Abstract Large Language Models perform well at natural language interpretation and reasoning, but their lack of formal correctness guarantees limits their adoption in regulated industries like finance and healthcare that operate under strict policies. To address this limitation, we launched Automated Reasoning checks (ARc) : a public service that (1) uses LLMs with optional human guidance to formalize natural language policies, allowing fine-grained control of the formalization process, and (2) uses inference-time autoformalization to validate logical correctness of natural language statements against those policies. ARc performs multiple redundant formalization steps at inference time, checking the formalizations for semantic equivalence. Our benchmarks show that ARc exceeds 99% soundness and achieves a near-zero false positive rate in identifying logical validity. Our approach produces auditable artifacts that substantiate the verification outcomes and can be used to improve the original text. ARc is the first commercial offering from a major cloud provider to integrate automated reasoning into a generative AI guardrail.

Low-coverage whole-genome sequencing (lcWGS) has emerged as a cost-effective and robust approach for population genomic studies. Despite its advantages, publicly available resources for large-scale lcWGS datasets remain limited. To our knowledge, there is yet a bioinformatics tool capable of directly simulating lcWGS datasets from variant call format (VCF) files. To address this gap, we developed a tool called lcSimVCF, which leverages multivariate Gaussian mixture models (MGMMs) to simulate lcWGS genotype likelihood distributions directly from high-coverage whole-genome sequencing (hcWGS) VCF files. In this study, we introduced a tool called lcSimVCF that aim to use 30× hcWGS VCF files to simulate 1× genotype likelihood distributions as a demonstration. We trained an MGMM framework for three genotypes: homozygous reference, heterozygous, and homozygous non-reference, each simulating its respective lcWGS genotype likelihood distribution. Our results demonstrate the robustness of the MGMM approach in capturing genotype likelihood distributions compared to single Gaussian mixture models (SGM). Simulated lcWGS data exhibited representative patterns in population stratification analyses and showed potential for applications in polygenic risk score (PRS) modeling. Analysis of 81,271,745 imputed single nucleotide polymorphisms (SNPs) revealed strong correlations among the PRS derived from different phenotypes: PRS CAD , PRS T2D , and PRS AF . The correlations demonstrated high coefficients of determination ( \({R}^{2}\) ) of 0.94, 0.87, and 0.85, respectively. Furthermore, we assessed simulation time across various configurations (1-16 CPUs, 1-800 individuals, 100-10,000 variants), finding its capability in simulating 10,000 variants across 800 individuals in under 30 seconds with 16 CPUs. The developed simulation tool has demonstrated its capability in generating large-scale lcWGS datasets. This tool holds significant potential to facilitate the development and evaluation of bioinformatics tools and analytical pipelines that rely on access to extensive lcWGS data resources.

Global pandemics call for large and diverse healthcare data to study various risk factors, treatment options, and disease progression patterns. Despite the enormous efforts of many large data consortium initiatives, scientific community still lacks a secure and privacy-preserving infrastructure to support auditable data sharing and facilitate automated and legally compliant federated analysis on an international scale. Existing health informatics systems do not incorporate the latest progress in modern security and federated machine learning algorithms, which are poised to offer solutions. An international group of passionate researchers came together with a joint mission to solve the problem with our finest models and tools. The SCOR Consortium has developed a ready-to-deploy secure infrastructure using world-class privacy and security technologies to reconcile the privacy/utility conflicts. We hope our effort will make a change and accelerate research in future pandemics with broad and diverse samples on an international scale.

