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ObjectivesDeveloping disease modifying therapies for Parkinson’s disease (PD) calls for outcome measurement strategies focused on characterizing early stage disease progression. We explored the psychometric evidence for using the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part II (patient motor experience of daily living) and part III (clinician motor examination) in this context.MethodsMDS-UPDRS-II and -III data were collected at screening, month 12, and month 24 from 384 early stage PD patients (diagnosis ≤ 2 years; Hoehn and Yahr stage 1/2) in the Parkinson’s Progression Markers Initiative (PPMI) study. Psychometric analysis, based on Rasch measurement theory (RMT), was performed on both the original MDS UPDRS-II and -III scales and exploratory content-driven scale structures.ResultsRMT analyses showed neither scale was well targeted to early PD. A marked floor effect appeared for most items and a clear item gap was consistently observed in very mild severity of motor signs and levels of motor impact. The original MDS-UPDRS-II and -III scales also displayed disordered thresholds (9/13 and 20/33 items, respectively), indicating response scales not functioning as expected, and misfit (5/13 and 12/33 items, respectively), flagging areas for potential improvement.ConclusionsThe MDS-UPDRS-II and -III have psychometric limitations which limits the precision of measurement of motor symptoms and impact in early PD. This can lead to insensitivity in detecting differences and clinical change. Importantly, the diagnostic psychometric evidence provided by the RMT analysis provides a clear starting point for how to improve the quantification of clinically relevant concepts to characterize the course of early PD.

Saturation, a core concept in qualitative research, suggests when data collection might end. It is reached when no new relevant information emerges with additional interviews. The aim of this research was to explore whether a mixed methods design could contribute to the demonstration of saturation. Firstly, saturation was conceptualized mathematically using set theory. Secondly, a conversion mixed design was conducted: a set of codes derived from qualitative interviews were quantitized and analyzed using partial least squares (PLS) regression to document whether saturation was reached. A qualitative study conducted by other researchers prior to this work (i.e. none of the present authors was involved in this study) was used to test saturation using PLS regression. This illustrative qualitative study aimed to investigate the impact of Clostridium difficile infection (CDI) on nurses' work in the hospital and the results were published elsewhere (Guillemin et al. 2015). Semi-structured interviews were conducted with 12 nurses. Saturation was characterized by the cumulative percentage of variability accounted for by PLS factors. After 12 interviews, this percentage was 51% which suggests that saturation was achieved at least on main themes. Two main themes identifying similarities in the experience of nurses caring for patients with CDI were identified: Organization/Coordination of the working day and Time-consuming work. Although dependent on the coding of qualitative data, PLS regression of quantitized data from qualitative interviews generated useful information for the determination of saturation.

Background The strict and demanding dietary treatment and mild cognitive abnormalities seen in PKU treated from a young age can be expected to affect the health-related quality of life (HRQoL) of patients and their families. Our aim was to describe the HRQoL of patients with PKU from a large international study, using generic HRQoL measures and an innovative PKU-specific HRQoL questionnaire (PKU-QOL). Analyses were exploratory, performed post-hoc on data collected primarily to validate the PKU-QOL. Methods A multicentre, prospective, non-interventional, observational study conducted in France, Germany, Italy, The Netherlands, Spain, Turkey and the UK. Patients diagnosed with PKU aged ≥9 years old and treated with a Phe-restricted diet and/or Phe-free amino acid protein supplements and/or pharmacological therapy were included in the study; parents of at least one patient with PKU aged <18 years were also included. HRQoL was assessed by generic measures (Pediatric Quality-of-Life Inventory; Medical Outcome Survey 36 item Short Form; Child Health Questionnaire 28 item Parent Form) and the newly developed PKU-QOL. Mean generic domain scores were interpreted using published reference values from the general population. PKU-QOL domain scores were described overall and in different subgroups of patients defined according to severity of PKU, overall assessment of patient’s health status by the investigator and treatment with tetrahydrobiopterin (BH 4 ). Results Data from 559 subjects were analysed: 306 patients (92 children, 110 adolescents, 104 adults) and 253 parents. Mean domain scores of generic measures in the study were comparable to the general population. The highest PKU-QOL impact scores (indicating greater impact) were for emotional impact of PKU, anxiety about blood Phe levels, guilt regarding poor adherence to dietary restrictions or Phe-free amino acid supplement intake and anxiety regarding blood Phe levels during pregnancy. Patients with mild/moderate PKU and those receiving BH 4 reported lower practical and emotional impacts of the diet and Phe-free amino acid supplement intake. Conclusion Patients with PKU showed good HRQoL in the study, both with the generic and PKU-specific measures. Negative impacts of PKU on a patient’s life, including the emotional impact of PKU and its management, was delineated by the PKU-QOLs across all age groups.

