Association of Tafamidis With Health Status in Patients With ATTR Cardiac Amyloidosis: A Post Hoc Analysis of the ATTR-ACT Randomized Clinical Trial.

Importance: Tafamidis reduced all-cause mortality and cardiovascular-related hospitalizations and minimized patient-reported health status deterioration at 30 months in patients with transthyretin (ATTR) amyloidosis. However, the clinical significance of health status changes remains unclear, particularly in patients with New York Heart Association (NYHA) class III symptoms who experienced more cardiovascular-related hospitalizations than those with NYHA class I-II symptoms. Objective: To evaluate the health status of patients taking tafamidis with baseline NYHA class III symptoms. Design, Setting, and Participants: This randomized clinical trial post hoc analysis evaluated data for patients with transthyretin (ATTR) cardiac amyloidosis and NYHA class I-III symptoms at baseline who were enrolled in ATTR-ACT, a placebo-controlled study of tafamidis held at 48 sites in 13 countries. Interventions: Tafamidis meglumine, 80 mg or 20 mg (pooled cohort), vs placebo. Main Outcomes and Measures: Established thresholds for clinical benefit on the Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) were used to define response groups (very large decline to very large improvement); the proportion of patients in each group was calculated within each baseline NYHA class. Results: Among 441 patients (264 tafamidis, 177 placebo), the mean (SD) age was 74.3 (7.0) years; 398 (90%) were male and 43 (10%) were female. Mean (SD) baseline KCCQ-OS scores were 67.3 (21.4) in the tafamidis group and 65.9 (21.7) in the placebo group (range: 0-100, with 100 indicating the best health). There was a significant shift toward better KCCQ-OS scores in patients receiving tafamidis (odds ratio for 10-point improvement 2.4; 95% CI, 1.6-3.4; P < .001). More patients taking tafamidis were alive and not worse at all time points (37% vs 15% at month 30). These findings were similar in patients with NYHA class III symptoms. In patients with NYHA class III symptoms alive at 30 months, improvements in health status were more common (35% vs 10%) and declines were less common (38% vs 57%) with tafamidis vs placebo. Conclusions and Relevance: In ATTR-ACT, although patients with baseline NYHA class III symptoms had worse overall outcomes, treatment with tafamidis yielded better health status compared with placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT01994889.

Key measurement concepts and appropriate clinical outcome assessments in pediatric achondroplasia clinical trials.

BACKGROUND: This study aimed to identify fit-for-purpose clinical outcome assessments (COAs) to evaluate physical function, as well as social and emotional well-being in clinical trials enrolling a pediatric population with achondroplasia. Qualitative interviews lasting up to 90 min were conducted in the US with children/adolescents with achondroplasia and/or their caregivers. Interviews utilized concept elicitation methodology to explore experiences and priorities for treatment outcomes. Cognitive debriefing methodology explored relevance and understanding of selected COAs. RESULTS: Interviews (N = 36) were conducted with caregivers of children age 0-2 years (n = 8) and 3-7 years (n = 7) and child/caregiver dyads with children age 8-11 years (n = 15) and 12-17 years (n = 6). Children/caregivers identified pain, short stature, impacts on physical functioning, and impacts on well-being (e.g. negative attention/comments) as key bothersome aspects of achondroplasia. Caregivers considered an increase in height (n = 9/14, 64%) and an improvement in limb proportion (n = 11/14, 71%) as successful treatment outcomes. The Childhood Health Assessment Questionnaire (CHAQ) and Quality of Life in Short Stature Youth (QoLISSY-Brief) were cognitively debriefed. CHAQ items evaluating activities, reaching, and hygiene were most relevant. QoLISSY-Brief items evaluating reaching, height bother, being treated differently, and height preventing doing things others could were most relevant. The CHAQ and QoLISSY-Brief instructions, item wording, response scales/options and recall period were well understood by caregivers and adolescents age 12-17. Some children aged 8-11 had difficulty reading, understanding, or required caregiver input. Feedback informed minor amendments to the CHAQ and the addition of a 7-day recall period to the QoLISSY-Brief. These amendments were subsequently reviewed and confirmed in N = 12 interviews with caregivers of children age 0-11 (n = 9) and adolescents age 12-17 (n = 3). CONCLUSIONS: Achondroplasia impacts physical functioning and emotional/social well-being. An increase in height and improvement in limb proportion are considered to be important treatment outcomes, but children/adolescents and their caregivers expect that a successful treatment should also improve important functional outcomes such as reach. The CHAQ (adapted for achondroplasia) and QoLISSY-Brief are relevant and appropriate measures of physical function and emotional/social well-being for pediatric achondroplasia trials; patient-report is recommended for age 12-17 years and caregiver-report is recommended for age 0-11 years.

