Discussion of "Optimal test procedures for multiple hypotheses controlling the familywise expected loss" by Willi Maurer, Frank Bretz, and Xiaolei Xun.

We provide commentary on the paper by Willi Maurer, Frank Bretz, and Xiaolei Xun entitled, "Optimal test procedures for multiple hypotheses controlling for the familywise expected loss." The authors provide an excellent discussion of the multiplicity problem in clinical trials and propose a novel approach based on a decision-theoretic framework that incorporates loss functions that can vary across multiple hypotheses in a family. We provide some considerations for the practical use of the authors' proposed methods as well as some alternative methods that may also be of interest in this setting.

The role of nonrandomized trials in the evaluation of oncology drugs.

Although randomized trials provide the most reliable evidence of a drug's safety and efficacy, there are situations where randomized trials are not possible or ethical. In this article we discuss when and how single-arm trials can be used to support full approval of oncology drugs. These include situations in which an unprecedented effect on tumor response is observed in a setting of high unmet medical need, clinical trial patients have been well characterized, enabling a target population to be clearly defined, experience exists in a sufficient number of patients to allow adequate assessment of the risk:benefit relationship, and a proper historical context can be provided for analysis. We also discuss how response rates might be considered predictive of long-term outcomes or clinically meaningful in and of themselves in certain contexts.

Double-masked, placebo-controlled safety and efficacy trial of diquafosol tetrasodium (INS365) ophthalmic solution for the treatment of dry eye.

PURPOSE: To investigate the safety and efficacy of diquafosol tetrasodium, a P2Y2 receptor agonist that stimulates fluid and mucin secretion on the ocular surface, as a novel topical treatment of dry eye disease. METHODS: Subjects with dry eye (n=527) were evaluated in a randomized, double-masked, parallel-group trial comparing 24 weeks of treatment with 2 concentrations of diquafosol (1% and 2%) versus placebo instilled 4 times daily. Corneal staining, conjunctival staining, Schirmer tests, and subjective symptoms of dry eye were evaluated. Use of artificial tears was permitted as necessary. RESULTS: Subjects treated with 2% diquafosol had significantly lower corneal staining scores compared with placebo at the 6-week, primary efficacy time point (P<0.001), and superiority continued throughout the 24-week study. Reductions in corneal staining were observed as early as after 2 weeks of treatment, were maintained throughout the 24-week study, and were observed to worsen slightly (toward baseline) when diquafosol treatment was discontinued (week 25). Results for conjunctival staining were consistent with those observed for corneal staining. Schirmer scores at week 6 were significantly higher with diquafosol treatment than with placebo (P

Applying sample survey methods to clinical trials data.

This paper outlines the utility of statistical methods for sample surveys in analysing clinical trials data. Sample survey statisticians face a variety of complex data analysis issues deriving from the use of multi-stage probability sampling from finite populations. One such issue is that of clustering of observations at the various stages of sampling. Survey data analysis approaches developed to accommodate clustering in the sample design have more general application to clinical studies in which repeated measures structures are encountered. Situations where these methods are of interest include multi-visit studies where responses are observed at two or more time points for each patient, multi-period cross-over studies, and epidemiological studies for repeated occurrences of adverse events or illnesses. We describe statistical procedures for fitting multiple regression models to sample survey data that are more effective for repeated measures studies with complicated data structures than the more traditional approaches of multivariate repeated measures analysis. In this setting, one can specify a primary sampling unit within which repeated measures have intraclass correlation. This intraclass correlation is taken into account by sample survey regression methods through robust estimates of the standard errors of the regression coefficients. Regression estimates are obtained from model fitting estimation equations which ignore the correlation structure of the data (that is, computing procedures which assume that all observational units are independent or are from simple random samples). The analytic approach is straightforward to apply with logistic models for dichotomous data, proportional odds models for ordinal data, and linear models for continuously scaled data, and results are interpretable in terms of population average parameters. Through the features summarized here, the sample survey regression methods have many similarities to the broader family of methods based on generalized estimating equations (GEE). Sample survey methods for the analysis of time-to-event data have more recently been developed and implemented in the context of finite probability sampling. Given the importance of survival endpoints in late phase studies for drug development, these methods have clear utility in the area of clinical trials data analysis. A brief overview of methods for sample survey data analysis is first provided, followed by motivation for applying these methods to clinical trials data. Examples drawn from three clinical studies are provided to illustrate survey methods for logistic regression, proportional odds regression and proportional hazards regression. Potential problems with the proposed methods and ways of addressing them are discussed.

Sertraline versus imipramine to prevent relapse in chronic depression.

