Development of the Scalp Hair Assessment PRO™ measure for alopecia areata.

BACKGROUND: Valid patient-reported outcome (PRO) measures are required to evaluate alopecia areata (AA) treatments. OBJECTIVES: To develop a content-valid and clinically meaningful PRO measure to assess AA scalp hair loss with scores comparable with the five-response-level Alopecia Areata Investigator Global Assessment (AA-IGA™). METHODS: A draft PRO measure was developed based on input from 10 clinical experts in AA. The PRO measure was cognitively debriefed, modified and finalized through two rounds of qualitative semistructured interviews with patients with AA who had experienced ≥ 50% scalp hair loss. Data were thematically analysed. RESULTS: Adults (round 1: n = 25; round 2: n = 15) and adolescents aged 15-17 years (round 1: n = 5) in North America participated. All patients named scalp hair loss as a key AA sign or symptom. Patients demonstrated the ability to self-report their current amount of scalp hair using percentages. In round 1 not all patients interpreted the measurement concept consistently; therefore, the PRO was modified to clarify the measurement concept to improve usability. Following modifications, patients in round 2 responded without difficulty to the PRO measure. Patients confirmed that they could use the five-level response scale to rate their scalp hair loss: no missing hair, 0%; limited, 1-20%; moderate, 21-49%; large, 50-94%; nearly all or all, 95-100%. Almost all patients deemed hair regrowth resulting in ≤ 20% scalp hair loss a treatment success. CONCLUSIONS: The Scalp Hair Assessment PRO™ is a content-valid, clinically meaningful assessment of distinct gradations of scalp hair loss for evaluating AA treatment for patients with ≥ 50% hair loss at baseline.

The Alopecia Areata Investigator Global Assessment scale: a measure for evaluating clinically meaningful success in clinical trials.

BACKGROUND: Content-valid and clinically meaningful instruments are required to evaluate outcomes of therapeutic interventions in alopecia areata (AA). OBJECTIVES: To develop an Investigator's Global Assessment (IGA) to interpret treatment response in AA treatment studies. METHODS: Qualitative interviews were conducted in the USA with expert dermatologists and with patients with AA who had experienced ≥ 50% scalp-hair loss. Thematic data analysis identified critical outcomes and evaluated the content validity of the new IGA. RESULTS: Expert clinicians (n = 10) judged AA treatment success by the amount of scalp-hair growth (median 80% scalp hair). Adult (n = 25) and adolescent (n = 5) patients participated. Scalp-hair loss was the most bothersome AA sign/symptom for most patients. Perceived treatment success - short of 100% scalp hair - was the presence of ~ 70-90% scalp hair (median 80%). Using additional clinician and patient insights, the Alopecia Areata Investigator Global Assessment (AA-IGA™) was developed. This clinician-reported outcome assessment is an ordinal, static measure comprising five severity categories of scalp-hair loss. Nearly all clinicians and patients in this study agreed that, for patients with ≥ 50% scalp-hair loss, successful treatment would be hair regrowth resulting in ≤ 20% scalp-hair loss. CONCLUSIONS: We recommend using the Severity of Alopecia Tool to assess the extent (0-100%) of scalp-hair loss. The AA-IGA is a robust ordinal measure providing distinct and clinically meaningful gradations of scalp-hair loss that reflects patients' and expert clinicians' perspectives and treatment expectations. What is already known about this topic? The Severity of Alopecia Tool is widely used to assess the extent of scalp-hair loss in patients with alopecia areata. Guidelines define treatment success as a 50% improvement in scalp hair, and clinical trials have used dynamic thresholds of 50% and 90%. However, there is no clinical consensus on these endpoints, and patient perspectives on treatment success are unknown. What does this study add? Through qualitative interviews with 10 expert dermatologists and 30 patients with alopecia areata who had experienced ≥ 50% scalp-hair loss, we developed the Alopecia Areata Investigator Global Assessment (AA-IGA™) to measure five clinically meaningful gradations of alopecia areata scalp-hair loss that reflects patients' and clinicians' perspectives and expectations of treatment success in alopecia areata treatment studies. What are the clinical implications of this work? The AA-IGA is a robust ordinal measure that can inform clinical evaluation of alopecia areata treatment outcomes. The AA-IGA can be used to determine clinically meaningful treatment success for alopecia areata, with success defined by patients and clinicians as reaching ≤ 20% scalp-hair loss. Linked Comment: Blome. Br J Dermatol 2020; 183:609.

