Zero is not absence: censoring-based differential abundance analysis for microbiome data.

MOTIVATION: Microbiome data analysis faces the challenge of sparsity, with many entries recorded as zeros. In differential abundance analysis, the presence of excessive zeros in data violates distributional assumptions and creates ties, leading to an increased risk of type I errors and reduced statistical power. RESULTS: We developed a novel normalization method, called censoring-based analysis of microbiome proportions (CAMP), for microbiome data by treating zeros as censored observations, transforming raw read counts into tie-free time-to-event-like data. This enables the use of survival analysis techniques, like the Cox proportional hazards model, for differential abundance analysis. Extensive simulations demonstrate that CAMP achieves proper type I error control and high power. Applying CAMP to a human gut microbiome dataset, we identify 60 new differentially abundant taxa across geographic locations, showcasing its usefulness. CAMP overcomes sparsity challenges, enabling improved statistical analysis and providing valuable insights into microbiome data in various contexts. AVAILABILITY AND IMPLEMENTATION: The R package is available at https://github.com/lapsumchan/CAMP.

Whole Exome Sequencing Enhanced Imputation Identifies 85 Metabolite Associations in the Alpine CHRIS Cohort.

Metabolites are intermediates or end products of biochemical processes involved in both health and disease. Here, we take advantage of the well-characterized Cooperative Health Research in South Tyrol (CHRIS) study to perform an exome-wide association study (ExWAS) on absolute concentrations of 175 metabolites in 3294 individuals. To increase power, we imputed the identified variants into an additional 2211 genotyped individuals of CHRIS. In the resulting dataset of 5505 individuals, we identified 85 single-variant genetic associations, of which 39 have not been reported previously. Fifteen associations emerged at ten variants with >5-fold enrichment in CHRIS compared to non-Finnish Europeans reported in the gnomAD database. For example, the CHRIS-enriched ETFDH stop gain variant p.Trp286Ter (rs1235904433-hexanoylcarnitine) and the MCCC2 stop lost variant p.Ter564GlnextTer3 (rs751970792-carnitine) have been found in patients with glutaric acidemia type II and 3-methylcrotonylglycinuria, respectively, but the loci have not been associated with the respective metabolites in a genome-wide association study (GWAS) previously. We further identified three gene-trait associations, where multiple rare variants contribute to the signal. These results not only provide further evidence for previously described associations, but also describe novel genes and mechanisms for diseases and disease-related traits.

Genome-wide association studies of metabolites in Finnish men identify disease-relevant loci.

Few studies have explored the impact of rare variants (minor allele frequency < 1%) on highly heritable plasma metabolites identified in metabolomic screens. The Finnish population provides an ideal opportunity for such explorations, given the multiple bottlenecks and expansions that have shaped its history, and the enrichment for many otherwise rare alleles that has resulted. Here, we report genetic associations for 1391 plasma metabolites in 6136 men from the late-settlement region of Finland. We identify 303 novel association signals, more than one third at variants rare or enriched in Finns. Many of these signals identify genes not previously implicated in metabolite genome-wide association studies and suggest mechanisms for diseases and disease-related traits.