An Adapted Clinical Measurement Tool for the Key Symptoms of CLN2 Disease

Abstract Neuronal ceroid lipofuscinosis type-2 (CLN2) disease is a rare, autosomalrecessive,pediatric-onset,neurodegenerative lysosomal storage disease caused by mutations in the TPP1 gene. Cerliponase alfa (Brineura®), a recombinant form of human tripeptidyl peptidase-1, was recently developed as a treatment for CLN2 disease. In clinical trials, the primary end point to evaluate treatment effect was the aggregate score for the motor and language (ML) domains of the CLN2 Clinical Rating Scale, an adaptation of the Hamburg scale's component items that include anchor point definitions to allow consistent ratings in multinational, multisite, clinical efficacy studies. Psychometric analyses demonstrated that the ML score of the CLN2 Clinical Rating Scale and individual item scores are well defined and possess adequate measurement properties (reliability, validity, and responsiveness) to demonstrate a clinical benefit over time. Additionally, analyses comparing the CLN2 Clinical Rating Scale ML ratings to the Hamburg scale's ML ratings demonstrated adequate similarity.

An Adaptation of the Profile of Mood States for Use in Adults With Phenylketonuria

Abstract Adults with phenylketonuria (PKU) experience disturbances in mood. This study used qualitative and quantitative techniques to adapt the 65-item Profile of Mood States (POMS) for the assessment of key mood domains in adults with PKU. First, cognitive interviews on 58 POMS items (excluding 7 Friendliness domain items) among 15 adults and adolescents (age ≥16 years) with PKU were conducted to eliminate items poorly understood or considered irrelevant to PKU; 17 items were removed. Next, the remaining POMS items were quantitatively examined (Mokken scaling and Rasch analysis) in 115 adult patients with PKU. An additional 21 items were removed iteratively, resulting in the 20-item draft PKU-POMS. Finally, the psychometric properties of the draft PKU-POMS were examined. The instrument displayed strong psychometric properties (reliability, validity, and responsiveness) over 6 domains (Anxiety, Depression, Anger, Activity, Tiredness, and Confusion) and all items were well understood in the final cognitive interviews with 10 adults with PKU.

Assessing the Content Validity of the Investigator-Rated ADHD Rating Scale Version IV Instrument Inattention Subscale for Use in Adults With Phenylketonuria

Abstract Content validity of the 18-item Investigator-Rated Attention-Deficit Hyperactivity Disorder (ADHD) Rating Scale IV (I-ADHD RS-IV) with adult prompts was investigated using qualitative interviews of US clinicians who had prior experience rating adults with phenylketonuria (PKU) using the I-ADHD RS-IV. Fourteen qualitative interviews were conducted to obtain key symptom experiences of adults with PKU and assessed the relevance, clarity, and administration of the I-ADHD RS-IV. Participants (n = 13, 92.9%) endorsed the inattention symptoms as key experiences by adults with PKU and endorsed the instrument as fit for purpose for adults with PKU. Participants generally reported low frequencies of occurrence for the 9 I-ADHD RS-IV hyperactivity/impulsivity items. Despite some clinicians' concerns for the lack of patient self-awareness, the participants reported no difficulty selecting a rating on these items. This in-depth study of the content validity of the I-ADHD RS-IV provides evidence that this clinician-reported instrument captures the severity of important inattention symptoms in adults with PKU.

