Margaret Sullivan Pepe

Intermittent Administration of Inhaled Tobramycin in Patients with Cystic Fibrosis

BACKGROUND AND METHODS We conducted two multicenter, double-blind, placebo-controlled trials of intermittent administration of inhaled tobramycin in patients with cystic fibrosis and Pseudomonas aeruginosa infection. A total of 520 patients (mean age, 21 years) were randomly assigned to receive either 300 mg of inhaled tobramycin or placebo twice daily for four weeks, followed by four weeks with no study drug. Patients received treatment or placebo in three on-off cycles for a total of 24 weeks. The end points included pulmonary function, the density of P. aeruginosa in sputum, and hospitalization. RESULTS The patients treated with inhaled tobramycin had an average increase in forced expiratory volume in one second (FEV1) of 10 percent at week 20 as compared with week 0, whereas the patients receiving placebo had a 2 percent decline in FEV1 (P<0.001). In the tobramycin group, the density of P. aeruginosa decreased by an average of 0.8 log10 colony-forming units (CFU) per gram of expectorated sputum from week 0 to week 20, as compared with an increase of 0.3 log10 CFU per gram in the placebo group (P<0.001). The patients in the tobramycin group were 26 percent (95 percent confidence interval, 2 to 43 percent) less likely to be hospitalized than those in the placebo group. Inhaled tobramycin was not associated with detectable ototoxic or nephrotoxic effects or with accumulation of the drug in serum. The proportion of patients with P. aeruginosa isolates for which the minimal inhibitory concentration of tobramycin was 8 microg per milliliter or higher increased from 25 percent at week 0 to 32 percent at week 24 in the tobramycin group, as compared with a decrease from 20 percent at week 0 to 17 percent at week 24 in the placebo group. CONCLUSIONS In a 24-week study of patients with cystic fibrosis, intermittent administration of inhaled tobramycin was well tolerated and improved pulmonary function, decreased the density of P. aeruginosa in sputum, and decreased the risk of hospitalization.

Continual Reassessment Method: A Practical Design for Phase 1 Clinical Trials in Cancer

This paper looks at a new approach to the design and analysis of Phase 1 clinical trials in cancer. The basic idea and motivation behind the approach stem from an attempt to reconcile the needs of dose-finding experimentation with the ethical demands of established medical practice. It is argued that for these trials the particular shape of the dose toxicity curve is of little interest. Attention focuses rather on identifying a dose with a given targeted toxicity level and on concentrating experimentation at that which all current available evidence indicates to be the best estimate of this level. Such an approach not only makes an explicit attempt to meet ethical requirements but also enables the use of models whose only requirements are that locally (i.e., around the dose corresponding to the targeted toxicity level) they reasonably well approximate the true probability of toxic response. Although a large number of models could be contemplated, we look at a particularly simple one. Extensive simulations show the model to have real promise.

Early Adiposity Rebound and the Risk of Adult Obesity

Objective. At 5 to 6 years of age, body fatness normally declines to a minimum, a point called adiposity rebound (AR), before increasing again into adulthood. We determined whether a younger age at AR was associated with an increased risk of adult obesity and whether this risk was independent of fatness at AR and parent obesity. Design. A retrospective cohort study using lifelong height and weight measurements recorded in outpatient medical records. Setting. Group Health Cooperative of Puget Sound (GHC), a health maintenance organization based in Seattle, Washington. Participants. All 390 GHC members (and their parents) born at GHC between January 1, 1965, and January 1, 1971, who had at least one recorded adult height and weight measurement plus two visits with recorded height and weight measurements in each of three age intervals: 1.5 to 4, 4 to 8, and 8 to 16 years. Main Outcome Measures. We calculated the mean body mass index (BMI) of each subject during young adulthood (age 21 to 29 years) and the BMI of the parents when each subject was 1.5 years of age. Adult obesity was defined as a BMI ≥27.8 for males and ≥27.3 for females. Curves were fit to each subjects BMI values between ages 1.5 and 16 years, and the age and BMI at AR were calculated from these curves. Subjects were divided into tertiles of age at AR (early, middle, and late), BMI at AR, and parent BMI (heavy, medium, and lean). Results. The mean age at AR was 5.5 years, and 15% of the cohort was obese in young adulthood. Adult obesity rates were higher in those with early versus late AR (25% vs 5%), those who were heavy versus lean at AR (24% vs 4%), those with heavy versus lean mothers (25% vs 5%), and those with heavy versus lean fathers (21% vs 5%). After adjusting for parent BMI and BMI at AR, the odds ratio for adult obesity associated with early versus late AR was 6.0 (95% CI, 1.3–26.6). Conclusion. An early AR is associated with an increased risk of adult obesity independent of parent obesity and the BMI at AR. Future research should examine the biological and behavioral determinants of AR.