Measurement properties of the Haem-A-QoL in haemophilia clinical trials.

INTRODUCTION: Patients with haemophilia on long-acting prophylactic treatment may experience an improvement in health-related quality of life (HRQoL) through reductions in breakthrough bleeds and associated complications, including long-term joint damage, compared with episodic treatment. AIM: This analysis examined clinical trial data to understand the psychometric characteristics (reliability, validity and sensitivity to change over time) of the Haem-A-QoL Questionnaire in adult males with haemophilia. METHODS: Two recent, multinational, Phase 3 clinical trials of new, long-acting factor concentrates (A-LONG: rFVIIIFc; B-LONG: rFIXFc) assessed HRQoL in adolescent and adult males with severe haemophilia A or B respectively. The adults' baseline assessments, via the 46-item Haem-A-QoL Questionnaire, and change over time at the 6-month assessment were used in the psychometric analyses. RESULTS: Internal consistency reliability was adequate (Cronbach's alpha > 0.70) for nine of the 10 Haem-A-QoL domains and for 'Total Score' in both trials at baseline (A-LONG, n = 133; B-LONG, n = 73). At baseline, several Haem-A-QoL domains and 'Total Score' demonstrated known-groups and convergent validity when compared with other trial measures, including the EQ-5D (items and total scores) and joint impairment. Change score correlations (baseline to 28 weeks) between the EQ-5D and the Haem-A-QoL 'Total Score', and 'Physical Health' and 'Feelings' domains were moderate in magnitude (│r│ ≥ 0.33; P < 0.03), demonstrating sensitivity to change for these outcome measures in A-LONG. CONCLUSION: These psychometric analyses provide evidence of the reliability, validity and ability to detect change of the Haem-A-QoL to assess the HRQoL of adult males with severe haemophilia A and B in longitudinal clinical trials.

Changes in health-related quality of life with treatment of longer-acting clotting factors: results in the A-LONG and B-LONG clinical studies.

INTRODUCTION: In haemophilia, prophylactic infusion of replacement factor can result in improvements in health-related quality of life (HRQoL) when compared with episodic treatment. The Haemophilia-specific Quality of Life (Haem-A-QoL) questionnaire assessed HRQoL in adults with severe haemophilia A or B who received prophylactic or episodic treatment with recombinant factor VIII or IX Fc fusion protein (rFVIIIFc or rFIXFc) in the A-LONG or B-LONG clinical studies. AIMS: Understand changes in HRQoL during the A-LONG and B-LONG trials. METHODS: Group-level and individual-level changes over time for the Haem-A-QoL key domains of 'Physical Health' and 'Sports & Leisure,' and 'Total Score' were evaluated in adults through baseline and 6-month HRQoL assessments. Previously determined responder definitions (RDs) were used for evaluating meaningful subject-level HRQoL improvements. RESULTS: The analysis included 67 A-LONG and 51 B-LONG subjects who completed the Haem-A-QoL (baseline and 6 months). While HRQoL improvements were observed among all treatment groups, greater improvements in HRQoL were observed among subjects who received episodic treatment pre-study (and prophylaxis on-study) compared to those who received hyphenate prophylaxis. Applying the RDs for interpreting 6-month changes, 47.4%/33.3% ('Physical Health'), 35.9%/50.0% ('Sports & Leisure') and 23.9%/33.3% ('Total Score') of A-LONG subjects who received individualized or weekly prophylaxis were classified as HRQoL responders. In B-LONG, 69.2%/57.9% ('Physical Health'), 44.4%/56.7% ('Sports & Leisure') and 41.7%/44.1% ('Total Score') of subjects who received individualized or weekly prophylaxis were classified as HRQoL responders. CONCLUSION: Changes in Haem-A-QoL key domains and 'Total Score' suggest that prophylaxis with long-acting rFVIIIFc or rFIXFc resulted in meaningful HRQoL improvements.

Analysis of the psychometric properties of the Multiple Sclerosis Impact Scale-29 (MSIS-29) in relapsing-remitting multiple sclerosis using classical and modern test theory.

