Body mass index, poor diet quality, and health-related quality of life are associated with mortality in rural older adults.

In an aging population, potentially modifiable factors impacting mortality such as diet quality, body mass index (BMI), and health-related quality of life (HRQOL) are of interest. Surviving members of the Geisinger Rural Aging Study (GRAS) (n = 5,993; aged ?74 years) were contacted in the fall of 2009. Participants in the present study were the 2,995 (1,267 male, 1,728 female; mean age 81.4 ± 4.4 years) who completed dietary and demographic questionnaires and were enrolled in the Geisinger Health Plan over follow-up (mean = 3.1 years). Cox proportional hazards multivariate regression models were used to examine the associations between all-cause mortality and BMI, diet quality, and HRQOL. Compared to GRAS participants with BMIs in the normal range, a BMI < 18.5 was associated with increased mortality (HR 1.85 95%CI 1.09, 3.14, P = 0.02), while a BMI of 25-29.9 was associated with decreased risk of mortality (HR 0.71 95%CI 0.55, 0.91, P =0.007). Poor diet quality increased risk for mortality (HR 1.53 95%CI 1.06, 2.22, P = 0.02). Finally, favorable health-related quality of life was inversely associated with mortality (HR 0.09 95%CI 0.06, 0.13, P < 0.0001). Higher diet quality and HALex scores, and overweight status, were associated with reduced all-cause mortality in a cohort of advanced age. While underweight (BMI < 18.5) increased risk of all-cause mortality, no association was found between obesity and all-cause mortality in this aged cohort.

Psychometric evaluation of the hepatitis C virus patient-reported outcomes (HCV-PRO) instrument: validity, responsiveness, and identification of the minimally important difference in a phase 2 clinical trial.

PURPOSE: To describe the psychometric properties and identify the minimally important difference (MID) of the hepatitis C virus patient-reported outcomes (HCV-PRO) instrument. Chronic HCV infection and associated treatments negatively affect PROs of function and well-being. METHODS: In a phase 2 trial, HCV-infected patients received direct-acting antivirals (DAAs) for 12 weeks with peg-interferon/ribavirin (peg-IFN/RBV) for 48 weeks, or placebo plus peg-IFN/RBV. The HCV-PRO total score, SF-36 PCS and MCS scores, EQ-5D-3L, and EQ VAS were measured at baseline, week 8, end of DAA treatment (EODT), end of peg-IFN/RBV treatment (EOT), and posttreatment week 24 (SVR24). Convergent validity of the HCV-PRO was assessed by Pearson's correlation coefficients. Discriminant validity was assessed by analyzing mean HCV-PRO total scores by EQ-5D anxiety/depression and pain/discomfort domain scores (none vs. some) and presence/absence of depression or fatigue adverse events. MID was identified through effect size (ES) and receiver-operating characteristic (ROC) curve analyses (HCV-PRO response vs. SF-36 PCS/MCS and EQ VAS MID thresholds). RESULTS: In 74 patients (22 % female; 81 % White; 51 % ≥50 years), correlations (0.64-0.96) between HCV-PRO total scores, SF-36 PCS/MCS scores, and EQ VAS scores at all time points supported convergent validity. HCV-PRO total scores were reduced to 10-30 points in patients impaired by depression, pain, or fatigue symptoms. Impact of peg-IFN/RBV regimen on HCV-PRO ES increased over time (EODT -0.76; EOT -0.93). ES and ROC curve analyses indicated an MID of -10 points. CONCLUSION: The HCV-PRO was valid and responsive in the population studied. An MID of -10 points represented a threshold of clinical significance for the HCV-PRO.

Development and initial psychometric evaluation of the hepatitis C virus-patient-reported outcomes (HCV-PRO) instrument.

BACKGROUND: Chronic hepatitis C virus (HCV) infection is an important public health issue owing to its worldwide prevalence and its profound effects on patients' well-being and function. We developed a new patient self-report tool, the HCV patient-reported outcomes (HCV-PRO) instrument, to assess patients' function and well-being reflecting both HCV disease and treatment burdens. METHODS: Items were developed through a qualitative phase including scientific literature review, expert appraisal, and semi-structured patient interviews. The item pool was initially psychometrically tested in 60 adult HCV patients, 18 years of age or older at a university hepatology clinic. A final psychometric test was conducted in 241 members of the online Harris International Panel to examine scale reliability, confirm factor structure, and assess convergent and discriminant validity. RESULTS: A single-factor 16-item HCV-PRO instrument demonstrated good model fit. The HCV-PRO items and total score (range 0-100) showed excellent item response (few floor and ceiling effects) and reliability (alpha > 0.90). Convergent validity was established from moderate to high (r > 0.50) correlation with symptom burden, life satisfaction (ladder of life), and SF-36v2 scales scores. Mean HCV-PRO scores differentiated between currently treated patients, those previously treated, and patients never treated (p < 0.01), suggesting strong known-groups validity. CONCLUSIONS: The results provide initial evidence that the HCV-PRO can yield reliable and valid measurement of the effects of HCV and its treatment on the well-being and function of HCV-infected patients.

