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.

Factors associated with clinical assessment of overactive bladder and selection of treatment.

BACKGROUND: Overactive bladder (OAB) affects >17 million individuals in the United States, but the symptoms of OAB are frequently underreported by patients and therefore untreated by physicians. OBJECTIVE: The purpose of this observational study was to investigate the demographic and clinical factors associated with the decision to treat OAB pharmacologically and identify factors associated with physicians' assessment of symptom severity. METHODS: We studied 31 physicians treating 217 patients with OAB and collected data on patient demographic characteristics, OAB symptoms, previous management strategies, physicians' assessments of OAB severity, and treatment prescribed. Stepwise logistic regression was used to identify factors associated with selecting pharmacologic treatment and with physician assessment of severity of OAB symptoms. RESULTS: The mean age of the patients was 61.3 years; approximately 82% were female, and approximately 73% were white. Participants with urinary incontinence were significantly (P < 0.001) more likely to be treated with medication than were those with only symptoms of nocturia or urinary frequency. Other significant factors associated with pharmacologic treatment were being white (odds ratio [OR], 9.5; 95% CI, 2.9-30.8); being black (OR, 5.9; 95% CI, 1.2-29.7); physician's clinical assessment of OAB as moderate (OR, 3.5; 95% CI, 1.5-8.2) or severe (OR, 3.8; 95% CI, 1.1-13.7); previous use of medication (OR, 2.9; 95% CI, 1.1-8.1); and number of incontinence episodes in the last 24 hours (OR, 1.2; 95% CI, 1.0-1.5). Factors associated with physician assessment of OAB severity included distress due to OAB symptoms (OR, 2.1; 95% CI, 1.3-3.2), number of incontinence episodes in the last 24 hours (OR, 1.2; 95% CI, 1.1-1.4), and use of previous treatment(s) (OR, 0.4; 95% CI, 0.2-0.8). CONCLUSIONS: Both demographic and clinical symptoms of OAB were associated with the decision to treat OAB with medication, whereas physicians' assessment of OAB severity was associated only with clinical symptoms. Urinary incontinence was the key symptom associated with the decision to treat patients with medication and with the assessment of OAB symptom severity.

The reliability and validity of the impact on lifestyle questionnaire in patients with acromegaly.

OBJECTIVES: Treatments for acromegaly, a growth hormone disorder, can be burdensome to patients, often requiring multiple self-administered injections daily. We developed the Impact on Lifestyle Questionnaire (ILQ) to measure the impact on patient's lifestyle imposed by the burden of injectable treatments for acromegaly. The primary objective of this study was to establish the reliability and validity of the ILQ. METHODS: The ILQ consists of the SF-12 and 30 additional questions. Thirty-four patients, from two sites, completed the ILQ and scales measuring related concepts. Fourteen patients also completed a retest survey 4 weeks later. Survey sample data were combined with ILQ data from another 56 patients with acromegaly for a factor analysis. Reliability was assessed with Cronbach's alpha and test-retest. Zero-order correlations were examined between ILQ subscales and symptoms, depression, SF-12 mental and physical components, a measure of self-care burden, appraisal of illness, and single-item measures of quality of life and satisfaction. RESULTS: The preconceived subscale structure was supported by factor analysis. These factors were internally consistent and stable over time. Good convergent validity was demonstrated between the Burden and Disruption scales with other measures of the burden of treatment. Patients indicated that they were generally compliant with therapy, and that treatment was not particularly burdensome or disruptive. Results based on the ILQ were consistent with other scales and qualitative responses. CONCLUSIONS: The ILQ has three subscales, Burden, Lifestyle Disruption, and Compliance, that are reliable and demonstrate preliminary evidence of construct validity.

The effects of venlafaxine on social activity level in depressed outpatients.

BACKGROUND: Although most depression treatment outcome scales focus on symptoms, depression also affects daily functioning, social activity, and quality of life. We examined the effects of venlafaxine on social activity, general life functioning, and depressive symptoms in 2 placebo-controlled clinical trials of venlafaxine. METHOD: Subjects were 600 outpatients with major depression (DSM-III-R criteria). Treatment outcomes were examined separately in each study, primarily because of differing lengths of follow-up. RESULTS: Treatment with venlafaxine significantly improved activity level, general life functioning, and depressive symptoms. Treatment accounted for statistically significant changes in both activity level and general life functioning even after controlling for changes in depression. CONCLUSION: We provide evidence that social activity is a behavioral domain distinct from depressive symptoms and that venlafaxine improves social activity level and general life functioning in addition to its positive effects on depressive symptoms in outpatients with major depression.