BACKGROUND: Investigations using classical test theory support the psychometric properties of the original version of the Multiple Sclerosis Impact Scale (MSIS-29v1), a disease-specific measure of multiple sclerosis (MS) impact (physical and psychological subscales). Later, assessments of the MSIS-29v1 in an MS community-based sample using Rasch analysis led to revisions of the instrument's response options (MSIS-29v2). OBJECTIVE: The objective of this paper is to evaluate the psychometric properties of the MSIS-29v1 in a clinical trial cohort of relapsing-remitting MS patients (RRMS). METHODS: Data from 600 patients with RRMS enrolled in the SELECT clinical trial were used. Assessments were performed at baseline and at Weeks 12, 24, and 52. In addition to traditional psychometric analyses, Item Response Theory (IRT) and Rasch analysis were used to evaluate the measurement properties of the MSIS-29v1. RESULTS: Both MSIS-29v1 subscales demonstrated strong reliability, construct validity, and responsiveness. The IRT and Rasch analysis showed overall support for response category threshold ordering, person-item fit, and item fit for both subscales. CONCLUSIONS: Both MSIS-29v1 subscales demonstrated robust measurement properties using classical, IRT, and Rasch techniques. Unlike previous research using a community-based sample, the MSIS-29v1 was found to be psychometrically sound to assess physical and psychological impairments in a clinical trial sample of patients with RRMS.

Interpreting important health-related quality of life change using the Haem-A-QoL.

The Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL) measures health-related quality of life (HRQoL) in adults with haemophilia; however, change score thresholds for identifying individuals experiencing a HRQoL benefit have not been appropriately investigated. The objective of this analysis was to derive appropriate HRQoL responder definitions (RDs) for two Haem-A-QoL domains that reflect key impairments, 'Physical Health' and 'Sports & Leisure,' and the Haem-A-QoL 'Total Score' using anchor- and distribution-based methods. In this analysis, data from adults in A-LONG and B-LONG, two Phase 3 clinical studies of rFVIIIFc in haemophilia A and rFIXFc in haemophilia B, respectively, were used. The anchor-based approach identified Haem-A-QoL changes corresponding to EQ-5D item improvements between baseline and 6 months; the distribution-based methods examined the magnitude at baseline of one-half standard deviation and the standard error of measurement. Through triangulation, the most appropriate RDs were derived. Of the 133 A-LONG and 73 B-LONG subjects with baseline Haem-A-QoL scores, 67 and 51 subjects, respectively, completed the Haem-A-QoL questionnaire at both baseline and 6 months follow-up. Triangulation of anchor- and distribution-based estimates with the observed Haem-A-QoL change scores identified a 10-point reduction in the 'Physical Health' and 'Sports & Leisure' domains, and a 7-point reduction in 'Total Score' as the RD thresholds most indicative of HRQoL benefit. These empirically derived RDs for two key Haem-A-QoL domains and 'Total Score' are reasonable and practical thresholds for identifying subjects with notable improvements in HRQoL, and provides HRQoL RDs that can be used for further analysis and interpretation of data from haemophilia clinical trials.

Methods for interpreting change over time in patient-reported outcome measures.

PURPOSE: Interpretation guidelines are needed for patient-reported outcome (PRO) measures' change scores to evaluate efficacy of an intervention and to communicate PRO results to regulators, patients, physicians, and providers. The 2009 Food and Drug Administration (FDA) Guidance for Industry Patient-Reported Outcomes (PRO) Measures: Use in Medical Product Development to Support Labeling Claims (hereafter referred to as the final FDA PRO Guidance) provides some recommendations for the interpretation of change in PRO scores as evidence of treatment efficacy. METHODS: This article reviews the evolution of the methods and the terminology used to describe and aid in the communication of meaningful PRO change score thresholds. RESULTS: Anchor- and distribution-based methods have played important roles, and the FDA has recently stressed the importance of cross-sectional patient global assessments of concept as anchor-based methods for estimation of the responder definition, which describes an individual-level treatment benefit. The final FDA PRO Guidance proposes the cumulative distribution function (CDF) of responses as a useful method to depict the effect of treatments across the study population. CONCLUSIONS: While CDFs serve an important role, they should not be a replacement for the careful investigation of a PRO's relevant responder definition using anchor-based methods and providing stakeholders with a relevant threshold for the interpretation of change over time.