Pivotal evaluation of the accuracy of a biomarker used for classification or prediction: standards for study design.

Research methods for biomarker evaluation lag behind those for evaluating therapeutic treatments. Although a phased approach to development of biomarkers exists and guidelines are available for reporting study results, a coherent and comprehensive set of guidelines for study design has not been delineated. We describe a nested case–control study design that involves prospective collection of specimens before outcome ascertainment from a study cohort that is relevant to the clinical application. The biomarker is assayed in a blinded fashion on specimens from randomly selected case patients and control subjects in the study cohort. We separately describe aspects of the design that relate to the clinical context, biomarker performance criteria, the biomarker test, and study size. The design can be applied to studies of biomarkers intended for use in disease diagnosis, screening, or prognosis. Common biases that pervade the biomarker research literature would be eliminated if these rigorous standards were followed.

A cautionary note on inference for marginal regression models with longitudinal data and general correlated response data

Inference for cross-sectional models using longitudinal data, can be accomplished with generalized estimating equations (Zeger and Liang, 1992). We show that either a diagonal working covariance matrix should be used or a key assumption should be verified. The assumption is non-trivial when covariates vary over time. The validity of this assumption is explored for some broad classes of correlation structures. Similar considerations are shown to be relevant for the more general problem of correlated response data and marginal regression analysis with individual level covariates.

Marrow transplantation from HLA-matched unrelated donors for treatment of hematologic malignancies

Less than 40% of the patients who could benefit from marrow transplantation have an HLA-matched relative who can serve as a donor. For this reason, several centers have explored marrow transplantation from other categories of donors. This retrospective study analyzes the results of marrow transplantation for 52 patients receiving grafts from HLA-A,B,DR,Dw-phenotypically matched, MLC-compatible, unrelated volunteer donors compared to a disease, disease-stage, and age-matched cohort of 104 patients transplanted from HLA-genotypically identical sibling donors. The patients transplanted from unrelated donors had an increased incidence of grade II-IV acute graft-versus-host disease compared to patients transplanted from related donors (79% vs. 36%, P much less than 0.001). However, the probability of relapse-free survival appears similar in the two groups (P = 0.39 over all, with estimates of 41% vs. 46% at 1 year). We conclude from this preliminary data that marrow transplantation from HLA-matched unrelated donors should be considered in most, if not all, circumstances where transplantation from an HLA-matched sibling would be indicated if such a donor were available.

Partial AUC Estimation and Regression

Accurate diagnosis of disease is a critical part of health care. New diagnostic and screening tests must be evaluated based on their abilities to discriminate diseased from nondiseased states. The partial area under the receiver operating characteristic (ROC) curve is a measure of diagnostic test accuracy. We present an interpretation of the partial area under the curve (AUC), which gives rise to a nonparametric estimator. This estimator is more robust than existing estimators, which make parametric assumptions. We show that the robustness is gained with only a moderate loss in efficiency. We describe a regression modeling framework for making inference about covariate effects on the partial AUC. Such models can refine knowledge about test accuracy. Model parameters can be estimated using binary regression methods. We use the regression framework to compare two prostate-specific antigen biomarkers and to evaluate the dependence of biomarker accuracy on the time prior to clinical diagnosis of prostate cancer.

