Measuring fatigue in people with multiple sclerosis - which questionnaire should be used? A Plain Language Summary of Publication.

WHAT IS THIS SUMMARY ABOUT?: This summary explains the findings of a recent study that compared different questionnaires used by doctors to measure levels of fatigue in people with multiple sclerosis (MS). The aim of the study was to find out which questionnaire doctors should use to measure fatigue in people with MS in the future. Fatigue, which can be described as the overwhelming feeling of tiredness or exhaustion, is a very common symptom of MS. For the majority of people with MS, fatigue is one of the worst symptoms of MS, so it is essential that doctors can measure it accurately. Currently, people with MS are asked to complete questionnaires so that their care team can see the effect of fatigue on their day-to-day lives. There are many questionnaires that are used to measure fatigue in people with MS. It would be valuable to come to an agreement, based on evidence from research like this study, on which questionnaire is the most appropriate for measuring fatigue in both research and healthcare settings. This study compared a questionnaire called the PROMIS® Fatigue (MS) 8a, referred to throughout this summary as the PROMIS® MS Fatigue Short Form, with two of the most commonly used questionnaires: the Fatigue Severity Scale (FSS) and the Modified Fatigue Impact Scale (MFIS). The questionnaires were compared to see which one should be recommended to doctors for measuring fatigue in people with MS. WHAT ARE THE KEY TAKEAWAYS?: It was found that while all three questionnaires were good, the PROMIS® MS Fatigue Short Form questionnaire was better than the other two questionnaires at showing differences in levels of fatigue between people with MS. The PROMIS® MS Fatigue Short Form was also found to be better than the Fatigue Severity Scale (FSS) at showing changes in the person with MS's level of fatigue. The PROMIS® MS Fatigue Short Form questionnaire may help people with MS to better communicate challenges with their fatigue to their doctors. WHAT WAS THE MAIN CONCLUSION REPORTED BY THE RESEARCHERS?: The study suggests that the PROMIS® MS Fatigue Short Form questionnaire is a helpful tool for doctors and people with MS to measure fatigue.

Exploring the Perspectives of Patients Living With Lupus: Retrospective Social Listening Study.

BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease affecting various organs with a wide range of clinical manifestations. Cutaneous lupus erythematosus (CLE) can manifest as a feature of SLE or an independent skin ailment. Health-related quality of life (HRQoL) is frequently compromised in individuals living with lupus. Understanding patients' perspectives when living with a disease is crucial for effectively meeting their unmet needs. Social listening is a promising new method that can provide insights into the experiences of patients living with their disease (lupus) and leverage these insights to inform drug development strategies for addressing their unmet needs. OBJECTIVE: The objective of this study is to explore the experience of patients living with SLE and CLE, including their disease and treatment experiences, HRQoL, and unmet needs, as discussed in web-based social media platforms such as blogs and forums. METHODS: A retrospective exploratory social listening study was conducted across 13 publicly available English-language social media platforms from October 2019 to January 2022. Data were processed using natural language processing and knowledge graph tagging technology to clean, format, anonymize, and annotate them algorithmically before feeding them to Pharos, a Semalytix proprietary data visualization and analysis platform, for further analysis. Pharos was used to generate descriptive data statistics, providing insights into the magnitude of individual patient experience variables, their differences in the magnitude of variables, and the associations between algorithmically tagged variables. RESULTS: A total of 45,554 posts from 3834 individuals who were algorithmically identified as patients with lupus were included in this study. Among them, 1925 (authoring 5636 posts) and 106 (authoring 243 posts) patients were identified as having SLE and CLE, respectively. Patients frequently mentioned various symptoms in relation to SLE and CLE including pain, fatigue, and rashes; pain and fatigue were identified as the main drivers of HRQoL impairment. The most affected aspects of HRQoL included "mobility," "cognitive capabilities," "recreation and leisure," and "sleep and rest." Existing pharmacological interventions poorly managed the most burdensome symptoms of lupus. Conversely, nonpharmacological treatments, such as exercise and meditation, were frequently associated with HRQoL improvement. CONCLUSIONS: Patients with lupus reported a complex interplay of symptoms and HRQoL aspects that negatively influenced one another. This study demonstrates that social listening is an effective method to gather insights into patients' experiences, preferences, and unmet needs, which can be considered during the drug development process to develop effective therapies and improve disease management.