A blueprint for symptom scales and responses: measurement and reporting.

Measurement of symptom status among patients with GORD has, to date, been conducted in a variety of ways. We applied a cognitive psychology framework, as well as reviewed the current psychometric literature, to develop a blueprint for the best methods of measuring and reporting symptoms of patients with gastro-oesophageal reflux disease (GORD). Our review suggests that the seven point scale with word anchors for each point is likely to afford better reliability, improved sensitivity to change in GORD symptoms, and greater ease in administration compared with visual analogue or other types of response scales.

Retest reliability of surveillance questions on health related quality of life.

STUDY OBJECTIVES: Health related quality of life (HRQoL) is an important surveillance measure for monitoring the health of populations, as proposed in the American public health plan, Healthy People 2010. The authors investigated the retest reliability of four HRQoL questions from the US Behavioral Risk Factor Surveillance System (BRFSS). DESIGN: Randomly sampled BRFSS respondents from the state of Missouri were re-contacted for a retest of the HRQoL questions. Reliability was estimated by kappa statistics for categorical questions and intraclass correlation coefficients for continuous questions. SETTING: Missouri, United States. PARTICIPANTS: 868 respondents were re-interviewed by telephone about two weeks after the initial interview (mean 13.5 days). Participants represented the adult, non-institutionalised population of Missouri: 59.1% women; mean age 49.5 years; 93.2% white race. MAIN RESULTS: Retest reliability was excellent (0.75 or higher) for Self-Reported Health and Healthy Days measures, and moderate (0.58 to 0.71) for other measures. Reliability was lower for older adults. Other demographic subgroups (for example, gender) showed no regular pattern of differing reliability and there was very little change in reliability by the time interval between the first and second interview. CONCLUSIONS: Retest reliability of the HRQoL Core is moderate to excellent. Scaling options will require future attention, as will research into appropriate metrics for what constitutes important population group differences and change in HRQoL.

Physical activity, disability, and the risk of hospitalization for breast cancer among older women.

BACKGROUND: A recent investigation of physical activity, disability, and the risk of breast cancer among older women in the Iowa 65 + Rural Health Study reported a decreased risk of breast cancer among women with any disability compared with physically capable but inactive women (relative risk [RR] = 0.4. 95% confidence interval [CI] 0.2-0.9). Because of the intriguing nature of that association, those investigators urged replication before drawing any conclusions. METHODS: We replicated the Iowa approach using the Longitudinal Study on Aging (LSOA). a nationally representative, prospective cohort study. The 3131 community-dwelling women for whom we had complete data for these analyses ranged in age from 70 to 98 years old at baseline in 1984. Using ICD9-CM 174 codes, linked Medicare hospital claims identified 77 women with hospitalizations for breast cancer between 1984 and 1991. Multivariable proportional hazards regression was used to model the risk for this event among disabled, inactive, moderately active, and highly active women. RESULTS: No significant association between disability in older women and the risk of hospitalization for breast cancer relative to inactive older women was detected (adjusted hazard ratio [AHR]-0.78, 95% CI 0.41-1.5). Highly active older women had a significantly reduced risk of hospitalization for breast cancer (AHR-0.42, 95% CI 0.194).95). CONCLUSION: The intriguing finding from the Iowa 65+ Rural Health Study that disabled older women's risk for breast cancer was reduced could not be replicated in the LSOA, although power was limited. Highly active older women, however, had a significantly lower risk for breast cancer in both studies.

Rethinking functional limitation pathways.

Functional limitation has received considerable attention in gerontology and geriatrics. Much of this work has focused on single-wave transitions devoid of context rather than on the pattern of transitions over time that constitute trajectories. This Forum article suggests that it is time for a different way of looking at functional limitation pathways. It focuses on trajectories. Responses to three Rosow and Breslau (1966) and two Nagi (1976) items, asked of 12,998 older adults who participated in up to seven waves of data collection as part of the Established Populations for the Epidemiologic Study of the Elderly, are used to illustrate this approach, emphasizing both its conceptual and pragmatic advantages. The results provide greater clarity in terms of those who become functionally limited, take on more functional limitations, or recover as well as those who are likely to be lost to follow-up and in terms of the outcomes associated with those individuals over time.