BACKGROUND: Chronic depressions are common, disabling and under-treated, and long-term treatment is little studied. We report the continuation phase results from a long-term treatment study. METHODS: After 12 weeks of acute phase treatment in a double-blind, randomized, parallel-group, multi-center trial of sertraline or imipramine, patients with chronic depression (> or = 2 years in major depression, or major depression superimposed on dysthymia) continued study drug for 16 weeks. Initially, 635 patients were randomized to sertraline or imipramine in a 2:1 ratio. Nonresponders after 12 weeks entered a 12-week double-blind crossover trial of the alternate medication. Entry into continuation treatment required at least a satisfactory response (partial remission) to initial or crossover treatment. RESULTS: Of 239 acute or crossover responders to sertraline, 60% entered continuation in full remission and 40% with a partial remission. These proportions were identical for imipramine patients (n = 147). For both drug groups, over two-thirds of those entering in full remission retained it. For those entering in partial remission, over 40% achieved full remission. Patients requiring crossover treatment were less likely to maintain or improve their response during continuation treatment. The two drugs did not differ significantly in response distribution, drop out rates or discontinuation due to side effects during continuation treatment. LIMITATIONS: The absence of a placebo group constrains interpretation of our results, but chronic depressions have low placebo response rates. CONCLUSIONS: Most chronic depression patients who remit with 12 weeks of sertraline or imipramine treatment maintain remission during 16 weeks of continuation treatment. Most patients with a satisfactory therapeutic response (partial remission) after 12 weeks of treatment maintain it or further improve. Patients treated with imipramine experienced more side effects, but both drugs were well tolerated.

Quality control of oncology clinical trials.

This article discusses issues that are essential to ensuring the reliability of the conclusions of oncology clinical trials. Though quality control is important at every stage of a well-run clinical trial, the authors focus on the quality of the data as evidenced by the results and conclusions of the study. Good quality control principles and practices are discussed for study planning, design, conduct, analysis, and interpretation.

MSQ: Migraine-Specific Quality-of-Life Questionnaire. Further investigation of the factor structure.

MSQ, the 16-item Migraine-Specific Quality-of-Life Questionnaire (Version 1.0), was developed by Glaxo Wellcome Inc. to assess the effect of migraine and its treatment on patients' health-related quality of life (HR-QOL). The MSQ was hypothesised to measure 3 meaningful dimensions: (i) Role Function-Restrictive; (ii) Role Function-Preventive; and (iii) Emotional Function. The objective of this research was to further investigate the number of dimensions as well as the items contained in each dimension through principal components factor analysis of clinical trial data. Secondary objectives were to determine whether the factor structure changed in post-treatment visits compared with screening visits, to make recommendations for coding the MSQ when the patient did not have a migraine in the previous 4 weeks, and to modify the MSQ if so indicated by this research. Results supported the existence of 3 distinct factors which agreed strongly with the hypothesised dimensions. The analysis of post-treatment data suggested that the underlying factor structure of the MSQ varies as a result of treatment. Based on evaluations of the 'did not have a migraine' response, it was concluded that it be dropped from the MSQ. All these changes have been incorporated into MSQ (Version 2.0) which is being evaluated in studies to determine if its psychometric properties are different than the properties of the previous version.

Predictors of emotional numbing in posttraumatic stress disorder.

Little is known about the mechanisms underlying emotional numbing (EN). The functional relationship between other classes of posttraumatic stress disorder (PTSD) symptoms and EN is also not well understood. In the present study, we examined the statistical predictors of EN. We hypothesized that the severity of EN would be most strongly associated with the hyperarousal symptoms rather than the avoidance symptoms of PTSD, or comorbid depression or substance abuse. This prediction was derived from psychological and biological models that posit EN to be a product of the depletion of emotional resources subsequent to chronic hyperarousal. Using hierarchical multiple regression in two separate samples of Vietnam combat veterans, we found hyperarousal symptoms to be the most robust predictor of EN. These data suggest that there is a substantive relationship between hyperarousal symptoms and EN in PTSD.

Urinary cotinine and parent history (questionnaire) as indicators of passive smoking and predictors of lower respiratory illness in infants.