Examining item content and structure in health status and health outcomes instruments: toward the development of a grammar for better understanding of the concepts being measured.

OBJECTIVES: Health outcomes instruments assess diverse health concepts. Although item-level concepts are considered fundamental elements, the field lacks structures for evaluating and organizing them for decision making. This article proposes a grammar using item stems, response options, and recall periods to systematically identify item-level concepts. The grammar uses "core concept," "evaluative component," and "recall period" as intuitive terms for communicating with stakeholders. Better characterization of concepts is necessary for classifying instrument content and linking it to treatment benefit. METHODS: Items in 2 generic and 21 disease-specific instruments were evaluated to develop and illustrate the use of the grammar. Concepts were assigned International Classification of Functioning, Disability and Health codes for exploring the value that the grammar and a classification system add to the understanding of content across instruments. RESULTS: The 23 instruments include many core concepts; emotional function is the only concept assessed in all instruments. Concepts in disease-specific instruments show obvious patterns; for example, arthritis instruments focus on physical function. The majority of instruments used the same response options across all items, with five-point scales being the most common. Most instruments used one recall period for all items. Shorter recall periods were used for conditions associated with "flares," such as chronic obstructive pulmonary disease and "skin disease." Every diagnosis, however, showed variation across instruments in the recall period used. CONCLUSIONS: This analysis indicates the proposed grammar's potential for discerning the conceptual content within and between health outcomes instruments and illustrates its value for improving communication between stakeholders and for making decisions related to treatment benefit.

Use of existing patient-reported outcome (PRO) instruments and their modification: the ISPOR Good Research Practices for Evaluating and Documenting Content Validity for the Use of Existing Instruments and Their Modification PRO Task Force Report.

BACKGROUND: Patient-reported outcome (PRO) instruments are used to evaluate the effect of medical products on how patients feel or function. This article presents the results of an ISPOR task force convened to address good clinical research practices for the use of existing or modified PRO instruments to support medical product labeling claims. The focus of the article is on content validity, with specific reference to existing or modified PRO instruments, because of the importance of content validity in selecting or modifying an existing PRO instrument and the lack of consensus in the research community regarding best practices for establishing and documenting this measurement property. METHODS: Topics addressed in the article include: definition and general description of content validity; PRO concept identification as the important first step in establishing content validity; instrument identification and the initial review process; key issues in qualitative methodology; and potential threats to content validity, with three case examples used to illustrate types of threats and how they might be resolved. A table of steps used to identify and evaluate an existing PRO instrument is provided, and figures are used to illustrate the meaning of content validity in relationship to instrument development and evaluation. RESULTS & RECOMMENDATIONS: Four important threats to content validity are identified: unclear conceptual match between the PRO instrument and the intended claim, lack of direct patient input into PRO item content from the target population in which the claim is desired, no evidence that the most relevant and important item content is contained in the instrument, and lack of documentation to support modifications to the PRO instrument. In some cases, careful review of the threats to content validity in a specific application may be reduced through additional well documented qualitative studies that specifically address the issue of concern. CONCLUSION: Published evidence of the content validity of a PRO instrument for an intended application is often limited. Such evidence is, however, important to evaluating the adequacy of a PRO instrument for the intended application. This article provides an overview of key issues involved in assessing and documenting content validity as it relates to using existing instruments in the drug approval process.

A concept taxonomy and an instrument hierarchy: tools for establishing and evaluating the conceptual framework of a patient-reported outcome (PRO) instrument as applied to product labeling claims.