Content Validity of the ADHD Rating Scale (ADHD RS-IV) and Adult ADHD Self-Report Scale (ASRS) in Phenylketonuria

Abstract The ADHD Rating Scale (ADHD RS-IV; parent report) and Adult ADHD Self-Rating Scale (ASRS; self-report) are validated instruments for measuring symptoms of attention-deficit/hyperactivity disorder (ADHD). The objectives of this study were to elicit descriptions of phenylketonuria (PKU) symptoms and assess content validity of these instruments in PKU. Parents (N = 15) of children with PKU (?8 years old) and adults with PKU (N=13) described PKU-related symptoms and commented on the scale's clarity, comprehensiveness, and relevance to their experience with PKU. Most of the adults (84.6%) and all of the children were on a phenylalanine-restricted diet, according to respondent report. The inattentiveness symptoms reported by participants mapped to the inattentive items of the questionnaires. Most participants felt the inattentive items were clear and relevant to their experience. Despite study design limitations, these results demonstrate the relevance of assessing inattentiveness in PKU, and both instruments achieved content validity for inattentive subscale items.

Differences in smokers and nonsmokers' assessments of an educational campaign about tobacco use.

The authors surveyed 1,998 Missourians to evaluate (a) awareness and (b) understanding of messages about the impact of tobacco use in Missouri, (c) belief in the accuracy of the messages, and (d) intention to vote for a tobacco tax increase on the basis of the messages. Using structural equation modeling, the relationships among these four constructs were evaluated. A comparison of smokers and nonsmokers indicated that these two groups were influenced by the messages in different ways, χ(2)(8) = 20.89, p < .05, and should be modeled separately. The nonsmokers' model demonstrated significant (p < .05) relationships between understanding the messages and belief in message accuracy (b = .41; R (2) = .17) and between belief in message accuracy and intention to vote in favor of the tobacco tax (b = .54; R (2) = .29). In the smokers' model, understanding the messages was not a statistically significant predictor of belief in message accuracy. However, belief in message accuracy had a significant and positive relationship with intention to vote in favor of the tax (b = .45; R (2) = .21). These findings indicate that media campaigns about tobacco use should approach smokers and nonsmokers differently.

Assessing fatigue in persons with cancer: further validation of the Wu Cancer Fatigue Scale.

Cancer-related fatigue (CRF) is a significant clinical symptom. Effective assessment of CRF attributes from the patients' perspective is essential. This study tested the psychometric properties of the Wu Cancer Fatigue Scale (WCFS). A total of 172 outpatients with breast cancer, who were at various stages and on various chemotherapy regimens, and were undergoing treatment at one of three cancer clinics in a Midwest metropolitan area, participated in this study. The participants were instructed to complete four instruments in the following order: the 16-item WCFS, Schwartz Cancer Fatigue Scale (SCFS), Geriatric Depression Scale (GDS), and Cancer-Related Fatigue Distress Scale (CRFDS). Structural equation modeling (LISREL 8.54) supported the one-factor measurement model with nine items remaining. Nonsignificant Satorra-Bentler Scaled Chi-square (27)=32.52, P=0.21, standardized root mean square residual=0.032, nonnormal fit index=0.97, comparative fit index=0.98, and incremental fit index=0.98 indicated a good model fit. Convergent validity with the SCFS was 0.78, concurrent validity with the GDS was 0.60, and predictive validity with the CRFDS was 0.73. Internal consistency reliability was alpha=0.91 for the nine-item scale. The revised WCFS is a reliable and valid instrument that aims to measure the subjective characteristics of CRF from the patients' perspective. It may prove useful in both clinical and research settings.

