Design of Case‐controls Studies with Unscreened Controls

Abstract

SummaryTraditionally in genetic case-control studies controls have been screened to exclude subjects with a personal history of illness. This control group has the advantage of optimal power to detect loci involved in illness, but requires more work and may incur substantial cost in recruitment. An alternative approach to screening is to use unscreened controls sampled from the general population. Such controls are generally plentiful and inexpensive, but in general there is a risk that some may have the same disease as the cases, which will reduce power to detect associations. We have quantified the extent of this power loss, and produced mathematical formulae for the number of unscreened controls necessary to achieve the same power as a fixed sample of screened controls. The effect of using unscreened controls will also depend on the ratio of the number of screened controls to cases specified in the original study design, and this is also investigated. We have also investigated the cost-benefits of the screened and unscreened approaches, according to variation in the relative costs of sampling screened and unscreened controls, together with genotyping costs. We have, thus, identified the range of situations in which using unscreened controls is a cost-effective alternative to the screened control method and could be considered when designing a study. In many of the typical, real-world situations in complex genetics, the use of unscreened controls is potentially cost-effective and can, in general, be considered for disorders with population prevalence K p < 0.2. With the steady reduction in genotyping costs and the availability of common sets of "population controls" this design is likely to become increasingly cost effective.

Genome-wide approaches to identify pharmacogenetic contributions to adverse drug reactions

“…Second, statistical power will be reduced relative to matched cases, as was noted in the ABC HSR results. This reduction in power worsens as the prevalence of the ADR increases 16 but can be partially compensated by increasing the number of population controls. A third disadvantage may result from differences in the genetic backgrounds of the cases and the population controls.…”

“…16 For ADRs with frequencies less than 1%, study power will not be significantly affected by using population controls, but for a prevalence of 5%, such as ABC HSR, the impact is noticeable (Supplementary Figures S1 and S2). For a fixed sample size, the difference in power between analyses using clinical versus population controls for the models depicted in Figure 1 are 0.1-0.2, with an increasing impact as r 2 decreases.…”

Molecular dissection of NRG1-ERBB4 signaling implicates PTPRZ1 as a potential schizophrenia susceptibility gene

“…They were not specifically screened for psychiatric illness but unless there is a major ascertainment bias towards patient inclusion, the use of unscreened controls does not affect power for disorder with the population prevalence of schizophrenia. 34 Multicentre and Local Research Ethics Committee approval were obtained, and all subjects, cases and controls, gave written informed consent to participate. Markers that were significantly associated in the primary sample were genotyped in an additional set of controls (n = 617; 233 males) that was drawn from the same source.…”

“…Because the pooled analysis was biased towards exons ( Figure 5) and also inaccuracies in pooling may result in type II error, 34 to follow up our findings, we undertook a more thorough and effectively independent analytic approach based on HapMap. We selected markers using the program Tagger 40 based on all markers available at the time in HapMap (Hapmap Data Ref # 19/phase II, Oct 05, on NCBI B34 assembly dbSNP b124) to derive a set of tagSNPs such that each common allele (minor allele frequency (MAF) X0.1) was captured with r 2 > 0.8 by a single marker.…”

Regulatory regions of the paraoxonase 1 (PON1) gene are associated with neovascular age-related macular degeneration (AMD)

“…All were of European descent, living in Switzerland. DNA of 288 individuals representing the general population was used as the control group (Moskvina et al 2005). These individuals were not age-matched and did not undergo clinical assessment for the present study.…”