Understanding the Symptoms and Impacts Experienced by People with Relapsing-Remitting MS: A Qualitative Investigation Using Semi-Structured Interviews.

INTRODUCTION: Multiple sclerosis (MS) is a disabling disease with unpredictable clinical manifestations. As clinical assessments may not fully capture the impact of MS on quality of life, they can be complemented by patient-reported outcome (PRO) measures to provide a more comprehensive picture of MS disease state and impact. The objectives of this study were to explore the experiences of people with relapsing-remitting MS, including symptoms and impacts on daily life, and to provide a conceptual model of MS outcomes. METHODS: A literature review of studies that evaluated the experiences of people with MS was completed and combined with semi-structured concept elicitation interviews conducted with 14 people with relapsing-remitting MS in the USA. RESULTS: The average age of the 14 participants was 43.9 (range 25-64) years, most were White (78.6%) and female (78.6%), and the mean duration since diagnosis was 6.6 (2-10) years. The most bothersome symptoms identified included fatigue (n = 9), cognitive dysfunction (n = 5), mobility/difficulty with walking (n = 3), and vision problems (n = 3). The most commonly reported impacts on daily life were balance problems/instability (n = 13), work life/productivity (n = 12), difficulty walking (n = 11), daily activities/household chores (n = 11), and leisure activities (n = 10). CONCLUSION: There was a high frequency of concepts associated with physical function, fatigue, and sensory-motor actions. A conceptual model was developed that captures the disease symptoms, impairments, and impacts identified in the interviews as well as known processes and symptoms identified in the literature search. This model underpins the appropriateness of PRO instruments, such as the PROMIS Fatigue (MS) 8a and PROMIS Physical Function (MS) 15a, which evaluate symptoms and impacts that matter most to people with MS.

Recommendations to address respondent burden associated with patient-reported outcome assessment.

Patient-reported outcomes (PROs) are increasingly used in healthcare research to provide evidence of the benefits and risks of interventions from the patient perspective and to inform regulatory decisions and health policy. The use of PROs in clinical practice can facilitate symptom monitoring, tailor care to individual needs, aid clinical decision-making and inform value-based healthcare initiatives. Despite their benefits, there are concerns that the potential burden on respondents may reduce their willingness to complete PROs, with potential impact on the completeness and quality of the data for decision-making. We therefore conducted an initial literature review to generate a list of candidate recommendations aimed at reducing respondent burden. This was followed by a two-stage Delphi survey by an international multi-stakeholder group. A consensus meeting was held to finalize the recommendations. The final consensus statement includes 19 recommendations to address PRO respondent burden in healthcare research and clinical practice. If implemented, these recommendations may reduce PRO respondent burden.

What do Hyperhidrosis Quality of Life Index (HidroQoL©) scores mean? Transferring science into practice by establishing a score banding system.

BACKGROUND: The Hyperhidrosis Quality of Life Index (HidroQoL©) is a measure of quality of life (QoL) impacts in hyperhidrosis (HH). OBJECTIVES: We aimed to establish score banding systems for the HidroQoL total score for specific contexts representing different severity/impact categories by using the Dermatology Life Quality Index (DLQI) and the Hyperhidrosis Disease Severity Scale (HDSS) as anchors, including data from 357 patients from a phase III clinical trial. METHODS: We used the HDSS, the established DLQI score bands and two single items (items 5 and 7) of the DLQI as anchors for the creation of banding systems for the HidroQoL. These anchors were chosen via consensus among an expert group according to relevance to patient experience. Due to the distribution of the HDSS and the single DLQI item 7, receiver operating characteristic curves were computed in order to create an optimal cut-off value of the HidroQoL total score. For the DLQI banding system and the single DLQI item 5, we created a banding system for the HidroQoL based on the distribution of their different categories. RESULTS: A score of 30 and greater is proposed as the cut-off value for sweating that 'always interferes in daily activities', based on the HDSS as anchor. In terms of overall skin QoL effects, score bands of 0-6, 7-18, 19-25, 26-32 and 33-36 represent 'no effect', 'small effect', 'moderate effect', 'very large effect' and 'extremely large effect' on the patient's life, respectively. CONCLUSIONS: In this study, we propose different banding systems for four different contexts: skin-specific QoL (DLQI banding), HH severity (HDSS), working and studying (single DLQI item 7) and social and leisure activities (single DLQI item 5). These banding systems and cut-off values can be used in clinical research and practice to place the patients in different severity categories.

