The future of genomics in pathology

The recent advances in technology and the promise of cheap and fast whole genomic data offer the possibility to revolutionise the discipline of pathology. This should allow pathologists in the near future to diagnose disease rapidly and early to change its course, and to tailor treatment programs to the individual. This review outlines some of these technical advances and the changes needed to make this revolution a reality

Genetic Networks of Complex Disorders: from a Novel Search Engine for PubMed Article Database

Finding genetic risk factors of complex disorders may involve reviewing hundreds of genes or thousands of research articles iteratively, but few tools have been available to facilitate this procedure. In this work, we built a novel publication search engine that can identify target-disorder specific, genetics-oriented research articles and extract the genes with significant results. Preliminary test results showed that the output of this engine has better coverage in terms of genes or publications, than other existing applications. We consider it as an essential tool for understanding genetic networks of complex disorders

Phylogenetically informed logic relationships improve detection of biological network organization

Background: A "phylogenetic profile" refers to the presence or absence of a gene across a set of organisms, and it has been proven valuable for understanding gene functional relationships and network organization. Despite this success, few studies have attempted to search beyond just pairwise relationships among genes. Here we search for logic relationships involving three genes, and explore its potential application in gene network analyses. Results: Taking advantage of a phylogenetic matrix constructed from the large orthologs database Roundup, we invented a method to create balanced profiles for individual triplets of genes that guarantee equal weight on the different phylogenetic scenarios of coevolution between genes. When we applied this idea to LAPP, the method to search for logic triplets of genes, the balanced profiles resulted in significant performance improvement and the discovery of hundreds of thousands more putative triplets than unadjusted profiles. We found that logic triplets detected biological network organization and identified key proteins and their functions, ranging from neighbouring proteins in local pathways, to well separated proteins in the whole pathway, and to the interactions among different pathways at the system level. Finally, our case study suggested that the directionality in a logic relationship and the profile of a triplet could disclose the connectivity between the triplet and surrounding networks. Conclusion: Balanced profiles are superior to the raw profiles employed by traditional methods of phylogenetic profiling in searching for high order gene sets. Gene triplets can provide valuable information in detection of biological network organization and identification of key genes at different levels of cellular interaction

Roundup 2.0: Enabling Comparative Genomics for over 1800 Genomes

Summary: Roundup is an online database of gene orthologs for over 1800 genomes, including 226 Eukaryota, 1447 Bacteria, 113 Archaea, and 21 Viruses. Orthologs are inferred using the Reciprocal Smallest Distance algorithm. Users may query Roundup for single-linkage clusters of orthologous genes based on any group of genomes. Annotated query results may be viewed in a variety of ways including as clusters of orthologs and as phylogenetic profiles. Genomic results may be downloaded in formats suitable for functional as well as phylogenetic analysis, including the recent OrthoXML standard. In addition, gene IDs can be retrieved using FASTA sequence search. All orthology results and source code are freely available

Use of Artificial Intelligence to Shorten the Behavioral Diagnosis of Autism

The Autism Diagnostic Interview-Revised (ADI-R) is one of the most commonly used instruments for assisting in the behavioral diagnosis of autism. The exam consists of 93 questions that must be answered by a care provider within a focused session that often spans 2.5 hours. We used machine learning techniques to study the complete sets of answers to the ADI-R available at the Autism Genetic Research Exchange (AGRE) for 891 individuals diagnosed with autism and 75 individuals who did not meet the criteria for an autism diagnosis. Our analysis showed that 7 of the 93 items contained in the ADI-R were sufficient to classify autism with 99.9% statistical accuracy. We further tested the accuracy of this 7-question classifier against complete sets of answers from two independent sources, a collection of 1654 individuals with autism from the Simons Foundation and a collection of 322 individuals with autism from the Boston Autism Consortium. In both cases, our classifier performed with nearly 100% statistical accuracy, properly categorizing all but one of the individuals from these two resources who previously had been diagnosed with autism through the standard ADI-R. Our ability to measure specificity was limited by the small numbers of non-spectrum cases in the research data used, however, both real and simulated data demonstrated a range in specificity from 99% to 93.8%. With incidence rates rising, the capacity to diagnose autism quickly and effectively requires careful design of behavioral assessment methods. Ours is an initial attempt to retrospectively analyze large data repositories to derive an accurate, but significantly abbreviated approach that may be used for rapid detection and clinical prioritization of individuals likely to have an autism spectrum disorder. Such a tool could assist in streamlining the clinical diagnostic process overall, leading to faster screening and earlier treatment of individuals with autism

Autworks: a Cross-Disease Network Biology Application for Autism and Related Disorders

Background: The genetic etiology of autism is heterogeneous. Multiple disorders share genotypic and phenotypic traits with autism. Network based cross-disorder analysis can aid in the understanding and characterization of the molecular pathology of autism, but there are few tools that enable us to conduct cross-disorder analysis and to visualize the results. Description: We have designed Autworks as a web portal to bring together gene interaction and gene-disease association data on autism to enable network construction, visualization, network comparisons with numerous other related neurological conditions and disorders. Users may examine the structure of gene interactions within a set of disorder-associated genes, compare networks of disorder/disease genes with those of other disorders/diseases, and upload their own sets for comparative analysis. Conclusions: Autworks is a web application that provides an easy-to-use resource for researchers of varied backgrounds to analyze the autism gene network structure within and between disorders

Molecular Signatures Reveal Circadian Clocks May Orchestrate the Homeorhetic Response to Lactation

Genes associated with lactation evolved more slowly than other genes in the mammalian genome. Higher conservation of milk and mammary genes suggest that species variation in milk composition is due in part to the environment and that we must look deeper into the genome for regulation of lactation. At the onset of lactation, metabolic changes are coordinated among multiple tissues through the endocrine system to accommodate the increased demand for nutrients and energy while allowing the animal to remain in homeostasis. This process is known as homeorhesis. Homeorhetic adaptation to lactation has been extensively described; however how these adaptations are orchestrated among multiple tissues remains elusive. To develop a clearer picture of how gene expression is coordinated across multiple tissues during the pregnancy to lactation transition, total RNA was isolated from mammary, liver and adipose tissues collected from rat dams (n = 5) on day 20 of pregnancy and day 1 of lactation, and gene expression was measured using Affymetrix GeneChips. Two types of gene expression analysis were performed. Genes that were differentially expressed between days within a tissue were identified with linear regression, and univariate regression was used to identify genes commonly up-regulated and down-regulated across all tissues. Gene set enrichment analysis showed genes commonly up regulated among the three tissues enriched gene ontologies primary metabolic processes, macromolecular complex assembly and negative regulation of apoptosis ontologies. Genes enriched in transcription regulator activity showed the common up regulation of 2 core molecular clock genes, ARNTL and CLOCK. Commonly down regulated genes enriched Rhythmic process and included: NR1D1, DBP, BHLHB2, OPN4, and HTR7, which regulate intracellular circadian rhythms. Changes in mammary, liver and adipose transcriptomes at the onset of lactation illustrate the complexity of homeorhetic adaptations and suggest that these changes are coordinated through molecular clocks

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research