OBJECTIVE: To facilitate development and evaluation of a PRO instrument conceptual framework, we propose two tools--a PRO concept taxonomy and a PRO instrument hierarchy. FDA's draft guidance on patient reported outcome (PRO) measures states that a clear description of the conceptual framework of an instrument is useful for evaluating its adequacy to support a treatment benefit claim for use in product labeling the draft guidance, however does not propose tools for establishing or evaluating a PRO instrument's conceptual framework. METHODS: We draw from our review of PRO concepts and instruments that appear in prescription drug labeling approved in the United States from 1997 to 2007. RESULTS: We propose taxonomy terms that define relationships between PRO concepts, including "family,""compound concept," and "singular concept." Based on the range of complexity represented by the concepts, as defined by the taxonomy, we propose nine instrument orders for PRO measurement. The nine orders range from individual event counts to multi-item, multiscale instruments. CONCLUSION: This analysis of PRO concepts and instruments illustrates that the taxonomy and hierarchy are applicable to PRO concepts across a wide range of therapeutic areas and provide a basis for defining the instrument conceptual framework complexity. Although the utility of these tools in the drug development, review, and approval processes has not yet been demonstrated, these tools could be useful to improve communication and enhance efficiency in the instrument development and review process.

Analysis and interpretation of results based on patient-reported outcomes.

This article is part of a series of manuscripts dealing with the incorporation of patient-reported outcomes (PROs) into clinical trials. The issues dealt with in this manuscript concern the common pitfalls to avoid in statistical analysis and interpretation of PROs. Specifically, the questions addressed by this manuscript involve the analysis pitfalls with PRO data in clinical trials and how can they be avoided (e.g.,missing data, multiplicity, null results etc.). The manuscript provides key literature for existing resources and proposes new guidelines.

Interpreting and reporting results based on patient-reported outcomes.

This article deals with the incorporation of patient-reported outcomes (PROs) into clinical trials and focuses on issues associated with the interpretation and reporting of PRO data. The primary focus and context of this information relates to the evidentiary support and reporting for a labeling or advertising claim of a PRO benefit for a new or approved pharmaceutical product. This manuscript focuses on issues associated with assessing clinical significance and common pitfalls to avoid in presenting results related to PROs. Specifically, the questions addressed by this manuscript involve: What are the best methods to assess clinical significance for PROs? How should investigators present PRO data most effectively in a Food and Drug Administration (FDA) application? In labeling or in a scientific publication? Guidelines for interpreting clinical significance of PROs and for comprehensively reporting on the methods, measures and results of clinical trials that incorporate PROs are important for clinicians, regulatory agencies, and most of all to patients. Clear specifications for considering a finding on a PRO measure, as clinically meaningful, need to be determined by instrument developers and psychometricians; they need to be reported for all clinical trials involving PRO end points. Clinical trial reports need to be comprehensive, clear, and sufficient to enable any reader to understand the methods, PRO measures, statistical analysis, and results.

Using real-world data for coverage and payment decisions: the ISPOR Real-World Data Task Force report.

OBJECTIVES: Health decision-makers involved with coverage and payment policies are increasingly developing policies that seek information on "real-world" (RW) outcomes. Motivated by these initiatives, the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) created a Task Force on Real-World Data to develop a framework to assist health-care decision-makers in dealing with RW data, especially related to coverage and payment decisions. METHODS: Task Force cochairs were selected by the ISPOR Board of Directors. Cochairs selected chairs for four working groups on: clinical outcomes, economic outcomes, patient-reported outcomes, and evidence hierarchies. Task Force members included representatives from academia, the pharmaceutical industry, and health insurers. The Task Force met on several occasions, conducted frequent correspondence and exchanges of drafts, and solicited comments on three drafts from a core group of external reviewers and from the ISPOR membership. RESULTS: We defined RW data as data used for decision-making that are not collected in conventional randomized controlled trials (RCTs). We considered several characterizations: by type of outcome (clinical, economic, and patient-reported), by hierarchies of evidence (which rank evidence according to the strength of research design), and by type of data source (supplementary data collection alongside RCTs, large simple trials, patient registries, administrative claims database, surveys, and medical records). Our report discusses eight key issues: 1) the importance of RW data; 2) limitations of RW data; 3) the fact that the level of evidence required depends on the circumstance; 4) the need for good research practices for collecting and reporting RW data; 5) the need for good process in using RW data in coverage and reimbursement decisions; 6) the need to consider costs and benefits of data collection; 7) the ongoing need for modeling; and 8) the need for continued stakeholder dialogue on these topics. CONCLUSIONS: Real-world data are essential for sound coverage and reimbursement decisions. The types and applications of such data are varied, and context matters greatly in determining the value of a particular type in any circumstance. It is critical that policymakers recognize the benefits, limitations, and methodological challenges in using RW data, and the need to consider carefully the costs and benefits of different forms of data collection in different situations.

Measuring treatment impact: a review of patient-reported outcomes and other efficacy endpoints in approved product labels.