Development and initial validation of a brief mental health outcome measure.

Using a combination of classical test theory and Rasch item analysis, we developed a short scale designed to measure the effectiveness of mental health treatment across a wide range of mental health services and populations. Item development for the scale was guided by literature review and interviews with senior clinicians and with patients. Using 3 different samples consisting of inpatients, outpatients, and nonpatients, we reduced our initial item pool from 81 to 10 items. The 10-item scale had an alpha of .96 and showed strong correlations with commonly used measures of psychological well-being and distress. Our results suggest that the scale appears to measure a broad domain of psychological health. The scale appeared to lack ceiling and floor effects, and it discriminated between inpatients, outpatients, and nonpatients, suggesting the scale has excellent potential to be broadly responsive to a variety of treatment effects. In addition, the new scale proved to be sensitive to treatment changes in a sample of 20 psychiatric inpatients. Overall, the initial data suggest that we have developed a brief, sensitive outcome measure designed to have wide application across psychiatric and psychological treatments and populations.

Unsafe sex in men who have sex with both men and women.

The sexual behaviors of bisexually active men, defined as men having sex with a man and a woman in previous 6 months, were compared with men who had sex with men only. Differential sexual practices associated with HIV risk between the two groups of men, as well as in the bisexual men with their male and female partners, were evaluated. Cross-sectional analyses were performed on baseline data from a prospective cohort of 508 young gay men recruited from bars, college campuses, and a health center in Boston from 1993 to 1994. Odds ratios (OR) and 95% confidence intervals (CI) were calculated on categorical variables, and McNemar's chi2 was used to compare the behaviors of bisexual men with their male versus female sex partners. Six months before the interview, 47 (10%) men had male and female sex partners, and 383 men had only male sex partners during the past year or ever. Fifty-eight percent of the men in the study had a female sexual partner in their lifetime, and 18% during the past year. Bisexual men were more likely to have drinking problems as identified by the Michigan Alcoholism Screening Test (MAST; OR = 3.96, 95% CI = 1.54-10.20), and fewer male partners over their lifetime (mean +/- standard deviation [SD], 24+/-42; median, 7; versus mean +/- SD, 69+/-516; median, 12), although this difference was not statistically significant. The two groups had similar levels of unprotected anal intercourse (25.5% versus 29.5%); however, bisexual men were half as likely to have anal sex as homosexual men (OR = 0.50; 95% CI = 0.27-0.93). Bisexual men were three times as likely to have unprotected sex with their female partner as their male partner (OR = 3.0; 95% CI = 1.02-8.8). Stratified analysis revealed similar discordant behavior while sober (OR = 4.0), drinking (OR = 7.0), and while drinking with concurrent drug use (OR = 8.0). Among this cohort of men who have sex with men (MSM), a sizable proportion also had vaginal sex with female partners in the previous 6 months. Bisexually active men were more likely to have unprotected sex with their female partners compared with their male partners, potentially increasing the risk for HIV and other sexually transmitted diseases. Behavioral interventions directed toward MSM need to address bisexual behaviors.

PIP: Data were collected from 508 gay men recruited from bars, 17 Boston area college campuses, and a health center in Boston during 1993-94 for use in a study comparing the sex behaviors of men who had sex with a man and a woman during the previous 6 months against men who had sex with only men. Study participants were aged 18 to over 27 years, although 85.1% were aged 18-26. 6 months before the interview, 10% of the men had both male and female sex partners, while 383 men had only male sex partners during the past year or ever. 58% of the men in the study had ever had a female sex partner, and 18% during the past year. Bisexual men were more likely to have drinking problems as identified by the Michigan Alcoholism Screening Test and fewer male partners over their lifetime. 25.5% of the bisexual men and 29.5% of the homosexuals reported having unprotected anal intercourse, but bisexual men were less likely than homosexual men to have anal sex. Bisexual men were 3 times more likely to have unprotected sex with a female partner as with their male partner. Stratified analysis revealed this same discordant behavior while sober, drinking, and drinking together with other drug use.

The social context of drinking, drug use, and unsafe sex in the Boston Young Men Study.