The effect of disease modifying therapies on fatigue in multiple sclerosis.

INTRODUCTION: Fatigue is one of the most common and debilitating symptoms in people with multiple sclerosis (PwMS). Disease-modifying therapies (DMTs) are currently the gold standard in the treatment of MS and their effectiveness has been assessed through randomized clinical trials (RCTs). However, there is limited evidence on the impact of DMTs on fatigue in (PwMS). We conducted a systematic review to 1) understand whether fatigue is included as an outcome in MS trials of DMTs; 2) determine the effects on fatigue of treating MS with DMTs and 3) assess the quality of MS trials including fatigue as an outcome. METHODS: Two independent researchers systematically searched MEDLINE, EMBASE and ClinicalTrials.gov from 1993 to January 2023 for RCTs that measured fatigue as an outcome. Adherence to reporting standards was assessed with the Consolidated Standards of Reporting Trials (CONSORT)-Patient-Reported Outcomes (PRO), while the risk of bias (RoB) was assessed with the RoB 2 tool by the Cochrane Handbook for Systematic Reviews of Interventions. The systematic review protocol was registered in PROSPERO (CRD42022383321). RESULTS: The search strategy identified 130 RCTs of DMTs of which 7 (5%) assessed fatigue as an outcome. Of the 7 trials, only two presented statistically significant results. In addition, the reporting of fatigue among RCTs was suboptimal with a mean adherence to the CONSORT-PRO Statement of 36% across all trials. Of the 7 trials included, four were assessed as 'high' RoB.. CONCLUSIONS: Fatigue has a major impact on PwMS yet there is limited trial-based evidence on the impact of DMTs on fatigue. Assessment of fatigue as an outcome is underrepresented in trials of DMTs and the reporting of PRO trial data is suboptimal. Thus, it is imperative that MS researchers conduct RCTs that include fatigue as an outcome, to support clinicians and people with MS (PwMS) to consider the impact of the different DMTs on fatigue.

Integrating qualitative interviews in drug development and the use of qualitative evidence in product labelling and health technology assessments: a review.

Objective: Including qualitative research in clinical trial design is an innovative approach to understanding patients' perspective and incorporate the patient's voice in all stages of drug development and evaluation. This review aims to explore current practices, lessons learned from the literature, as well as how qualitative interviews are considered by health authorities for marketing authorization and reimbursement. Methods: A targeted literature review of Medline and Embase databases was conducted in February 2022 to identify publications on qualitative methods embedded in clinical trial of pharmaceutical products. An additional search of guidelines and labeling claims of approved products regarding qualitative research was performed in various sources of grey literature. Results: From the 24 publications and nine documents reviewed, we identified the research questions addressed with qualitative methods during clinical trials (e.g., change in quality of life, symptoms assessment, treatment benefit), preferred data collection methods (e.g., interviews), and data collection points (e.g., baseline and exit interviews). Moreover, the data from labels and HTAs demonstrate that qualitative data can play an important role in approval processes. Conclusion: The use of in-trial interviews is still emerging and is not yet common practice. Although the industry, scientific community, regulatory agencies and HTAs are showing an increasing interest in the use of evidence generated via in-trial interviews, guidance from regulators and HTAs would be helpful. Developing new methods and technologies to address the common challenges for such interviews is key to progress.

Hyperhidrosis quality of life index (HidroQoL): further validation by applying classical test theory and item response theory using data from a phase III clinical trial.