BACKGROUND: Whole genome and exome sequencing usually include reads containing mitochondrial DNA (mtDNA). Yet, state-of-the-art pipelines and services for human nuclear genome variant calling and annotation do not handle mitochondrial genome data appropriately. As a consequence, any researcher desiring to add mtDNA variant analysis to their investigations is forced to explore the literature for mtDNA pipelines, evaluate them, and implement their own instance of the desired tool. This task is far from trivial, and can be prohibitive for non-bioinformaticians. RESULTS: We have developed SG-ADVISER mtDNA, a web server to facilitate the analysis and interpretation of mtDNA genomic data coming from next generation sequencing (NGS) experiments. The server was built in the context of our SG-ADVISER framework and on top of the MtoolBox platform (Calabrese et al., Bioinformatics 30(21):3115-3117, 2014), and includes most of its functionalities (i.e., assembly of mitochondrial genomes, heteroplasmic fractions, haplogroup assignment, functional and prioritization analysis of mitochondrial variants) as well as a back-end and a front-end interface. The server has been tested with unpublished data from 200 individuals of a healthy aging cohort (Erikson et al., Cell 165(4):1002-1011, 2016) and their data is made publicly available here along with a preliminary analysis of the variants. We observed that individuals over ~90 years old carried low levels of heteroplasmic variants in their genomes. CONCLUSIONS: SG-ADVISER mtDNA is a fast and functional tool that allows for variant calling and annotation of human mtDNA data coming from NGS experiments. The server was built with simplicity in mind, and builds on our own experience in interpreting mtDNA variants in the context of sudden death and rare diseases. Our objective is to provide an interface for non-bioinformaticians aiming to acquire (or contrast) mtDNA annotations via MToolBox. SG-ADVISER web server is freely available to all users at https://genomics.scripps.edu/mtdna .

MOTIVATION: Traditional gene expression analysis techniques capture an average gene expression state across sample replicates. However, the average signal across replicates will not capture activated gene networks in different states across replicates. For example, if a particular gene expression network is activated within a subset or all sample replicates, yet the activation state across the sample replicates differs by the specific genes activated in each replicate, the activation of this network will be washed out by averaging across replicates. This situation is likely to occur in single cell gene expression experiments or in noisy experimental settings where a small sub-population of cells contributes to the gene expression signature of interest. RESULTS AND IMPLEMENTATION: In this light, we developed a novel network-based approach which considers gene expression within each replicate across its entire gene expression profile, and identifies outliers across replicates. The power of this method is demonstrated by its ability to enrich for distant metastasis related genes derived from noisy expression data of CD44+CD24-/low tumor initiating cells.

MOTIVATION: Limited availability of data has hindered the development of algorithms that can identify functionally meaningful regulatory single nucleotide polymorphisms (rSNPs). Given the large number of common polymorphisms known to reside in the human genome, the identification of functional rSNPs via laboratory assays will be costly and time-consuming. Therefore appropriate bioinformatics strategies for predicting functional rSNPs are necessary. Recent data from the Encyclopedia of DNA Elements (ENCODE) Project has significantly expanded the amount of available functional information relevant to non-coding regions of the genome, and, importantly, led to the conclusion that many functional elements in the human genome are not conserved. RESULTS: In this article we describe how ENCODE data can be leveraged to probabilistically determine the functional and phenotypic significance of non-coding SNPs (ncSNPs). The method achieves excellent sensitivity ( approximately 80%) and speci.city ( approximately 99%) based on a set of known phenotypically relevant and non-functional SNPs. In addition, we show that our method is not overtrained through the use of cross-validation analyses. AVAILABILITY: The software platforms used in our analyses are freely available (http://www.cs.waikato.ac.nz/ml/weka/). In addition, we provide the training dataset (Supplementary Table 3), and our predictions (Supplementary Table 6), in the Supplementary Material. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

MOTIVATION: Contemporary, high-throughput sequencing efforts have identified a rich source of naturally occurring single nucleotide polymorphisms (SNPs), a subset of which occur in the coding region of genes and result in a change in the encoded amino acid sequence (non-synonymous coding SNPs or 'nsSNPs'). It is hypothesized that a subset of these nsSNPs may underlie common human disease. Testing all these polymorphisms for disease association would be time consuming and expensive. Thus, computational methods have been developed to both prioritize candidate nsSNPs and make sense of their likely molecular physiologic impact. RESULTS: We have developed a method to prioritize nsSNPs and have applied it to the human protein kinase gene family. The results of our analyses provide high quality predictions and outperform available whole genome prediction methods (74% versus 83% prediction accuracy). Our analyses and methods consider both DNA sequence conservation, which most traditional methods are based on, as well unique structural and functional features of kinases. We provide a ranked list of common kinase nsSNPs that have a higher probability of impacting human disease based on our analyses.