The objective of this study was to evaluate the relation between drinking, drug use, and unprotected anal intercourse in young men who have sex with men. A cross-sectional analysis of first-visit data from a prospective cohort of 508 young gay men recruited from 1993 through 1994 from bars, college campuses, and the Fenway Community Health Center in Boston was performed. The major outcome measures were any unprotected anal intercourse, after drinking and when sober, stratified by type of sexual partner (steady or nonsteady) during the previous 6 months and during the most recent sexual encounter. The average age of the cohort was 23.3 years; 77.6% were white, and 76.4% were in college. These young men had a median of 10.5 male sexual partners in their lifetimes, and 3 sexual partners in the previous 6 months before enrollment. One hundred and thirty-four (26%) reported unprotected anal intercourse during the previous 6 months. Individuals who had unprotected anal intercourse were more likely to have a drinking problem (odds ratio [OR] = 1.95; 95% confidence interval [CI] = 1.26-3.01) and drank more (20.4 ml/day versus 13.9 ml/day; p < or = 0.01), compared with individuals who did not engage in unprotected anal intercourse. Overall, men were significantly less likely to have unprotected anal intercourse after alcohol or drug use, based on a series of paired analysis (OR = 0.27; 95% CI = 0.15-0.48). However, when we stratified by type of sexual partner, men were significantly more likely to have unprotected anal intercourse with their nonsteady sexual partners after drinking than when sober (OR = 4.33; 95% CI = 1.37-13.7), but were significantly less likely to have unprotected anal intercourse with steady partners (OR = 0.27; 95% CI = 0.15-0.48). The patterns observed as already mentioned for drinking were also found for substance use in general. Men who were more likely to have unprotected anal intercourse after substance use were significantly more likely to have a drinking problem (OR = 7.65; 95% CI = 2.34-24.59). These results suggest that the role of alcohol and unsafe sex in young gay men is complex, with the role of situational factors of paramount importance. Alcohol and substance use interventions designed to reduce HIV risk need to specify the role of substance use in the sexual context to be successful.

Measuring quality of life in early HIV disease: the modular approach.

RATIONALE: to examine the reliability and validity of the General Health Self-assessment, a modular questionnaire for self-assessment of quality of life (QoL) in human immunodeficiency virus (HIV) clinical trials and to describe the baseline QoL of participants in a large HIV clinical trial. DESIGN: the domains assessed include health perceptions, physical, psychological and role/social functioning, health care utilization and symptom distress. METHOD: 1,694 subjects with early HIV infection enrolled in the AIDS Clinical Trials Group Protocol 175 completed the scale at baseline. RESULTS: the domains demonstrated reliability, construct and discriminant validity. A worse QoL was associated with recent hospitalization and symptomatic status. Prior antiretroviral therapy was associated with higher health perceptions and well-being. The presence of symptom distress was related to lower QoL on the other scales. There was no relationship between QoL scales and the baseline CD4 count. Women showed a lower QoL than men on all scales, while ethnicity was related to differences in health perceptions and physical and psychological functioning. CONCLUSIONS: the General Health Self-assessment shows excellent potential as a measure of QoL for HIV-infected patients in clinical trials. Further research is necessary to determine the responsiveness of the scale to clinical and immunological changes in HIV-infected individuals.

Childhood sexual abuse among homosexual men. Prevalence and association with unsafe sex.

Of 327 homosexual and bisexual men participating in an ongoing cohort study pertaining to risk factors for HIV infection who completed a survey regarding history of sexual abuse, 116 (35.5%) reported being sexually abused as children. Those abused were more likely to have more lifetime male partners, to report more childhood stress, to have lied in the past in order to have sex, and to have had unprotected receptive anal intercourse in the past 6 months (odds ratio 2.13; 95% confidence interval 1.15-3.95). Sexual abuse remained a significant predictor of unprotected receptive anal intercourse in a logistic model adjusting for potential confounding variables.

HIV and hepatitis B infection and risk behavior in young gay and bisexual men.

OBJECTIVES: To estimate the prevalence of and identify risk factors for human immunodeficiency virus type 1 (HIV-1) and hepatitis B virus (HBV) infections and unprotected anal intercourse among young homosexual and bisexual men. METHODS: The authors performed a cross-sectional analysis of data from a prospective cohort of 508 young gay and bisexual men ages 18-29. RESULTS: HIV-1 seroprevalence was 2.4%, with five (1.3%) of 390 college students and seven (6.0%) of 117 non-students infected. After adjusting for confounders, HIV-1 infection was associated with having a history of a sexually transmitted disease other than HIV-1 or hepatitis B. The prevalence of hepatitis B markers in unvaccinated men was 12.9%. The presence of hepatitis B markers in unvaccinated men was significantly associated with Asian ethnicity, off-campus residence, and history of a sexually transmitted disease other than HIV-1 or hepatitis B and inversely associated with recent non-intravenous drug use. Eighteen percent of the participants reported having had sex with women during the previous 12 months, and 26.4% reported a history of unprotected anal intercourse during the previous six months. Men who reported unprotected anal intercourse were more likely to have at least one steady partner, to have met their partners in anonymous settings, and to be identified as probably alcohol dependent. CONCLUSIONS: Although the prevalence of HIV-1 infection among young homosexual and bisexual men in Boston was relatively low, the high rates of unprotected anal intercourse suggest a potential for future HIV-1 and hepatitis B transmission. Interventions should focus on young men with histories of sexually transmitted diseases, alcohol abuse, and depression.

