of probability of true change can complement existing distribution-based approaches and facilitates interpretation of improvement or decline.

Transitions in depression: if, how, and when depressive symptoms return during and after discontinuing antidepressants.

PURPOSE: The aim of the current study is to provide insight into if, how, and when meaningful changes occur in individual patients who discontinue antidepressant medication. Agreement between macro-level quantitative symptom data, qualitative ratings, and micro-level Ecological Momentary Assessments is examined. METHODS: During and shortly after antidepressant discontinuation, depressive symptoms and 'feeling down' were measured in 56 participants, using the SCL-90 depression subscale weekly (macro-level) for 6 months, and 5 Ecological Momentary Assessments daily (micro-level) for 4 months (30.404 quantitative measurements in total). Qualitative information was also obtained, providing additional information to verify that changes were clinically meaningful. RESULTS: At the macro-level, an increase in depressive symptoms was found in 58.9% of participants that (a) was statistically reliable, (b) persisted for 3 weeks and/or required intervention, and (c) was clinically meaningful to patients. Of these increases, 30.3% happened suddenly, 42.4% gradually, and for 27.3% criteria were inconclusive. Quantitative and qualitative criteria showed a very high agreement (Cohen's κ = 0.85) regarding if a participant experienced a recurrence of depression, but a moderate agreement (Cohen's κ = 0.49) regarding how that change occurred. At the micro-level, 41.1% of participants experienced only sudden increases in depressed mood, 12.5% only gradual, 30.4% experienced both types of increase, and 16.1% neither. CONCLUSION: Meaningful change is common in patients discontinuing antidepressants, and there is substantial heterogeneity in how and when these changes occur. Depressive symptom change at the macro-level is not the same as depressive symptom change at the micro-level.

Inferring meaningful change in quality of life with posterior predictive distribution: an alternative to standard error of measurement.

OBJECTIVE: In the absence of population-based information, distribution-based meaningful change metrics have been previously found to perform similarly. Yet, it is unknown how a Bayesian approach derived from Posterior Predictive Distribution (PPD) of anticipated changes would compare against existing metrics. METHODS: PPD defines meaningful change as change scores that exceed the amount expected from the posterior predictive distribution given a previous score. The PPD adjusts for common statistical phenomena that arise in a pre-test-post-test setting, such as regression to the mean and post-test drift. The PPD was compared to Reliable Change Index (RCI) and Gulliksen-Lord-Novick (GLN) methods using published real-world data and simulated hypothetical data, respectively. RESULTS: Real-world data showed that the methods made similar classifications when the measurement reliability was above 0.80. When reliability was low at 0.50 and thus more susceptible to regression to the mean effects, PPD and GLN were able to correct for it but not the RCI. However, PPD was more conservative and sensitive to biased priors. The simulation study showed that the three methods performed similarly overall, but PPD was slightly better in detecting prevalent changes, e.g., at time 2 (against RCI at p < 0.0001; against GLN at p < 0.0001) and time 3 (p = 0.024, p = 0.002). CONCLUSIONS: When measurement reliability is high, as is frequent in HRQOL development efforts, the three methods performed similarly. At a cost of more conservative cutoffs and complex calculations, the Bayesian PPD nevertheless confers practical advantages when reliability is low. It may be worthy of further research and applications.

How scoring limits the usability of minimal important differences (MIDs) as responder definition (RD): an exemplary demonstration using EORTC QLQ-C30 subscales.

PURPOSE: The recommended method for establishing a meaningful threshold for individual changes in patient-reported outcome (PRO) scores over time uses an anchor-based method. The patients assess their perceived level of change and this is used to define a threshold on the PRO score which may be considered meaningful to the patient. In practice, such an anchor may not be available. In the absence of alternative information often the meaningful change threshold for assessing between-group differences, the minimally important difference, is used to define meaningful change at the individual level too. This paper will highlight the issues with this, especially where the underlying measurement scale is not continuous. METHODS: Using the EORTC QLQ-C30 as an example, plausible score increments ("state changes") are calculated for each subscale highlighting why commonly used thresholds may be misleading, including leading to sensitivity analyses that are inadvertently testing the same underlying threshold. RESULTS: The minimal possible individual score change varies across subscales; 6.7 for Physical Functioning, 8.3 for Global Health Scale and Emotional Functioning, 11.1 for fatigue, 16.7 for role functioning, cognitive functioning, social functioning, nausea and vomiting, pain and 33.3 for single items. CONCLUSIONS: The determination of meaningful change for an individual patient requires input from the patients but being mindful of the underlying scale ensures that these thresholds are also guided by what is a plausible change for patients to achieve on the scale.

Estimating meaningful change for The Impact of Weight on Self-Perception (IW-SP) questionnaire among people with type 2 diabetes.

