Genomes undergo changes in organization as a result of gene duplications, chromosomal rearrangements and local mutations, among other mechanisms. In contrast to prokaryotes, in which genes of a common function are often organized in operons and reside contiguously along the genome, most eukaryotes show much weaker clustering of genes by function, except for few concrete functional groups. We set out to check systematically if there is a relation between gene function and gene organization in the human genome. We test this question for three types of functional groups: pairs of interacting proteins, complexes and pathways. We find a significant concentration of functional groups both in terms of their distance within the same chromosome and in terms of their dispersal over several chromosomes. Moreover, using Hi-C contact map of the tendency of chromosomal segments to appear close in the 3D space of the nucleus, we show that members of the same functional group that reside on distinct chromosomes tend to co-localize in space. The result holds for all three types of functional groups that we tested. Hence, the human genome shows substantial concentration of functional groups within chromosomes and across chromosomes in space.

Chances of treatment success were improved if patients received the model-predicted treatment. Using the model's prediction system may enable personalized, evidence-based epilepsy care, accelerating the match between patients and their ideal therapy, thereby delivering significantly better health outcomes for patients and providing health-care savings by applying resources more efficiently. Our goal will be to strengthen the predictive power of the model by integrating diverse data sets and potentially moving to prospective data collection.

BackgroundChromosomal aneuploidy, that is to say the gain or loss of chromosomes, is the most common abnormality in cancer. While certain aberrations, most commonly translocations, are known to be strongly associated with specific cancers and contribute to their formation, most aberrations appear to be non-specific and arbitrary, and do not have a clear effect. The understanding of chromosomal aneuploidy and its role in tumorigenesis is a fundamental open problem in cancer biology.ResultsWe report on a systematic study of the characteristics of chromosomal aberrations in cancers, using over 15,000 karyotypes and 62 cancer classes in the Mitelman Database. Remarkably, we discovered a very high co-occurrence rate of chromosome gains with other chromosome gains, and of losses with losses. Gains and losses rarely show significant co-occurrence. This finding was consistent across cancer classes and was confirmed on an independent comparative genomic hybridization dataset of cancer samples. The results of our analysis are available for further investigation via an accompanying website.ConclusionsThe broad generality and the intricate characteristics of the dichotomy of aneuploidy, ranging across numerous tumor classes, are revealed here rigorously for the first time using statistical analyses of large-scale datasets. Our finding suggests that aneuploid cancer cells may use extra chromosome gain or loss events to restore a balance in their altered protein ratios, needed for maintaining their cellular fitness.

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A central problem in genome rearrangement is finding a most parsimonious rearrangement scenario using certain rearrangement operations. An important problem of this type is sorting a signed genome by reversals and translocations (SBRT). Hannenhalli and Pevzner presented a duality theorem for SBRT which leads to a polynomial time algorithm for sorting a multi-chromosomal genome using a minimum number of reversals and translocations. However, there is one case for which their theorem and algorithm fail. We describe that case and suggest a correction to the theorem and the polynomial algorithm. The solution of SBRT uses a reduction to the problem of sorting a signed permutation by reversals (SBR). The best extant algorithms for SBR require quadratic time. The common approach to solve SBR is by finding a safe reversal using the overlap graph or the interleaving graph of a permutation. We describe a family of signed permutations which proves a quadratic lower bound on the number of affected vertices in the overlap/interleaving graph during any optimal sorting scenario. This implies, in particular, an Omega(n3) lower bound for Bergeron's algorithm.

Objective Observational medical databases, such as electronic health records and insurance claims, track the healthcare trajectory of millions of individuals. These databases provide real-world longitudinal information on large cohorts of patients and their medication prescription history. We present an easy-to-customize framework that systematically analyzes such databases to identify new indications for on-market prescription drugs. Materials and Methods Our framework provides an interface for defining study design parameters and extracting patient cohorts, disease-related outcomes, and potential confounders in observational databases. It then applies causal inference methodology to emulate hundreds of randomized controlled trials (RCTs) for prescribed drugs, while adjusting for confounding and selection biases. After correcting for multiple testing, it outputs the estimated effects and their statistical significance in each database. Results We demonstrate the utility of the framework in a case study of Parkinson’s disease (PD) and evaluate the effect of 259 drugs on various PD progression measures in two observational medical databases, covering more than 150 million patients. The results of these emulated trials reveal remarkable agreement between the two databases for the most promising candidates. Discussion Estimating drug effects from observational data is challenging due to data biases and noise. To tackle this challenge, we integrate causal inference methodology with domain knowledge and compare the estimated effects in two separate databases. Conclusion Our framework enables systematic search for drug repurposing candidates by emulating RCTs using observational data. The high level of agreement between separate databases strongly supports the identified effects.

Background: Digital breast tomosynthesis (DBT) has higher diagnostic accuracy than digital mammography, but interpretation time is substantially longer. Artificial intelligence (AI) could improve reading efficiency. Purpose:To evaluate the use of AI to reduce workload by filtering out normal DBT screens. Materials and Methods:The retrospective study included 13 306 DBT examinations from 9919 women performed between June 2013 and November 2018 from two health care networks. The cohort was split into training, validation, and test sets (3948, 1661, and 4310 women, respectively). A workflow was simulated in which the AI model classified cancer-free examinations that could be dismissed from the screening worklist and used the original radiologists' interpretations on the rest of the worklist examinations. The AI system was also evaluated with a reader study of five breast radiologists reading the DBT mammograms of 205 women. The area under the receiver operating characteristic curve (AUC), sensitivity, specificity, and recall rate were evaluated in both studies. Statistics were computed across 10 000 bootstrap samples to assess 95% CIs, noninferiority, and superiority tests. Results:The model was tested on 4310 screened women (mean age, 60 years 6 11 [standard deviation]; 5182 DBT examinations). Compared with the radiologists' performance (417 of 459 detected cancers [90.8%], 477 recalls in 5182 examinations [9.2%]), the use of AI to automatically filter out cases would result in 39.6% less workload, noninferior sensitivity (413 of 459 detected cancers; 90.0%; P = .002), and 25% lower recall rate (358 recalls in 5182 examinations; 6.9%; P = .002). In the reader study, AUC was higher in the standalone AI compared with the mean reader (0.84 vs 0.81; P = .002). Conclusion:The artificial intelligence model was able to identify normal digital breast tomosynthesis screening examinations, which decreased the number of examinations that required radiologist interpretation in a simulated clinical workflow.Published under a CC BY 4.0 license.

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