A review of the quality-of-life aspects of urinary urge incontinence.

Urinary incontinence (UI) is prevalent and costly, occurring in 15 to 30% of the US population over the age of 60 years. Among people aged 15 to 64 years, UI occurs in 1.5 to 5% of men and 10 to 25% of women. Severe incontinence occurs in 6% of the general US population, and it is estimated that $US10 billion per year is spent in direct costs alone on care for these patients. This review presents a description of the various types of UI and describes the prevalence and costs of the condition. In addition, 3 approaches to assessing the impact of UI on quality of life are discussed, namely generic measures, disease-specific measures and qualitative approaches. We also review papers on UI and sexual functioning, UI in men, and some aspects of treatment. The review was conducted in the process of developing a new disease-specific measure for urinary urge incontinence (UUI). In general, the literature suggests that UUI has a greater impact than stress incontinence on quality of life, and that UI affects social and psychological functioning more than physical functioning. Only in a minority of individuals is the impact of UI disabling; however, most individuals with UI show significant reduction in their social functioning. Several studies suggest that the impact of UI is not solely a function of its severity, but also depends on individual coping abilities. Some studies also indicate that the social problems associated with UI grow with time, but it is not clear if that is a function of increasing severity of the condition, or the particular adaptations required for coping with this problem. An important distinction appears to be the ability of individuals to avoid public notice of their condition because of uncontrolled accidents. In summary, there is a need for a new measure of the quality-of-life impact of UUI that is based on the literature and on in-depth interviews with patients.

A brief male sexual function inventory for urology.

OBJECTIVES: To develop a brief questionnaire to measure male sexual function. METHODS: An initial set of questions was refined and reduced through cognitive testing and two serial validation studies. In each study, men were recruited from a sexual dysfunction clinic and a general medicine practice to complete the instrument. Test-retest reliabilities, internal consistencies, and construct validities were examined. RESULTS: The final instrument covers sexual drive (two items), erection (three items), ejaculation (two items), perceptions of problems in each area (three items), and overall satisfaction (one item). Psychometric performance was generally very satisfactory, although self-assessments of ejaculate volume are problematic. Translations have been developed and pilot tested in a number of languages. CONCLUSIONS: The Brief Sexual Function Inventory may be useful for measuring male sexual function in practice and research.

Evaluation of the quality of life associated with zidovudine treatment in asymptomatic human immunodeficiency virus infection. The AIDS Clinical Trials Group.

BACKGROUND: Zidovudine therapy is recommended for asymptomatic patients infected with the human immunodeficiency virus (HIV) who have fewer than 500 CD4+ cells per cubic millimeter. An analysis of the quality of life associated with therapy that integrated both the effects of adverse events and the benefits of delayed disease progression might influence this recommendation. METHODS: We applied a survival analysis adjusted for the quality of life to data from a randomized trial conducted by the AIDS Clinical Trials Group. The trial compared treatment with 500 mg of zidovudine per day, 1500 mg of zidovudine per day, and placebo (Protocol 019) in 1338 asymptomatic HIV-infected patients. RESULTS: The average time with neither a progression of disease nor an adverse event (symptom or laboratory finding) was 15.7, 15.6, and 14.8 months for patients receiving placebo, 500 mg of zidovudine, and 1500 mg of zidovudine, respectively. The incidence of severe symptoms was 13.8 percent in the placebo group, 15.2 percent in the 500-mg group, and 19.9 percent in the 1500-mg group (P = 0.038). After 18 months, the 500-mg group gained an average of 0.5 months without disease progression, as compared with the placebo group, but had severe adverse events an average of 0.6 months sooner. The 500-mg group had more quality-of-life--adjusted time than the placebo group only if the time lived after the progression of disease was considered by a patient to have less value than the time after the occurrence of a severe symptom. CONCLUSIONS: For asymptomatic patients treated with 500 mg of zidovudine, a reduction in the quality of life due to severe side effects of therapy approximately equals the increase in the quality of life associated with a delay in the progression of HIV disease.

Effectiveness of a meditation-based stress reduction program in the treatment of anxiety disorders.