Identifying meaningful intra-individual change standards for health-related quality of life measures.

Although numerous measures have been developed for the evaluation of health-related quality of life (HRQoL), strategies for identifying meaningful intra-individual change in these measures have not kept pace with instrument development. As a result, clinical trial researchers, quality assurance assessment teams and practising clinicians are without established standards to evaluate individual patient change in HRQoL measures as improved, stable or declined. This article reviews and critiques the methods that have been applied to establish intra-individual HRQoL change standards. These methods include within-person and between-persons anchor-based studies, as well as distribution-based techniques using the effect size, the standard error of measurement, the mean squared error or individual slope coefficients derived from hierarchical linear modelling. Practical approaches to improving and advancing HRQoL change evaluations that enhance the interpretation of intra-individual change are provided. Two future methodological challenges in this area of HRQoL research are examined: (1) the development of individual change standards for generic HRQoL measures; and (2) the incorporation of individual clinical assessments into the process for establishing significant intra-individual change standards.

Further evidence supporting an SEM-based criterion for identifying meaningful intra-individual changes in health-related quality of life.

This study used the standard error of measurement (SEM) to evaluate intra-individual change on both the Chronic Respiratory Disease Questionnaire (CRQ) and the SF-36. After analyzing the reliability and validity of both instruments at baseline among 471 COPD outpatients, the SEM was compared to established minimal clinically important difference (MCID) standards for three CRQ dimensions. A value of one SEM closely approximated the MCID standards for all CRQ dimensions. This SEM-based criterion was then validated by cross-classifying the change status (improved, stable, or declined) of 393 follow-up outpatients using the one-SEM criterion and the MCID standard. Excellent agreement was achieved for all three CRQ dimensions. Although MCID standards have not been established for the SF-36, the one-SEM criterion was explored in these change scores. Among SF-36 scales demonstrating acceptable reliability and reasonable variance, the percent of individuals within each change category was consistent with those seen in the CRQ dimensions. These results replicate previous findings where a value of one SEM also closely approximated MCIDs for all dimensions of the Chronic Heart Disease Questionnaire among cardiovascular outpatients. The one-SEM criterion should be explored in other health-related quality of life instruments with established MCIDs.

The risk of hospitalization for acute myocardial infarction among older adults.

BACKGROUND: The purpose of this study was to prospectively examine the risk of hospitalization for acute myocardial infarction (AMI) in a large, nationally representative sample of very old men and women. METHODS: We utilized secondary analysis of the Longitudinal Study of Aging. Baseline (1984) in-person interview data were linked to Medicare hospitalization records for 1984-1991. Subjects were 6,071 noninstitutionalized adults 70 years old or older at baseline. Hospitalization for AMI was defined as having primary discharge diagnoses containing ICD9-CM 410 codes. Multivariable proportional hazards regression was used to evaluate the epidemiologic risks for all persons, and separately for women, men, self-respondents, those with no previous AMIs, and those with no history of coronary heart disease. RESULTS: Of the sample, 357 persons (5.9%; 172 women and 185 men) had at least one primary discharge diagnosis of AMI. Significant (p<.05) risk factors for being hospitalized with an AMI (adjusted hazards ratios in parentheses) from the pooled analysis were male gender (1.86), having no more than a grade school education (1.35), atherosclerosis (1.43), hypertension (1.29), coronary heart disease (1.63), angina (1.60), previous AMI (1.52), diabetes (1.89), and four or more lower body limitations (1.43). The gender-specific analyses, however, revealed that hypertension, angina, diabetes, and lower body limitations were risk factors only for women, and that having no more than a grade school education was a risk factor only for men. CONCLUSION: Men, especially those with low education, women with diabetes, angina, hypertension, or lower body limitations, and either men or women with previous AMIs, coronary heart disease, or atherosclerosis have elevated risks for AMI resulting in hospitalization, and they should be considered for evaluation and monitoring. Current protocols for therapeutic management should be adopted, and compliance should be encouraged.

Linking clinical relevance and statistical significance in evaluating intra-individual changes in health-related quality of life.

