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This work demonstrates the use of cluster analysis in detecting fair and unbiased novel discoveries. Given a sample population of elective spinal fusion patients, we identify two overarching subgroups driven by insurance type. The Medicare group, associated with lower socioeconomic status, exhibited an over-representation of negative risk factors. The findings provide a compelling depiction of the interwoven socioeconomic and racial disparities present within the healthcare system, highlighting their consequential effects on health inequalities. The results are intended to guide design of fair and precise machine learning models based on intentional integration of population stratification.

Objective We investigated the relationship between the amount and frequency of fish intake, and the white blood cell (WBC) count and aerobic exercise habits. Methods We conducted a cross-sectional study between April 2019 and March 2020 at the Health Planning Center of Nihon University Hospital on a cohort of 8,981 male subjects. Results The average amount and frequency of fish intake were 134±85 g/week and 2.14±1.28 days/week, respectively. The WBC count decreased significantly as the amount of fish intake increased (p<0.0001). According to a multivariate regression analysis, a high fish intake amount (β=-0.082, p<0.0001) and regular aerobic exercise (β=-0.083, p<0.0001) were independent determinants of a low WBC count. The proportion of subjects engaged in regular aerobic exercise increased with an increase in the amount of fish intake (p<0.0001). Furthermore, the amount and frequency of fish intake significantly correlated with the amount of n-3 polyunsaturated fatty acid intake determined using the Japan's National Nutrition Survey results (both r=0.962 and 0.958). Therefore, the amount of fish intake could be substituted by the average number of days of fish intake per week. Conclusion A high fish intake was an independent determinant of a low WBC count and engagement in regular aerobic exercise, regardless of whether the fish intake was defined by the amount or frequency of fish intake. However, since fish intake frequency can be measured more easily, this may be used to measure the fish intake.

Background: Although the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for variant interpretation are used widely in clinical genetics, there is room for improvement of these knowledge-based guidelines., Methods: Statistical assessment of average deleteriousness of start-lost, stop-lost, and in-frame insertion and deletion (indel) variants and extraction of deleterious subsets was performed, being informed by proportions of rare variants in the general population of the Genome Aggregation Database (gnomAD). A machine learning-based model scoring the pathogenicity of start-lost variants (the PoStaL model) was constructed by predicting possible translation initiation sites on transcripts by deep learning and training a random forest on known pathogenic and likely benign variants., Findings: The proportion of rare variants was highest in stop-lost variants, followed by in-frame indels and start-lost variants, suggesting that the criteria in the ACMG/AMP guidelines assigning PVS (pathogenic very strong) to start-lost variants and PM (pathogenic moderate) to stop-lost and in-frame indel variants would not be appropriate. Regarding deleterious subsets, stop-lost variants introducing extensions of more than 30 amino acids and in-frame indels computationally predicted to be damaging are enriched for rare and known pathogenic variants. For start-lost variants, we developed the PoStaL model, which outperforms existing tools. We also provide comprehensive lists of the PoStaL scores for start-lost variants and the length of extended amino acids by stop-lost variants., Conclusions: Our study could contribute to refinement of the ACMG/AMP guidelines, provides resources for future investigation, and provides an example of how to improve knowledge-based frameworks by data-driven approaches., Funding: The study was supported by grants from the Japan Agency for Medical Research and Development (AMED) and the Japan Society for the Promotion of Science (JSPS)., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

We performed whole genome sequencing in 16 unrelated patients with autosomal recessive retinitis pigmentosa (ARRP), a disease characterized by progressive retinal degeneration and caused by mutations in over 50 genes, in search of pathogenic DNA variants. Eight patients were from North America, whereas eight were Japanese, a population for which ARRP seems to have different genetic drivers. Using a specific workflow, we assessed both the coding and noncoding regions of the human genome, including the evaluation of highly polymorphic SNPs, structural and copy number variations, as well as 69 control genomes sequenced by the same procedures. We detected homozygous or compound heterozygous mutations in 7 genes associated with ARRP (USH2A, RDH12, CNGB1, EYS, PDE6B, DFNB31, and CERKL) in eight patients, three Japanese and five Americans. Fourteen of the 16 mutant alleles identified were previously unknown. Among these, there was a 2.3-kb deletion in USH2A and an inverted duplication of ~446 kb in EYS, which would have likely escaped conventional screening techniques or exome sequencing. Moreover, in another Japanese patient, we identified a homozygous frameshift (p.L206fs), absent in more than 2,500 chromosomes from ethnically matched controls, in the ciliary gene NEK2, encoding a serine/threonine-protein kinase. Inactivation of this gene in zebrafish induced retinal photoreceptor defects that were rescued by human NEK2 mRNA. In addition to identifying a previously undescribed ARRP gene, our study highlights the importance of rare structural DNA variations in Mendelian diseases and advocates the need for screening approaches that transcend the analysis of the coding sequences of the human genome.

Genetic mechanisms are implicated as a cause of some male infertility, yet are poorly understood. Mouse meiotic mutant mei1 (meiosis defective 1) was isolated by a screening of infertile mice. Male mei1 mice have azoospermia due to meiotic arrest, and the mouse Mei1 gene is responsible for the mei1 phenotype. To investigate whether human MEI1 gene defects are associated with azoospermia by meiotic arrest, we isolated the human MEI1 cDNA based on the mouse Mei1 amino acid sequence. MEI1 is expressed specifically in the testis. Mutational analysis by direct sequencing of all MEI1 coding regions was performed in 27 men (13 European Americans, 13 Israeli and 1 Japanese) having azoospermia due to complete early meiotic arrest. This identified four novel, coding single-nucleotide-polymorphisms (cSNPs), i.e., SNP1 (T909G), SNP2 (A1582G), SNP3 (C1791A) and SNP4 (C2397T) in exons 4, 8, 9 and 14, respectively. Using these cSNPs, an association study was carried out between 26 non-Japanese patients with azoospermia and two sets of normal control men (61 normal European Americans and 60 Israelis). Consequently, SNP3 and SNP4 were shown to be associated with azoospermia among European Americans (P =0.0289 and P =0.0299 for genotype and allele frequencies at both the polymorphic sites, respectively), although no such association was observed among Israelis (P >0.05). Haplotype estimation revealed that the frequencies of SNP3-SNP4 (C-T), SNP3-SNP4 (A-C) and SNP3-SNP4 (A-T) were higher in the European American patients, and the frequency of SNP3-SNP4 (A-T) was also higher than in both control groups. These results suggest that MEI1 may play a role in meiosis during spermatogenesis, especially in European Americans.