OBJECTIVE: This study was designed to determine the effectiveness of a group stress reduction program based on mindfulness meditation for patients with anxiety disorders. METHOD: The 22 study participants were screened with a structured clinical interview and found to meet the DSM-III-R criteria for generalized anxiety disorder or panic disorder with or without agoraphobia. Assessments, including self-ratings and therapists' ratings, were obtained weekly before and during the meditation-based stress reduction and relaxation program and monthly during the 3-month follow-up period. RESULTS: Repeated measures analyses of variance documented significant reductions in anxiety and depression scores after treatment for 20 of the subjects--changes that were maintained at follow-up. The number of subjects experiencing panic symptoms was also substantially reduced. A comparison of the study subjects with a group of nonstudy participants in the program who met the initial screening criteria for entry into the study showed that both groups achieved similar reductions in anxiety scores on the SCL-90-R and on the Medical Symptom Checklist, suggesting generalizability of the study findings. CONCLUSIONS: A group mindfulness meditation training program can effectively reduce symptoms of anxiety and panic and can help maintain these reductions in patients with generalized anxiety disorder, panic disorder, or panic disorder with agoraphobia.

Interpreting pharmacoeconomic and quality-of-life clinical trial data for use in therapeutics.

Interpretation of quality-of-life (QOL) and pharmacoeconomic data for therapeutic decision making and therapeutic policy planning requires a basic understanding of the methods, assumptions and limitations of the data and associated methods of analysis. Measures of the effectiveness of different pharmaceutical agents can be modified by including functions which involve assessment of the treated individual's quality of life. These quality-adjusted effectiveness measures will alter conclusions concerning clinical decisions as well as the cost-effectiveness of the comparative agents under consideration. To provide a conceptual and analytical framework for understanding the relationship between QOL assessment and pharmacoeconomic modelling, interpretations of the quality-adjusted analyses are reviewed, conceptual and analytical models are proposed, and recommendations for using QOL data in pharmacoeconomic models are outlined. Techniques for incorporating QOL measures in pharmacoeconomic models are examined using a hypothetical model involving therapeutic assessments of antiviral treatments for individuals with HIV disease. Adjustments of effectiveness measures based upon QOL-related functions are then globally addressed using stochastic compartmental models. Three specific methods for adjustment used in therapeutic trials are reviewed. Applications of these techniques to 3 studies involving the treatment of HIV disease and hypertension are critically reviewed. Issues relevant to choosing or estimating measures of quality of life for use in pharmacoeconomic models are summarised, and research guidelines are proposed.

Quality-of-life evaluation in a clinical trial of zidovudine therapy in patients with mildly symptomatic HIV infection. The AIDS Clinical Trials Group.

OBJECTIVE: To evaluate the effects of zidovudine therapy in patients with mildly symptomatic HIV infection using Q-TWiST (quality-adjusted: Time Without Symptoms and Toxicity). DESIGN: Analysis of a previously reported multicenter, randomized, placebo-controlled clinical trial. SETTING: Thirty-two AIDS Clinical Trial units. PATIENTS: A total of 351 patients with mildly symptomatic HIV infection were assigned to placebo, and 360 patients were assigned to zidovudine, 1200 mg/d. MEASUREMENTS: A modified Q-TWiST method for comparing treatments based on time spent without severe symptomatic adverse events and without disease progression. Zidovudine and placebo were compared in a threshold utility analysis considering reduction in quality of life associated with adverse events and disease progression. Adverse events defined by laboratory findings were distinguished from findings representing symptomatic events. RESULTS: The incidence of severe symptomatic adverse events was 22.8% for the zidovudine group and 15.1% for the placebo group (P = 0.01), but, as previously reported, zidovudine improved progression-free survival relative to placebo (at 18 months, 91% compared with 81%; P = 0.001). In an 18-month period, patients receiving zidovudine went an average of 14.5 months without disease progression or a severe symptomatic adverse event compared with 14.7 months for placebo. The zidovudine group gained 0.9 months without disease progression but lost 1.1 months due to adverse events. Within the 18-month observation period, treatment provided more Q-TWiST than placebo if the quality of life after HIV disease progression was assumed to be 10% to 20% worse than the quality of life after a severe symptomatic adverse event. CONCLUSIONS: The Q-TWiST analysis projects that quality-of-life reductions due to severe symptomatic adverse events might be balanced by the quality-of-life benefits of delayed HIV disease progression for patients who received zidovudine for mildly symptomatic HIV infection. At currently recommended doses (500 to 600 mg/d, half the dose used in this study) zidovudine therapy is likely to yield a more favorable result.