Subgroup analysis and other (mis)uses of baseline data in clinical trials.

BACKGROUND: Baseline data collected on each patient at randomisation in controlled clinical trials can be used to describe the population of patients, to assess comparability of treatment groups, to achieve balanced randomisation, to adjust treatment comparisons for prognostic factors, and to undertake subgroup analyses. We assessed the extent and quality of such practices in major clinical trial reports. METHODS: A sample of 50 consecutive clinical-trial reports was obtained from four major medical journals during July to September, 1997. We tabulated the detailed information on uses of baseline data by use of a standard form. FINDINGS: Most trials presented baseline comparability in a table. These tables were often unduly large, and about half the trials inappropriately used significance tests for baseline comparison. Methods of randomisation, including possible stratification, were often poorly described. There was little consistency over whether to use covariate adjustment and the criteria for selecting baseline factors for which to adjust were often unclear. Most trials emphasised the simple unadjusted results and covariate adjustment usually made negligible difference. Two-thirds of the reports presented subgroup findings, but mostly without appropriate statistical tests for interaction. Many reports put too much emphasis on subgroup analyses that commonly lacked statistical power. INTERPRETATION: Clinical trials need a predefined statistical analysis plan for uses of baseline data, especially covariate-adjusted analyses and subgroup analyses. Investigators and journals need to adopt improved standards of statistical reporting, and exercise caution when drawing conclusions from subgroup findings.

Prediction of adverse outcomes in children with sickle cell disease.

BACKGROUND: The ability to identify infants with sickle cell anemia who are likely to have severe complications later in life would permit accurate prognostication and tailoring of therapy to match disease-related risks and facilitate planning of clinical trials. We attempted to define the features of such babies by following the clinical course of 392 children with sickle cell disease from infancy to about the age of 10 years. METHODS: We analyzed the records of 392 infants who received the diagnosis of homozygous sickle cell anemia or sickle cell-Beta(0)-thalassemia before the age of six months and for whom comprehensive clinical and laboratory data were recorded prospectively; data were available for a mean (+/-SD) of 10.0+/-4.8 years. Results obtained before the age of two years were evaluated to determine whether they predicted the outcome later in life. RESULTS: Of the 392 infants in the cohort, 70 (18 percent) subsequently had an adverse outcome, defined as death (18 patients [26 percent]), stroke (25 [36 percent]) frequent pain (17 [24 percent]), or recurrent acute chest syndrome (10 [14 percent]). Using multivariate analysis, we found three statistically significant predictors of an adverse outcome: an episode of dactylitis before the age of one year (relative risk of an adverse outcome, 2.55; 95 percent confidence interval, 1.39 to 4.67), a hemoglobin level of less than 7 g per deciliter (relative risk, 2.47; 95 percent confidence interval, 1.14 to 5.33), and leukocytosis in the absence of infection (relative risk, 1.80; 95 percent confidence interval, 1.05 to 3.09). CONCLUSIONS: Three easily identifiable manifestations of sickle cell disease that may appear in the first two years of life (dactylitis, severe anemia, and leukocytosis) can help to predict the possibility of severe sickle cell disease later in life.