PURPOSE: The Impact of Weight on Self-perception Questionnaire (IW-SP) is a three-item patient-reported outcome measure (PROM) instrument assessing the impact of body weight on self-perception. To date no published threshold for meaningful change exists. The objective of this study was to estimate the minimal important change (MIC) for the IW-SP among people with type 2 diabetes. METHODS: Responder analyses were conducted using anchor- and distribution-based approaches with existing clinical trial data (SURPASS-2). As SURPASS-2 did not include a priori anchors, a set of alternative exploratory anchors were identified based on the MICs and items from two conceptually related measures used in the trial as well as percent change in body weight. Exploratory anchors with change estimates that were sufficiently related to change in IW-SP (r ≥ 0.30) and were not redundant with other anchors were retained for the MIC analyses. The analyses were conducted in two stages (estimation = 2/3 of sample) to derive initial IW-SP MIC estimates, and a subsequent confirmation stage (remaining 1/3 of sample). RESULTS: While the most conceptually related anchors and items performed best in responsiveness analyses, all anchors resulted in a similar estimate of minimal meaningful change for the IW-SP total score: a 1-point change in raw units (1-5-point scale), corresponding to a 25-point change for transformed scores (0-100 scale). Distribution-based analyses supported these MIC estimates. Results were similar across both stages for all analyses. CONCLUSION: The MIC for the IW-SP for patients with T2D is a 25-point change on the transformed score.

Using qualitative methods to establish the clinically meaningful threshold for treatment success in alopecia areata.

PURPOSE: Traditionally, appropriate anchors are used to investigate the amount of change on a clinician-reported outcome assessment that is meaningful to individual patients. However, novel qualitative methods involving input from disease state experts together with patients may better inform the individual improvement threshold for demonstrating the clinical benefit of new treatments. This study aimed to establish a clinically meaningful threshold for treatment success for the clinician-reported Severity of Alopecia Tool (SALT) score for patients with alopecia areata (AA). METHODS: A purposive sample of 10 dermatologists expert in AA and 30 adult and adolescent patients with AA and a history of ≥ 50% scalp hair loss were recruited. Semi-structured interview questions explored the outcome that represented treatment success to clinicians and patients. Findings were analyzed using thematic methods to identify treatment success thresholds. RESULTS: Both informant groups confirmed scalp hair amount as the outcome of priority. Most expert clinicians considered a static threshold of 80% (n = 5) or 75% (n = 3) of the scalp hair as a treatment success. Most patient responses ranged from 70 to 90% (median: 80% of the scalp hair). Subsequently, queried patients confirmed that achieving SALT score ≤ 20 with treatment would be a success, as reflected in the Alopecia Areata Investigator Global Assessment (AA-IGA™). The novel qualitative processes used to inform this meaningful threshold reflects a clinician-then-patient process for: (a) confirmation of the patient outcome of priority; and (b) clinician input on a preliminary treatment success level for independent understanding among patients. CONCLUSION: This qualitative investigation of expert clinicians-then-patients with AA confirmed that achieving an amount of 80% or more scalp hair (SALT score ≤ 20) was an appropriate individual treatment success threshold indicating clinically meaningful improvement for patients with ≥ 50% scalp hair loss. A qualitative investigation of a quantifiable treatment success threshold is possible through a well-designed interview process with expert clinicians and the appropriate patient population.

Comparison of anchor-based methods for estimating thresholds of meaningful within-patient change using simulated PROMIS PF 20a data under various joint distribution characteristic conditions.

PURPOSE: To compare the performance of anchor-based methods for estimating thresholds of meaningful within-patient change (i.e., individual change) of clinical outcome assessments in conditions reflecting data characteristics of small- to medium-sized clinical trials. METHODS: Datasets were generated from the joint distributions of the PROMIS PF 20a T-score changes and a seven-point global change anchor measure. The 108 simulation conditions (1000 replications per condition) included combinations of three marginal distributions of T-score changes, three improvement percentages in the anchor measure, four levels of responsiveness correlations, and three sample sizes. Threshold estimation methods included mean change, median change, ROC curve, predictive modeling, half SD, and SEM. Relative bias, precision, accuracy, and measurement significance of the estimates were evaluated based on comparison with true thresholds and IRT-based individual reliable changes of PROMIS scores. Quantile regression models were applied to select and interpret effects of simulation conditions on estimation bias. RESULTS: When PROMIS T-score changes were distributed normally, the predictive modeling method performed best with 50% or more responders identified by the anchor; the mean and median methods were preferred with 30% responders. For skewed distributions, the median method and ROC method gained more advantages. Among the evaluated study conditions, the improvement percentage condition had the most obvious effects on estimation bias. CONCLUSION: To establish accurate and precise thresholds, clinical researchers are recommended to prioritize study designs with at least 50% anchor-defined responders and strongly responsive target endpoints with highly reliable scoring calibration and to select optimal anchor-based methods given the data characteristics.