CONTEXT: The term "patient-reported outcomes" (PROs) has evolved to include any endpoint derived from patient reports, whether collected in the clinic, in a diary, or by other means, including single-item outcome measures, event logs, symptom reports, formal instruments to measure health-related quality of life (HRQL), health status, adherence, and satisfaction with treatment. This term coincides with the explicit interest from drug development researchers and regulatory authorities in the appropriate utilization and reporting of treatment impact measures. OBJECTIVE: To determine the level and nature of use of PROs compared to other types of effectiveness endpoints in approved product labeling for new drugs recently approved in the United States. DESIGN AND SOURCES: Review and analysis of effectiveness endpoints as reported in clinical study descriptions in approved product labeling of new molecular entities (NMEs) approved in the United States from 1997 through 2002. MAIN OUTCOME MEASURES: Effectiveness study endpoints reported in approved product labeling that fall into the following categories of measurement: PROs, clinician-reported outcomes (CROs), and laboratory test/device measurement endpoints. RESULTS: PROs were reported in 64 (30%) of the 215 product labels reviewed. Clinician-reported outcomes were reported most frequently (62%) followed by laboratory/device endpoints (50%). PROs were the only type of endpoint used in the FDA-approved label for 23 products. Formal multiitem PRO scales were cited 22 times. Use of PROs is most common in antiinflammatory, CNS, gastrointestinal, respiratory, allergic conjunctivitis, and urologic therapy areas. The frequency of reported PRO use over this period did not change. CONCLUSION: PROs, although quite variable as a class of study endpoints, were found to have a significant role in the development and evaluation of new medicines. More formal guidance from the FDA about use of such measures along with continued collaboration by PRO researchers to develop and disseminate standards will enhance the appropriate use of PROs in future drug development and labeling.

A health outcomes framework for assessing health status and quality of life: enhanced data for decision making.

BACKGROUND: Currently, information to improve health status and quality of life is derived from independently designed data systems that range from population-based health surveys to health records used in managing individual patient care. But there is no coherent strategy for using these data sources in concert across diverse applications. Thus, it is frequently difficult to compare or combine results across studies to provide population-level inferences based on findings from specific subpopulations. OBJECTIVE: The Health Outcomes Framework is an analytic structure to provide more comprehensive information about the health status and quality-of-life impact of disease and its treatment. This framework consists of three components: (1) a core set of health, lifestyle, and economic questionnaires that collect data from an individual's perspective; (2) applications that range from population to patient care levels; and (3) time. Although health is the outcome of interest, lifestyle behaviors and economic and political factors are important determinants of health, which also need to be studied using standardized procedures; thus, they are included in the core. This article focuses on the nature and application of a core health status and quality-of-life instrument. To be useful across a range of applications, such a core instrument needs to have three conceptual characteristics: (1) a theoretical model that regards health as a continuum of states; (2) domains that represent policy-relevant aspects of impairment, disability, and handicap; and (3) a set of societal preferences for these domains. In addition, the core needs to address three practical concerns: (1) brevity, (2) methods of administration that are suitable for respondents with diverse capabilities, and (3) documentation that is publicly available. These features are discussed using examples from currently available, multi-domain generic instruments, each of which has some, but not all, of the necessary features of the core instrument. CONCLUSION: The Health Outcomes Framework is intended to be a cooperative effort. It is proposed that the National Cancer Institute and the Centers for Disease Control and Prevention take leadership roles not only by adopting a core health status and quality-of-life instrument for use in current and future cancer data collection activities but also in encouraging industry and academic investigators to implement this core instrument in their cancer studies. Having a vertically integrated core instrument can lead to more representative data for informing decision making and ultimately for obtaining a more equitable distribution of health.

Depression and health-related quality of life.

Chronic medical conditions drastically affect the lives of those afflicted, leading to pain, disability, and disruption. Comorbid depression can exacerbate the effects of medical illness and may be an independent source of suffering and disability. Data from the Epidemiological Follow-Up Study (NHEFS) of the first National Health and Nutrition Examination Survey (NHANES I) are used to examine the manner in which depression and comorbid medical conditions interact to affect health-related quality of life (HRQOL). The findings suggest a) that the effects of depression are comparable with those of arthritis, diabetes, and hypertension; and b) that depression and chronic medical illnesses interact to amplify the effects of the medical illness. The data also support the merit of adopting a multidimensional approach to HRQOL rather than treating it unidimensionally.

Coronary Artery Bypass Surgery and Health Related Quality of Life: Data From the National Health and Nutrition Examination Survey.

This chapter is reproduced with permission from the book, Coronary Bypass Surgery in the Elderly: Ethical, Economical and Quality of Life Aspects, edited by Paul J. Walter, and published by Kluwer Academic Publishers. For further information on the book format see the advertisement appearing on page 37 of the July/August 1996 issue of AJGC.