Power to detect linkage with heterogeneity in samples of small nuclear families

Abstract

Computer simulation methods were used to investigate the power of genetically homogeneous or heterogeneous samples of nuclear families to detect linkage of a rare dominant disease allele to flanking DNA markers (three-point analysis, admixture text). Phase was assumed to be unknown (no grandparents available), and unaffected siblings were not considered. A sample of 95 families with an ill parent and two ill offspring, or 45 families with three ill offspring, demonstrated 90% power to detect a lod score of 3.0 when 50% of families were assumed to be segregating for a disease allele located midway between two DNA markers (PIC = .70) that were .05 M apart. When the proportion of linked families (alpha) = .25, 90% power required 380 and 160 families, respectively. For alpha < .25, samples size requirements become prohibitive. Issues are reviewed concerning the use of the admixture test in the case of more complex disease models. Screening of the genome with adequate sample sizes for low values of alpha is likely to require multiple large collaborative efforts.

Assessing the statistical power to detect linkage in a sample of 51 bipolar affective disorder pedigrees

“…Our result is consistent with other published data (Cavalli-Sforza and King, 1986;Martinez and Goldin, 1989;Chen et aL, 1992;Levinson, 1993). The power in detecting linkage drops from 98.3 to 67.1% when 75% of the families are linked to the putative marker.…”

“…Chen et aL (1992), using a simulation method and model consistent with epidemiological data for schizophrenia, estimated that 200 three-generation families of three or more affected members showed 84% power to detect linkage at a of .50. Likewise, a sample of 95 families with one ill parent and two ill offspring, or 45 families with three ill offspring, demonstrated 90% power to detect linkage when 50% of families were assumed to be segregating for a disease allele located midway between two DNA markers that were 0.05 M apart (Levinson, 1993). Indeed, most studies concluded that the sample size becomes prohibitive when o~ < 25% (Chen et al, 1992;Levinson, 1993).…”

Genome-wide scans of three independent sets of 90 Irish multiplex schizophrenia families and follow-up of selected regions in all families provides evidence for multiple susceptibility genes

“…Without a good estimate of the number of important genes, plausible hypotheses about their mechanism of action, or some idea of the relative roles of epistasis and heterogeneity, debates over 'the' optimal set of ascertainment and analytic strategies will inevitably continue. 6,7 Furthermore, many power analyses [8][9][10][11] have shown that the sample sizes needed to detect susceptibility loci for complex diseases by linkage methods alone are far greater than for Mendelian disorders. Since collection of large samples is difficult and expensive, false-negative linkage results may remain a major problem.…”

Resemblance of psychotic symptoms and syndromes in affected sibling pairs from the Irish Study of High-Density Schizophrenia Families: evidence for possible etiologic heterogeneity

“…The most widely used linkage tests for heterogeneity (14,15) are a posteriori-they divide families into linked and unlinked subgroups solely on the basis of the family-by-family evidence for linkage. This test has only modest power, particularly when applied to the relatively small families most commonly ascertained in schizophrenia linkage studies (16)(17)(18)(19). If it is possible, on clinical grounds, to divide the sample before linkage into etiologically distinct subgroups, a great gain in power is possible.…”