BACKGROUND: The Hyperhidrosis Quality of Life Index (HidroQoL ©) is a well-developed and validated patient-reported outcome measure assessing the quality-of-life impacts in hyperhidrosis with 18 items. Our aim was to extend the already existing validity evidence for the HidroQoL, especially in relation to structural validity. Especially Rasch analysis has not been applied to the final 18-item HidroQoL before. METHODS: Data from a phase III clinical trial were used. Confirmatory factor analysis was conducted to confirm the two a priori HidroQoL scales within classical test theory. Furthermore, the assumptions of the Rasch model (model fit, monotonicity, unidimensionality, local independence) and Differential Item Functioning (DIF) were assessed using item response theory. RESULTS: The sample included 529 patients with severe primary axillary hyperhidrosis. The two-factor structure could be confirmed by the confirmatory factor analysis (SRMR = 0.058). The item characteristic curves showed mainly optimally functioning response categories, indicating monotonicity. The overall fit to the Rasch model was adequate and unidimensionality for the HidroQoL overall scale could be confirmed, since the first factor had an eigenvalue of 2.244 and accounted for 18.7%. Local independence was below assumed thresholds (residual correlations ≤ 0.26). DIF analysis, controlling for age or gender, was critical for four and three items, respectively. However, this DIF could be explained. CONCLUSION: Using classical test theory and item response theory/Rasch analyses, this study provided further evidence for the structural validity of the HidroQoL. This study confirmed several specific (measurement) properties of the HidroQoL questionnaire in patients with physician-confirmed severe primary axillary hyperhidrosis: the HidroQoL is a unidimensional scale allowing the summation of scores to generate a single score, and simultaneously it has a dual structure, also allowing the calculation of separate domain scores for daily activities and psychosocial impacts. With this study, we provided new evidence of the structural validity of the HidroQoL in the context of a clinical trial. Trial registration The study was registered (ClinicalTrials.gov identifier: NCT03658616, 05 September 2018, https://clinicaltrials.gov/ct2/show/NCT03658616?term=NCT03658616&draw=2&rank=1 ).

Key considerations to reduce or address respondent burden in patient-reported outcome (PRO) data collection.

Patient-reported outcomes (PROs) are used in clinical trials to provide evidence of the benefits and risks of interventions from a patient perspective and to inform regulatory decisions and health policy. The collection of PROs in routine practice can facilitate monitoring of patient symptoms; identification of unmet needs; prioritisation and/or tailoring of treatment to the needs of individual patients and inform value-based healthcare initiatives. However, respondent burden needs to be carefully considered and addressed to avoid high rates of missing data and poor reporting of PRO results, which may lead to poor quality data for regulatory decision making and/or clinical care.

A comparison of the measurement properties of the PROMIS Fatigue (MS) 8a against legacy fatigue questionnaires.

BACKGROUND: Amidst the growing number of patient-reported outcome (PRO) measures of fatigue being used in multiple sclerosis (MS) clinical trials and clinics, evidence-based consensus on the most appropriate and generalizable measures across different settings would be beneficial for clinical research and patient care. The objective of this research was to compare the validity and responsiveness of scores from the PROMIS Fatigue (MS) 8a with those of the Fatigue Severity Scale (FSS) and the Modified Fatigue Impact Scale (MFIS), across US and UK MS populations. METHODS: Two observational studies were performed in MS populations as part of a PRO measure development project, including a cross-sectional study in two tertiary US MS centers (n = 340) and a 96-week longitudinal study in the UK MS Register cohort (n = 352). In post-hoc analyses, we examined  relative validity, based on ability to discriminate across patient groups with different fatigue levels or functional status at baseline (i.e., ANOVA-F PROX ÷ ANOVA-F PROMIS (MS) 8a), and relative responsiveness, based on baseline-to-Week-52 score change (effect sizes) across fatigue or functional status response groups . RESULTS: Mean ± standard deviation (SD) age was 44.6 ± 11.3/50.0 ± 9.7; and 72.9%/77.3% were female (US/UK samples). The mean PROMIS Fatigue (MS) 8a T-score ± SD at baseline was 57.7 ± 10.5/58.9 ± 9.3 (US/UK samples). Compared with the PROMIS Fatigue (MS) 8a, relative validity (anchor: Global Health Score [GHS] fatigue global question) was 85% for MFIS symptom score, 48% for MFIS total score, and 44% for the FSS. Relative to the FSS, PROMIS Fatigue (MS) 8a scores were more sensitive to worsening (effect size = -0.43 versus -0.18) as well as improvement (effect size = 0.5 versus 0.2) in fatigue (≥1-point increase/decrease in GHS fatigue global question) over 52 weeks of follow-up. A similar pattern of score changes was observed based on a second anchor. CONCLUSION: The PROMIS Fatigue (MS) 8a scores showed higher responsiveness to fatigue changes than those of the FSS. The PROMIS measure also had higher precision in differentiating levels of fatigue compared to the FSS, the MFIS physical, and MFIS total scores. These differences have practical implications for the application of these questionnaires in both clinical practice and research settings (e.g., sample size estimation in clinical trials).

