Analytic Perspective

Flexible Two-Phase studies for rare exposures: Feasibility, planning and efficiency issues of a new variant

Pascal Wild¹ , Nadine Andrieu^2,3,4 , Alisa M Goldstein⁵ and Walter Schill⁶

¹INRS, French National Institute for Research and Safety, Department of Epidemiology, France

²INSERM, U900, Paris, F-75248, France

³Institut Curie, Paris, F-75248, France

⁴Ecole des Mines de Paris, ParisTech, Fontainebleau, F-77300, France

⁵Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, USA

⁶BIPS, Bremen Institute for Prevention Research and Social Medicine, University of Bremen, Germany

author email corresponding author email

Epidemiologic Perspectives & Innovations 2008, 5:4doi:10.1186/1742-5573-5-4

Published:	1 October 2008

Abstract

The two-phase design consists of an initial (Phase One) study with known disease status and inexpensive covariate information. Within this initial study one selects a subsample on which to collect detailed covariate data. Two-phase studies have been shown to be efficient compared to standard case-control designs. However, potential problems arise if one cannot assure minimum sample sizes in the rarest categories or if recontact of subjects is difficult.

In the case of a rare exposure with an inexpensive proxy, the authors propose the flexible two-phase design for which there is a single time of contact, at which a decision about full covariate ascertainment is made based on the proxy. Subjects are screened until the desired numbers of cases and controls have been selected for full data collection. Strategies for optimizing the cost/efficiency of this design and corresponding software are presented. The design is applied to two examples from occupational and genetic epidemiology. By ensuring minimum numbers for the rarest disease-covariate combination(s), we obtain considerable efficiency gains over standard two-phase studies with an improved practical feasibility.

The flexible two-phase design may be the design of choice in the case of well targeted studies of the effect of rare exposures with an inexpensive proxy.