Some Graphical Displays and Marginal Regression Analyses for Recurrent Failure Times and Time Dependent Covariates

Abstract Recurrent event time data are common in medical research; examples include infections in AIDS patients and seizures in epilepsy patients. In this context, as well as in the more usual context of a single failure time variable, time-dependent covariates are frequently of interest. We suggest some rate functions that might be displayed when analyzing recurrent failure time data or when the effect of a categorical time-dependent covariate is of interest. Estimators of these functions are provided along with two-sample test statistics. A new approach to regression modeling of these data is suggested and contrasted with existing methods. Our methods do not require that an explicit model be formulated for the probabilistic association between failure times within an individual. This is in line with the currently popular generalized estimating equation approach to longitudinal data. If the nature of such associations is known or is of particular interest, then alternative methods may be appropriate.

Inactivation of p16, RUNX3, and HPP1 occurs early in Barrett's-associated neoplastic progression and predicts progression risk

Patients with Barretts esophagus (BE) are at increased risk of developing esophageal adenocarcinoma (EAC). Clinical neoplastic progression risk factors, such as age and the length of the esophageal BE segment, have been identified. However, improved molecular biomarkers predicting increased progression risk are needed for improved risk assessment and stratification. Using real-time quantitative methylation-specific PCR, we screened 10 genes (HPP1, RUNX3, RIZ1, CRBP1, 3-OST-2, APC, TIMP3, p16, MGMT, p14) for promoter hypermethylation in 77 EAC, 93 BE, and 64 normal esophagus (NE) specimens. A subset of genes manifesting significant differences in methylation frequencies between BE and EAC was then analysed in 20 dysplastic specimens. All 10 genes except p14 were frequently methylated in EACs, with RUNX3, HPP1, CRBP1, RIZ1, and OST-2 representing novel methylation targets in EAC and/or BE. p16, RUNX3, and HPP1 displayed increasing methylation frequencies in BE vs EAC. Furthermore, these increases in methylation occurred early, at the interface between BE and low-grade dysplasia (LGD). To demonstrate the silencing effect of hypermethylation, we selected the EAC cells BIC1, in which the HPP1 promoter is natively methylated, and subjected them to 5-aza-2′-deoxycytidine (Aza-C) treatment. Real-time RT–PCR indicated increased HPP1 mRNA levels after 3 days of Aza-C treatment, as well as decreased levels of methylated HPP1 DNA. Hypermethylation of a subset of six genes (APC, TIMP3, CRBP1, p16, RUNX3, and HPP1) was then tested in a retrospective longitudinal study of 99 BE and nine LGD specimens obtained from 53 BE patients undergoing surveillance endoscopy. Only high-grade dysplasia (HGD) or EAC were defined as progression end points. Two patient groups were compared: eight progressors (P) and 45 nonprogressors (NP), using Cox proportional hazards models to determine the relative progression risks of age, BE segment length, and methylation events. Multivariate analyses revealed that only hypermethylation of p16 (odds ratio (OR) 1.74, 95% confidence interval (CI) 1.33–2.20), RUNX3 (OR 1.80, 95% CI 1.08–2.81), and HPP1 (OR 1.77, 95% CI 1.06–2.81) were independently associated with an increased risk of progression, whereas age, BE segment length, and hypermethylation of TIMP3, APC, or CRBP1 were not independent risk factors. In combined analyses, risk was detectable up to, but not earlier than, 2 years preceding neoplastic progression. Hypermethylation of p16, RUNX3, and HPP1 in BE or LGD may represent independent risk factors for the progression of BE to HGD or EAC. These findings have implications regarding risk stratification, early EAC detection, and the appropriate endoscopic surveillance interval for patients with BE.

Weighted Kaplan-Meier statistics: a class of distance tests for censored survival data

A class of statistics based on the integrated weighted difference in Kaplan-Meier estimators is introduced for the two-sample censored data problem. With positive weight functions these statistics are intuitive for and sensitive against the alternative of stochastic ordering. The standard weighted log-rank statistics are not always sensitive against this alternative, particularly if the hazard functions cross. Qualitative comparisons are made between the weighted log-rank statistics and these weighted Kaplan-Meier (WKM) statistics. A statement of null asymptotic distribution theory is given and the choice of weight function is discussed in some detail. Results from small-sample simulation studies indicate that these statistics compare favorably with the log-rank procedure even under the proportional hazards alternative, and may perform better than it under the crossing hazards alternative.