Estimating clinically significant differences in quality of life outcomes.

OBJECTIVE: This report extracts important considerations for determining and applying clinically significant differences in quality of life (QOL) measures from six published articles written by 30 international experts, in the field of QOL assessment and evaluation. The original six articles were presented at the Symposium on Clinical Significance of Quality of Life Measures in Cancer Patients at the Mayo Clinic in April 2002 and subsequently were published in Mayo Clinic Proceedings. PRINCIPAL FINDINGS: Specific examples and formulas are given for anchor-based methods, as well as distribution-based methods that correspond to known or relevant anchors to determine important differences in QOL measures. Important prerequisites for clinical significance associated with instrument selection, responsiveness, and the reporting of QOL trial results are provided. We also discuss estimating the number needed to treat (NNT) relative to clinically significant thresholds. Finally, we provide a rationale for applying group-derived standards to individual assessments. CONCLUSIONS: While no single method for determining clinical significance is unilaterally endorsed, the investigation and full reporting of multiple methods for establishing clinically significant change levels for a QOL measure, and greater direct involvement of clinicians in clinical significance studies are strongly encouraged.

Methods to explain the clinical significance of health status measures.

One can classify ways to establish the interpretability of quality-of-life measures as anchor based or distribution based. Anchor-based measures require an independent standard or anchor that is itself interpretable and at least moderately correlated with the instrument being explored. One can further classify anchor-based approaches into population-focused and individual-focused measures. Population-focused approaches are analogous to construct validation and rely on multiple anchors that frame an individual's response in terms of the entire population (eg, a group of patients with a score of 40 has a mortality of 20%). Anchors for population-based approaches include status on a single item, diagnosis, symptoms, disease severity, and response to treatment. Individual-focused approaches are analogous to criterion validation. These methods, which rely on a single anchor and establish a minimum important difference in change in score, require 2 steps. The first step establishes the smallest change in score that patients consider, on average, to be important (the minimum important difference). The second step estimates the proportion of patients who have achieved that minimum important difference. Anchors for the individual-focused approach include global ratings of change within patients and global ratings of differences between patients. Distribution-based methods rely on expressing an effect in terms of the underlying distribution of results. Investigators may express effects in terms of between-person standard deviation units, within-person standard deviation units, and the standard error of measurement. No single approach to interpretability is perfect. Use of multiple strategies is likely to enhance the interpretability of any particular instrument.

Hospitalization for prostate cancer among the older men in the longitudinal study on aging, 1984-1991.

BACKGROUND: Factors associated with being hospitalized with indications of prostate cancer were examined. A secondary analysis of the older men in the Longitudinal Study on Aging (LSOA) used baseline (1984) interview data and Medicare hospital claims for 1984 through 1991. METHODS: The analytic sample consisted of 2254 men who were 70 to 95 years old (mean 75.8 years) at baseline and who were self-respondents to the LSOA. Case-identification involved primary prostate cancer (ICD9-CM code 185) and personal history of prostate cancer (ICD9-CM code V10.46) hospital discharge diagnoses. Multivariable logistic regression techniques were used. RESULTS: There were 154 cases (6.8%) of prostate cancer, including 109 identified by active diagnostic codes only, 15 identified by personal history codes only, and 30 identified by both. No associations with age, race, or ethnicity were observed. Being hospitalized with indications of prostate cancer was more likely in the presence of a history of cancer at any site, urinary control problems, greater body mass, maximum social interaction, or living in core Standard Metropolitan Statistical Area counties. Men who regularly attended religious services, had not seen a physician for 2 years, and did not feel in control of their health were less likely to have been hospitalized with indications of prostate cancer. CONCLUSIONS: These data suggest that the traditional associations between prostate cancer and age, race, and ethnicity do not apply to being hospitalized with indications of the disease among older men. However, body mass, history and symptoms, personal beliefs, access, and geographic practice patterns are associated with being hospitalized with indications of prostate cancer.