Studies of the effects of passive smoking on lower respiratory illness (LRI) have relied on questionnaires to measure exposure. We studied the association between two measures of passive smoking and the incidence of acute LRI in infants. We analyzed data from a community-based cohort study of respiratory illness during the first year of life in North Carolina. The incidence of LRI was determined by telephone calls at 2-week intervals. Environmental, demographic, and psychosocial risk factors for LRI were measured during home interviews. Tobacco smoke exposure was measured as the mean number of cigarettes smoked per day in the infant's presence. Smoke absorption by the infants was measured by the urinary cotinine/ creatinine ratio. Of the 485 infants in the study, 325 (67%) had telephone follow-up and at least two home interviews. In bivariate analyses, reported tobacco smoke exposure and urinary cotinine were associated with LRI. Only the association between reported exposure and LRI remained significant after adjusting for confounders, [adjusted incidence of LRI (episodes/child-year) non-exposed: 0.6; < or = 10 cigarettes/day: 0.9 (RR 1.5, 95% CI: 1.1, 2.0); > 10 cigarettes/day: 1.3 (RR 2.2, 95% CI: 1.3, 3.8)]. We conclude that infants reportedly exposed to tobacco smoke have an increased incidence of LRI. There are differences between questionnaire and biochemical measures of passive smoking. Urinary cotinine will not necessarily improve the validity of studies of the relationship of passive smoking to LRI in infants.

Innovative strategies using SUDAAN for analysis of health surveys with complex samples.

Large-scale health surveys provide a wealth of information for addressing problems in health sciences research. Designed for multiple purposes, these surveys frequently have large sample sizes and extensive measurements of demographic and socioeconomic characteristics, risk factors, disease outcomes and health care service use and costs. Complex features of the sampling design typically employed to select the survey sample, coupled with the vast amount of information available from the survey database, underlie issues that must be addressed during data processing and analysis. Numerous articles in the literature have focused on the debate of whether or not, and how, to control for features of the sample design during data analysis. Traditional statistical methods for simple random samples and the software that accompanies them have historically not had the capacity to account for the survey design. Recent advancements in statistical methodology for survey data analysis have greatly expanded the analytical tools available to the survey analyst. Commercial software packages that incorporate these methods offer the analyst convenient ways for applying such tools to large survey databases in an easy and efficient manner. We present an overview of analysis strategies for survey data and illustrate their application via the SUDAAN software system. Examples for analyses are provided through data from two large US health surveys, the National Health Interview Survey and the Longitudinal Study of Aging. Questions of both a cross-sectional and longitudinal nature are addressed. The examples involve logistic regression, time-to-event analysis, and repeated measures analysis.

Evaluation of a home-based intervention program to reduce infant passive smoking and lower respiratory illness.

We conducted a randomized controlled trial to determine whether a home-based intervention program could reduce infant passive smoking and lower respiratory illness. The intervention consisted of four nurse home visits during the first 6 months of life, designed to assist families to reduce the infant's exposure to tobacco smoke. Among the 121 infants of smoking mothers who completed the study, there was a significant difference in trend over the year between the intervention and the control groups in the amount of exposure to tobacco smoke; infants in the intervention group were exposed to 5.9 fewer cigarettes per day at 12 months. There was no group difference in infant urine cotinine excretion. The prevalence of persistent lower respiratory symptoms was lower among intervention-group infants of smoking mothers whose head of household had no education beyond high school: intervention group, 14.6%; and controls, 34.0%.

Application of sample survey methods for modelling ratios to incidence densities.

We describe ratio estimation methods for multivariately analysing incidence densities from prospective epidemiologic studies. Commonly used in survey data analysis, these ratio methods require minimal distributional assumptions and take into account the random variability in the at-risk periods. We illustrate their application with data from a study of lower respiratory illness (LRI) in children during the first year of life. One question of interest is whether children with passive exposure to tobacco smoke have a higher rate of LRI, on average, than those with no exposure and in a setting where age of child and season are taken into account. A second question is whether the relationship persists after adjusting for background variables such as family's socioeconomic status, crowding in the home, race, and type of feeding. The basic strategy consists of a two-step process in which we first estimate subgroup-specific incidence densities and their covariance matrix via a first-order Taylor series approximation. These estimates are used to test for differences in marginal rates of LRI between children exposed to tobacco smoke and those not exposed. We then fit a log-linear model to the estimated ratios in order to test for significant covariate effects. The ability to produce direct estimates of adjusted incidence density ratios for risk factors of interest is an important advantage of this approach. For comparison purposes and to address the limitations of the ratio method with respect to the number of covariates that can be controlled simultaneously, we consider survey logistic regression methods for the example data as well as logistic and Poisson regression models fitted via generalized estimating equation methods. Although the analysis strategy is illustrated with illness data from an epidemiologic study, the context of application is broader and includes, for example, data on adverse events from a clinical trial.

Lower respiratory illness in infants and low socioeconomic status.

