Effective variant filtering and expected candidate variant yield in studies of rare human disease.

In studies of families with rare disease, it is common to screen for de novo mutations, as well as recessive or dominant variants that explain the phenotype. However, the filtering strategies and software used to prioritize high-confidence variants vary from study to study. In an effort to establish recommendations for rare disease research, we explore effective guidelines for variant (SNP and INDEL) filtering and report the expected number of candidates for de novo dominant, recessive, and autosomal dominant modes of inheritance. We derived these guidelines using two large family-based cohorts that underwent whole-genome sequencing, as well as two family cohorts with whole-exome sequencing. The filters are applied to common attributes, including genotype-quality, sequencing depth, allele balance, and population allele frequency. The resulting guidelines yield ~10 candidate SNP and INDEL variants per exome, and 18 per genome for recessive and de novo dominant modes of inheritance, with substantially more candidates for autosomal dominant inheritance. For family-based, whole-genome sequencing studies, this number includes an average of three de novo, ten compound heterozygous, one autosomal recessive, four X-linked variants, and roughly 100 candidate variants following autosomal dominant inheritance. The slivar software we developed to establish and rapidly apply these filters to VCF files is available at https://github.com/brentp/slivar under an MIT license, and includes documentation and recommendations for best practices for rare disease analysis.

Safely Managed Sanitation for All Means Fecal Sludge Management for At Least 1.8 Billion People in Low and Middle Income Countries.

Although global access to sanitation is increasing, safe management of fecal waste is a rapidly growing challenge in low- and middle-income countries (LMICs). The goal of this study was to evaluate the current need for fecal sludge management (FSM) in LMICs by region, urban/rural status, and wealth. Recent Demographic and Health Survey data from 58 countries (847 685 surveys) were used to classify households by sanitation facility (facilities needing FSM, sewered facilities, ecological sanitation/other, or no facilities). Onsite piped water infrastructure was quantified to approximate need for wastewater management and downstream treatment. Over all surveyed nations, 63% of households used facilities requiring FSM, totaling approximately 1.8 billion people. Rural areas had similar proportions of toilets requiring FSM as urban areas. FSM needs scaled inversely with wealth: in the poorest quintile, households' sanitation facilities were almost 170 times more likely to require FSM (vs sewerage) than in the richest quintile. About one out of five households needing FSM had onsite piped water infrastructure, indicating domestic or reticulated wastewater infrastructure may be required if lacking for safe management of aqueous waste streams. FSM strategies must be included in future sanitation investment to achieve safe management of fecal wastes and protect public health.