Age-at-first-registration and heterogeneity in affective psychoses

Background: Previous research into age of onset in affective disorders has produced conflicting results. This paper examines the influence of heterogeneity on the age-at-first-registration distribution for the ICD-9 diagnostic group 'affective psychosis'. Method: For 1979-1991, data for age-at-first-registration for 4985 individuals diagnosed with affective psychosis (ICD-9 296.x) were extracted from a name-linked mental health register. These data were divided into (i) '296.1 only', a category used to code unipolar depression (males = 700; females = 1321); and (ii) '296 other', all 296 cases other than 296.1 (males = 1280; females = 1684). Inception rates for each 5-year age division were adjusted for the background population age-structure as a rate per 100 000 population. Results: The age-at-first-registration distribution for affective psychosis has a wide age range, with women outnumbering men. There is a near-linear increase in inception rates for both men and women with 296.1 only, while the bulk of those with affective psychoses (296 other) have an inverted U-shaped age distribution. Males have an earlier modal age-at-first-registration for 296 other compared to females. Conclusion: The heterogeneity in terms of subtypes and sex in affective psychosis clouds the interpretation of age-at-first-registration. Separating those with unipolar psychotic depression from other subclassifications and differentiating by sex may provide clues to factors that precipitate the onset of affective psychosis.

The importance of modelling heterogeneity in complex disease: application to NIMH Schizophrenia Genetics Initiative data

As for other complex diseases, linkage analyses of schizophrenia (SZ) have produced evidence for numerous chromosomal regions, with inconsistent results reported across studies. The presence of locus heterogeneity appears likely and may reduce the power of linkage analyses if homogeneity is assumed. In addition, when multiple heterogeneous datasets are pooled, intersample variation in the proportion of linked families ( a) may diminish the power of the pooled sample to detect susceptibility loci, in spite of the larger sample size obtained. We compare the significance of linkage. findings obtained using allele- sharing LOD scores ( LODexp) - which assume homogeneity - and heterogeneity LOD scores ( HLOD) in European American and African American NIMH SZ families. We also pool these two samples and evaluate the relative power of the LODexp and two different heterogeneity statistics. One of these ( HLOD- P) estimates the heterogeneity parameter a only in aggregate data, while the second ( HLOD- S) determines a separately for each sample. In separate and combined data, we show consistently improved performance of HLOD scores over LODexp. Notably, genome-wide significant evidence for linkage is obtained at chromosome 10p in the European American sample using a recessive HLOD score. When the two samples are combined, linkage at the 10p locus also achieves genome-wide significance under HLOD- S, but not HLOD- P. Using HLOD- S, improved evidence for linkage was also obtained for a previously reported region on chromosome 15q. In linkage analyses of complex disease, power may be maximised by routinely modelling locus heterogeneity within individual datasets, even when multiple datasets are combined to form larger samples.