OBJECTIVES: Infants from families of low socioeconomic status are said to suffer higher rates of lower respiratory illness, but this assertion has not been carefully examined. METHODS: We studied the frequency and determinants of lower respiratory illness in infants of different socioeconomic status (n = 393) by analyzing data from a community-based cohort study of respiratory illness during the first year of life in central North Carolina. RESULTS: The incidence of lower respiratory illness was 1.41 in the low socioeconomic group, 1.26 in the middle group, and 0.67 in the high group. The prevalence of persistent respiratory symptoms was 39% in infants in the low socioeconomic group, 24% in infants in the middle group, and 14% in infants in the high group. The odds of persistent respiratory symptoms in infants of low and middle socioeconomic status were reduced after controlling for environmental risk factors for lower respiratory illness. Enrollment in day care was associated with an increased risk of persistent symptoms among infants of high but not low socioeconomic status. CONCLUSIONS: Infants of low socioeconomic status are at increased risk of persistent respiratory symptoms. This risk can be partly attributed to environmental exposures, most of which could be changed.

Infant Health and Development Program for low birth weight, premature infants: program elements, family participation, and child intelligence.

The Infant Health and Development Program was an eight-site randomized controlled trial testing the efficacy of early intervention to enhance the cognitive, behavioral, and health status of low birth weight, premature infants. The 377 intervention families received for the first 3 years of life: (1) pediatric follow-up, (2) home visits, (3) parent support groups, and (4) a systematic educational program provided in specialized child development centers. The control group (n = 608) received the same pediatric follow-up and referral services only. This paper describes the delivery of the intervention and its outcomes. A Family Participation Index that was the sum of participation frequencies in each of the program modalities unique to the intervention revealed that program implementation was not different across the eight sites. Index scores did not vary systematically with mother's ethnicity, age, or education or with child's birth weight, gender, or neonatal health status; but they were positively related to children's IQ scores at age 3. Only 1.9% of children of families in the highest tercile of participation scored in the mentally retarded range (IQ less than or equal to 70), whereas 3.5% and 13% of children in the middle and lowest participation terciles, respectively, scored in the retarded range. Similar findings were obtained for borderline intellectual functioning. These findings are consistent with previous research linking intensity of intervention services with degree of positive cognitive outcomes for high-risk infants. The determinants of variations in individual family participation remain unknown.

An overview of statistical issues and methods of meta-analysis.

A meta-analysis is a statistical analysis of the data from some collection of studies in order to synthesize the results. In this paper we discuss issues that frequently arise in meta-analysis and give an overview of the methods used, with particular attention to the use of fixed- and random-effects approaches. The methods are then applied to two sample datasets.

Outpatient prescription drug utilization and expenditure patterns of noninstitutionalized aged Medicare beneficiaries.

The goal of the National Medical Care Utilization and Expenditure Survey (NMCUES) of 1980 was to improve the understanding of the ways in which Americans use and pay for health care. This report is one in a series of descriptive reports based on NMCUES data. This report provides data regarding prescription drugs obtained on an outpatient basis by noninstitutionalized elderly people who reported being covered by Medicare in 1980. The results presented are based on NMCUES data collected about the civilian noninstitutionalized persons in the NMCUES national household sample who at any time during the survey year of 1980: (1) were 65 years of age or over, and (2) reported having been covered by Medicare hospital insurance (HI) or Medicare supplementary medical insurance (SMI) or both. These results include the number of prescriptions obtained during the survey year, the total charges for these prescriptions, the amounts paid by various sources, and the types of drugs obtained. Noninstitutionalized aged Medicare beneficiaries obtained an estimated 288 million prescriptions during 1980 and spent an estimated $2.3 billion for prescription drugs. Four of five beneficiaries used prescription drugs during the year. Although aged Medicare beneficiaries represented only 10.9 percent of the U.S. population during 1980, they accounted for 28.6 percent of all prescriptions and 30.2 percent of total prescription drug charges. The average aged beneficiary during the year purchased 12.1 prescriptions and incurred $98 of expenditures, about three times the average of those under 65 years of age. The average charge per prescription was $8.05. Prescription drug charges accounted for 5.5 percent of an estimated $42 billion spent by aged Medicare beneficiaries for health care during 1980, excluding charges for institutional care. Prescription drug use and expenditures were lower among people 65-69 years of age than among people 70-74 or 75-79 years of age. On average, women used more prescriptions and incurred higher charges than did men. Regionally, the average number of prescriptions that were filled per beneficiary was highest in the South and lowest in the West. People who perceived their health status to be poor had approximately four times as many prescriptions filled per person and incurred four times the average annual charge of people who perceived their health status to be excellent. Approximately 68 percent of the total dollars spent by aged Medicare beneficiaries for prescription drugs was paid out-of-pocket, 13.9 percent was paid by private health insurance, and 10.8 percent was paid by Medicaid. The remaining charges were distributed among other payers.(ABSTRACT TRUNCATED AT 400 WORDS)