The validity, responsiveness, and score interpretation of the PROMISnq Physical Function - Multiple Sclerosis 15a short form in multiple sclerosis.

BACKGROUND: A valid, sensitive patient-reported outcome (PRO) measure of physical function (PF) for people with multiple sclerosis (MS) would have substantial value in routine care and clinical research. We now describe development of the PROMISnq Short Form v2.0 PF - Multiple Sclerosis 15a [PROMISnq PF(MS)15a] for assessing PF in relapsing and progressive MS. Also, the validity, reliability, and responsiveness of the PROMISnq PF(MS)15a is evaluated, minimal important difference (MID) thresholds for score change estimated and a score interpretation guide developed. METHODS: A mixed-methods sequential design was employed. Relevant PF concepts were elicited through semi-structured interviews with people with relapsing MS, and then mapped to the PROMIS PF item bank. Measurement experts integrated results from interviews with people with MS and input from a panel of neurologists to generate a draft short form. Relevance and comprehensiveness of the draft short form were assessed in cognitive debriefing interviews with people with relapsing or progressive MS. Subsequently, item reduction and evaluation of psychometric properties were performed in two observational studies: a cross-sectional study in the US (n = 296), and a 96-week longitudinal study in the UK MS Register cohort (n = 558). The main outcomes and measures are estimates of: known-groups validity, convergent validity, reliability, responsiveness; MID for worsening. RESULTS: Factor analyses supported the unidimensionality of the newly derived 15-item short form. Cronbach's alpha (≥ 0.97) and intraclass correlation coefficient (≥ 0.97) of test-retest scores (5-27 days) indicated strong reliability. Convergent validity was demonstrated by moderate-to-strong correlations with scores on related PRO measures. Scores discriminated among patient groups classified by levels of physical health and other criteria. Score changes of 2.3-2.7 points are proposed as MID criteria for minimal worsening in PF. CONCLUSION: PROMISnq PF(MS)15a demonstrated reliability, validity and sensitivity to change. Input from patients and clinicians ensured the content is comprehensive and relevant for people with MS.

Standardizing fatigue measurement in multiple sclerosis: the validity, responsiveness and score interpretation of the PROMIS SF v1.0 - Fatigue (MS) 8a.