OBJECTIVE: To compare the standard error of measurement (SEM) with established standards for clinically relevant intra-individual change in an evaluation of health-related quality of life. DESIGN: Secondary analysis of data from a randomized controlled trial. SUBJECTS: Six hundred and five outpatients with a history of cardiac problems attending the general medicine clinics of a major academic medical center. MEASURES: Baseline and follow-up interviews included a modified version of the Chronic Heart Failure Questionnaire (CHQ) and the SF-36. The SEM values corresponding to established standards for minimal clinically important differences (MCIDs) on the CHQ were determined. Individual change on the SF-36 was explored using the same SEM criterion. RESULTS: One-SEM changes in this population corresponded well to the patient-driven MCID standards on all CHQ dimensions (weighted kappas (0.87; P < 0.001). The distributions of outpatients who improved, remained stable, or declined (defined by the one-SEM criterion) were generally consistent between CHQ dimensions and SF-36 subscales. CONCLUSIONS: The use of the SEM to evaluate individual patient change should be explored among other health-related quality of life instruments with established standards for clinically relevant differences. Only then can it be determined whether the one-SEM criterion can be consistently applied as a proxy for clinically meaningful change.

Gender differences in the sequelae of hospitalization for acute myocardial infarction among older adults.

OBJECTIVE: To examine the effect of gender differences among older adults hospitalized for an acute myocardial infarction (AMI) on subsequent health outcomes. DESIGN: Secondary analysis of the Longitudinal Study on Aging. Data from baseline interviews (1984) and three biennial (1986, 1988, and 1990) re-interviews were linked to Medicare hospitalization and National Death Index records for 1984-1991. PARTICIPANTS: A total of 6071 community-dwelling adults aged 70 years or older at baseline. METHODS: Pooled and stratified multivariable models were used to examine gender differences in the independent effects of being hospitalized for an AMI on all-cause mortality, the risk and volume of subsequent hospitalization, and increases in the number of functional limitations. Two comparison groups were used. RESULTS: Three hundred fifty-seven AMI cases (6%; 172 women and 185 men) were compared with 3976 hospitalized controls and 1738 nonhospitalized controls. The risk of all-cause mortality for AMI cases was greater than that for either hospitalized controls or nonhospitalized controls (referent), and this increased risk was significantly (P < .001) stronger for women (adjusted hazards ratio (AHR) = 14.24, 95%CI = 10.99, 18.46) than for men (AHR = 9.91, 95%CI = 7.75, 12.67). Overall, AMI cases were also more likely to be hospitalized subsequently than the hospitalized controls (referent; adjusted odds ratio (AOR) = 1.47, 95%CI = 1.17, 1.85), although in the stratified analysis this association held for men (AOR = 1.73, 95%CI = 1.25, 2.41) but not for women (AOR = 1.25, 95%CI = .90, 1.73). Among those subsequently hospitalized, both women and men AMI cases consumed more hospital resources than the hospitalized controls, and there were gender differences suggesting that the effects on total charges and length of stay were greater for women than for men with AMI. Finally, although the AMI cases had greater adjusted mean increases in the number of instrumental activities of daily living limitations and lower body limitations than the nonhospitalized controls, they were no worse off than the hospitalized controls, and there were no gender differences in those effects. CONCLUSION: Relative to the appropriate comparison groups, hospitalization for an AMI increases the risk of death and the total costs and lengths of stay of subsequent hospitalizations for women more than for men. Therefore, increased primary prevention, diagnosis, and treatment efforts should be directed toward women.

Generic versus disease-specific health status measures. An example using coronary artery disease and congestive heart failure patients.

The objectives of this study were to evaluate and compare the psychometric properties of a generic health status measure, the Medical Outcomes Study SF-36, and a disease-specific health status measure, a modified version of the Chronic Heart Failure Questionnaire (CHQ), among outpatients known to have coronary artery disease (CAD) and/or congestive heart failure (CHF). A cross-sectional analysis of baseline data obtained from 670 outpatients participating in a randomized controlled clinical trial in the general medicine clinics of a major academic medical center was performed. The SF-36 was more comprehensive in its coverage of different health status domains. In contrast, the CHQ had fewer problems with floor and ceiling effects, was more internally consistent, had better dimensional reproducibility, and exhibited less factorial complexity. Although both instruments are appropriate for use among outpatients known to have CAD and/or CHF, the CHQ has significantly better psychometric properties than does the SF-36.