Background Myasthenia gravis (MG) is a chronic autoimmune neuromuscular disease, characterised by fluctuating muscle weakness which makes it challenging to assess symptom severity. Mixed methods psychometrics (MMP), which combines evidence from qualitative research and modern psychometrics, is a versatile approach to the development of patient-centred outcome measures (PCOM) in the context of rare disease. Our objective was to develop the MG Symptom patient-reported outcome (PRO) to assess key aspects of MG severity from the patient perspective. Methods We used MMP to develop a novel PRO instrument in a multi-step process. An initial conceptual model for MG patient experience was developed and expanded based on preliminary literature review and two waves of concept elicitation interviews with people with MG (Step 1). Based on this, the novel PRO instrument, the MG Symptoms PRO, was drafted. The draft instrument was refined by combining qualitative and quantitative data collected in a Phase 2 clinical study (Step 2). Results Findings from the literature review and concept elicitation interviews (n = 96) indicated that patient experience in MG includes proximal muscle weakness symptoms related to several body parts, along with muscle weakness fatigability and general fatigue. Then, a set of 42 items across five scales (ocular-, bulbar-, and respiratory muscle weakness, physical fatigue, and muscle weakness fatigability) was developed. Qualitative evidence endorsed its relevance, clarity, and ease of completion; quantitative analysis with Rasch measurement theory methods demonstrated strong measurement properties, including good targeting and high reliability. Classical test theory analyses showed adequate reliability of the instrument and mild to moderate correlations with other widely used MG-specific outcome measures. Conclusions The MG Symptoms PRO has potential to be used both to measure treatment benefit in clinical trials and monitor symptom severity in clinical practice. Its component scales were purposefully designed to stand alone, enhancing interpretability of scores given the heterogeneity of MG, and enabling modular use. Compared with existing MG PROs, it contains more detailed assessments of muscle weakness and muscle weakness fatigability symptoms, which are of key importance to people with MG. The MMP approach used may serve as a case study for developing PCOMs across rare disease indications.

Background Meaningfully interpreting patient-reported outcomes (PRO) results from randomized clinical trials requires that the PRO scores obtained in the trial have the same meaning across patients and previous applications of the PRO instrument. Calibration of PRO instruments warrants this property. In the Rasch measurement theory (RMT) framework, calibration is performed by fixing the item parameter estimates when measuring the targeted concept for each individual of the trial. The item parameter estimates used for this purpose are typically obtained from a previous “calibration” study. But imposing this constraint on item parameters, instead of freely estimating them directly in the specific sample of the trial, may hamper the ability to detect a treatment effect. The objective of this simulation study was to explore the potential negative impact of calibration of PRO instruments that were developed using RMT on the comparison of results between treatment groups, using different analysis methods. Methods PRO results were simulated following a polytomous Rasch model, for a calibration and a trial sample. Scenarios included varying sample sizes, with instrument of varying number of items and modalities, and varying item parameters distributions. Different treatment effect sizes and distributions of the two patient samples were also explored. Cross-sectional comparison of treatment groups was performed using different methods based on a random effect Rasch model. Calibrated and non-calibrated approaches were compared based on type-I error, power, bias, and variance of the estimates for the difference between groups. Results There was no impact of the calibration approach on type-I error, power, bias, and dispersion of the estimates. Among other findings, mistargeting between the PRO instrument and patients from the trial sample (regarding the level of measured concept) resulted in a lower power and higher position bias than appropriate targeting. Conclusions Calibration does not compromise the ability to accurately assess a treatment effect using a PRO instrument developed within the RMT paradigm in randomized clinical trials. Thus, given its essential role in producing interpretable results, calibration should always be performed when using a PRO instrument developed using RMT as an endpoint in a randomized clinical trial.

Patient-reported outcomes (PROs) are increasingly used in single-arm cancer studies. We reviewed 60 papers published between 2018 and 2021 of single-arm studies of cancer treatment with PRO data for current practice on design, analysis, reporting, and interpretation. We further examined the studies’ handling of potential bias and how they informed decision making. Most studies (58; 97%) analysed PROs without stating a predefined research hypothesis. 13 (22%) of the 60 studies used a PRO as a primary or co-primary endpoint. Definitions of PRO objectives, study population, endpoints, and missing data strategies varied widely. 23 studies (38%) compared the PRO data with external information, most often by using a clinically important difference value; one study used a historical control group. Appropriateness of methods to handle missing data and intercurrent events (including death) were seldom discussed. Most studies (51; 85%) concluded that PRO results supported treatment. Conducting and reporting of PROs in cancer single-arm studies need standards and a critical discussion of statistical methods and possible biases. These findings will guide the Setting International Standards in Analysing Patient-Reported Outcomes and Quality of Life Data in Cancer Clinical Trials–Innovative Medicines Initiative (SISAQOL-IMI) in developing recommendations for the use of PRO-measures in single-arm studies.