BACKGROUND: Fatigue is one of the most common and the single most disabling symptom of multiple sclerosis (MS). However, there is a lack of consensus on the most appropriate fatigue measures in clinical practice and research, based upon rigorously validated, generalizable, and publicly available instruments. The objective of this research was to generate additional evidence regarding the validity and applicability of the PROMIS SF v1.0 - Fatigue (MS) 8a, including content validity, reliability, construct validity and responsiveness, as well as to assess minimal important difference (MID) estimates and a score interpretation tool to aide meaningful individual level score interpretation. METHODS: A mixed-methods, sequential design was followed. Cognitive debriefing (CD) interviews (n=29) were performed with MS patients, to assess the relevance and comprehensiveness of the PROMIS Fatigue (MS) 8a scores. To evaluate the psychometric properties of the PROMIS Fatigue (MS) 8a, two observational studies were conducted: a cross-sectional study at two US MS centers (n=296), and a 96-week longitudinal study in a UK MS Register cohort (n=384). Main outcomes and measures were estimates of known-groups validity, convergence validity, reliability, and responsiveness, a guide for interpreting PROMIS Fatigue (MS) 8a T-scores, and anchor-based MID estimates. RESULTS: The CD interviews confirmed the comprehensiveness and relevance of the PROMIS Fatigue (MS) 8a in assessing MS fatigue. Cronbach's alpha (>0.9) and intra-class correlation coefficient (≥0.9) for test-retest scores at 5-7 days follow-up, supported strong internal consistency and test-retest reliability. Hypothesized differences were found across patient groups in patient reported fatigue and related concepts (analysis of variance [ANOVA], P <0.001). PROMIS Fatigue (MS) 8a scores were sensitive to bi-directional changes in fatigue (GHS fatigue global question) and physical health (PROMIS GHS GPH), over a 52-week follow-up. Score changes of 3.4-4 points are proposed as MID criteria for minimal improvement or worsening in fatigue. CONCLUSION: This research extends the evidence supporting the content validity and the robust psychometric performance of the PROMIS Fatigue (MS) 8a across US and UK MS populations. Importantly, data supporting the measure's integration in clinical practice and research, including meaningful score interpretation, are now available.

An estimate of the economic burden of vitamin D deficiency in pregnant women in the United Kingdom.

Pregnancy is associated with an increased risk of vitamin D deficiency beyond that of the general population. The aim of the current analysis was to synthesize the current evidence on the dose-outcome relationship of vitamin D/serum 25 hydroxyvitamin D (25-OHD) and complications during pregnancy. An additional aim was to estimate the economic burden attributable to inadequate levels of serum 25-OHD. Published literature on the effects of vitamin D supplementation/serum 25-OHD on pregnancy complications, including randomized control trials and non-interventional studies, was searched in bibliographic databases including Pubmed, Google Scholar, Scopus and EMBASE. A positive and significant treatment effect was obtained for pre-eclampsia (OR = 0.75 95% CI 0.662-0.843), but not for preterm birth (OR = 0.783, 95% CI 0.49-1.251) or small for gestational age (OR = 0.76 95% CI 0.38-1.28). Inadequate vitamin D accounted for 14.04% of risk for pre-eclampsia. It is estimated that addressing vitamin D inadequacy in pregnant women in England and Wales would reduce the number of cases of pre-eclampsia by 4126; and would result in a net saving of £18.6 million for the NHS in England and Wales. The current results suggest that based on current evidence a public health policy preventing vitamin D inadequacy in pregnant women is likely to have a positive impact on the NHS budget in England and Wales. This is contingent upon further evidence regarding the vitamin D dose-pregnancy outcome relationship becoming available.

PFI-14©: A Rasch Analysis Refinement of the Psoriasis Family Index.

OBJECTIVE: We aimed to assess the psychometric properties of the Psoriasis Family Index (PFI), a disease-specific instrument, to measure the secondary impact of psoriasis on the quality of life (QoL) of family members and partners of psoriasis patients. METHODS: PFI data were collected from 150 accompanying family members of psoriasis patients attending the dermatology department of a secondary referral hospital. Rasch analysis was used to examine various psychometric properties of the PFI, including dimensionality, response category functioning, fit statistics, scale reliability and validity, item targeting and differential item functioning (DIF). RESULTS: The 15-item PFI with 4 response options showed good overall fit to the Rasch model. The response category almost entirely followed the Linacre criteria, demonstrating its optimal functionality. All items except one had good fit to the Rasch model. The mean fit residual for the items was -0.085 ± 1.184 (range -1.54 to 2.7). Strict unidimensionality was achieved following removal of the misfitting item 5. The revised 14-item PFI maintained strong reliability (person separation index = 0.87). The scale showed minor mistargeting (mean difference between person and item location = 0.95 logits). None of the items displayed DIF across gender or relationship type. CONCLUSIONS: The PFI is the first disease-specific measure to quantify the QoL of family members of psoriasis patients. Following the application of Rasch analysis we now recommend the use of a 14-item version of the PFI: question No. 5 from the 15-item version has been deleted. This study demonstrates the promising psychometric performance of the PFI and confirms its potential as a useful outcome measure in future clinical research.