The MDS-UPDRS was not specifically developed for early-stage Parkinson’s disease (PD). This study investigated a sub-score of MDS-UPDRS Part III to assess bradykinesia and rigidity, which would be more targeted and clinically meaningful to assess disease progression in early-stage PD. A cross-sectional Rasch model was applied to the Parkinson’s Progression Markers Initiative (PPMI) untreated PD cohort data ( N  = 423) to define an adequate item set. Additionally, we evaluated how the daily life items from MDS-UPDRS Part II relate to bradykinesia and rigidity severity. A sub-score of 15 MDS-UPDRS Part III items focusing on limb-related bradykinesia and rigidity demonstrated good measurement properties in early-stage PD. Items adequately targeted to the study sample, and a meaningful hierarchy supported the validity of the scale. The scale was invariant to symptomatic treatment intake. Onset of clinical signs was represented as a milestone in the emergence of impairment in patients’ daily functioning.

Purpose Physical functioning and fatigue are key patient concerns in myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML). The objective of this research was to generate supportive quantitative evidence for modular physical functioning and fatigue measures based on the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 items (QLQ-C30) and a customized selection of 10 supplemental items from the EORTC Item Library. Methods The 40 items were completed online cross-sectionally by 51 patients (higher risk [HR] MDS: 53%; CMML: 26%; AML: 10%). Psychometric analyses based on Rasch measurement theory (RMT) were conducted on the QLQ-C30 physical functioning and fatigue domains as well as measures combining QLQ-C30 and supplemental items. A measure of anemia-related symptoms composed of QLQ-C30 and supplemental items covering fatigue, dyspnea, and dizziness was also investigated. Results The QLQ-C30 physical functioning and fatigue domains showed good targeting to the sample and adequate reliability, with few conceptual gaps identified. Combining the QLQ-C30 and supplemental physical functioning and fatigue items improved the conceptual coverage and the reliability of the measures. The patient-reported anemia-related symptom measure showed good measurement performance, underpinned by a clinically meaningful characterization of severity of these symptoms over a spectrum, starting with fatigue, then dyspnea, and finally dizziness (most severe). Conclusion The modular measurement approach of combining EORTC QLQ-C30 and Item Library offers a promising pragmatic solution to the measurement of physical functioning and fatigue, as well as anemia-related symptoms in clinical trials conducted in HR MDS, CMML, and AML.

Background Trials of disease-modifying therapies (DMTs) for multiple sclerosis (MS) often include patients with minimal disability. Patient-reported outcome instruments used in these trials have often not captured physical and psychological treatment effects concomitant with observed clinical benefits. Objective To examine whether the Multiple Sclerosis Impact Scale-29 (MSIS-29) captures changes in the impact of MS in a sample of patients enrolled in the Phase 3 ASCLEPIOS studies (ofatumumab vs. teriflunomide). Methods Measurement properties (i.e. item fit, reliability, and targeting) of the MSIS-29 were analyzed using Rasch measurement theory (RMT) in data from two phase 3 ofatumumab clinical trials including patients with relapsing-remitting or secondary progressive MS (N = 1882). Targeting of the MSIS-29 items to the patient population was explored within groups categorized by Expanded Disability Status Scale (EDSS) scores. Results Under RMT analyses, both the Physical and Psychological Impact scales of the MSIS-29 were not appropriately targeted to the overall sample of patients. In particular, 49% and 30% of patients with an EDSS score ≤ 2.5 had fewer physical and psychological impacts, respectively, than would typically be captured by these MSIS-29 items compared to patients with EDSS scores of ≥ 3. Conclusion The MSIS-29 is commonly used to evaluate the patient-reported physical and psychological impact of MS. However, it may be limited in evaluating changes associated with DMTs in patients with minimal disability.

Purpose The aim of this study is to illustrate an example application of Rach Measurement Theory (RMT) in the evaluation of patient-reported outcome (PRO) measures. RMT diagnostic methods were applied to evaluate the PROMIS® Depression items as part of a series of papers applying different psychometric paradigms in parallel to the same data. Methods RMT was used to examine scale-to-sample targeting, scale performance and sample measurement of two PROMIS depression item pools including respectively 28 and 51- items. Results Sub-optimal but improved targeting was displayed in the 51-item pool which covered 27% of the range of depression measured in the sample compared to only 15% in the 28-item bank, further reducing the sample percentage with lower depression not covered by the scale (28% Vs 34%). Satisfactory scale performance was observed by the 28-item bank with marginal item misfit. However, deviations from the RMT criteria in the 51-itempool were observed including: 9 reversed thresholds; 12 misfitting items and 12 item-pairs displaying dependency. Overall reliability was good for sets of items (Person Separation Index = 0.93 and 0.95), but sub-optimal sample measurement (17% Vs 19% fit residuals outside of the recommended range). Conclusions The RMT approach in this exercise provided evidence that compared to the 28-item bank, the extended 51-item version of the PROMIS depression, improved sample-to-scale targeting. However, targeting in the lower end of the concept of interest remained sub-optimal and scale performance deteriorated. There may be a need to improve the conceptual breadth of the construct under investigation to ensure the inclusion of items that capture the full range of the concept of interest for this context of use.