The Product Guides the Process: Discovering Disease Mechanisms

The nature of the product to be discovered guides the reasoning to discover it. Biologists and medical researchers often search for mechanisms. The "new mechanistic philosophy of science" provides resources about the nature of biological mechanisms that aid the discovery of mechanisms. Here, we apply these resources to the discovery of mechanisms in medicine. A new diagrammatic representation of a disease mechanism chain indicates both what is known and, most significantly, what is not known at a given time, thereby guiding the researcher and collaborators in discovery. Mechanisms of genetic diseases provide the examples

The Product Guides the Process: Discovering Disease Mechanisms

The nature of the product to be discovered guides the reasoning to discover it. Biologists and medical researchers often search for mechanisms. The "new mechanistic philosophy of science" provides resources about the nature of biological mechanisms that aid the discovery of mechanisms. Here, we apply these resources to the discovery of mechanisms in medicine. A new diagrammatic representation of a disease mechanism chain indicates both what is known and, most significantly, what is not known at a given time, thereby guiding the researcher and collaborators in discovery. Mechanisms of genetic diseases provide the examples

Nijmegen Breakage Syndrome Detected by Newborn Screening for T Cell Receptor Excision Circles (TRECs)

PURPOSE: Severe combined immunodeficiency (SCID) encompasses a group of disorders characterized by reduced or absent T-cell number and function and identified by newborn screening utilizing T-cell receptor excision circles (TRECs). This screening has also identified infants with T lymphopenia who lack mutations in typical SCID genes. We report an infant with low TRECs and non-SCID T lymphopenia, who proved upon whole exome sequencing to have Nijmegen breakage syndrome (NBS). METHODS: Exome sequencing of DNA from the infant and his parents was performed. Genomic analysis revealed deleterious variants in the NBN gene. Confirmatory testing included Sanger sequencing and immunoblotting and radiosensitivity testing of patient lymphocytes. RESULTS: Two novel nonsense mutations in NBN were identified in genomic DNA from the family. Immunoblotting showed absence of nibrin protein. A colony survival assay demonstrated radiosensitivity comparable to patients with ataxia telangiectasia. CONCLUSIONS: Although TREC screening was developed to identify newborns with SCID, it has also identified T lymphopenic disorders that may not otherwise be diagnosed until later in life. Timely identification of an infant with T lymphopenia allowed for prompt pursuit of underlying etiology, making possible a diagnosis of NBS, genetic counseling, and early intervention to minimize complications

Production of He-4 and (4) in Pb-Pb collisions at root(NN)-N-S=2.76 TeV at the LHC

Results on the production of He-4 and (4) nuclei in Pb-Pb collisions at root(NN)-N-S = 2.76 TeV in the rapidity range vertical bar y vertical bar <1, using the ALICE detector, are presented in this paper. The rapidity densities corresponding to 0-10% central events are found to be dN/dy4(He) = (0.8 +/- 0.4 (stat) +/- 0.3 (syst)) x 10(-6) and dN/dy4 = (1.1 +/- 0.4 (stat) +/- 0.2 (syst)) x 10(-6), respectively. This is in agreement with the statistical thermal model expectation assuming the same chemical freeze-out temperature (T-chem = 156 MeV) as for light hadrons. The measured ratio of (4)/He-4 is 1.4 +/- 0.8 (stat) +/- 0.5 (syst). (C) 2018 Published by Elsevier B.V.Peer reviewe

Multigenerational mobility in India

Most studies of intergenerational mobility focus on adjacent generations, and there is limited knowledge about multigenerational mobility that is, status transmission across three generations. We examine multigenerational educational and occupational mobility in India, using a nationally representative data-set the Indian Human Development Survey which contains information about education and occupation for three generations. We find that mobility has increased over generations for education, but not for occupation. We also find that there are stark differences across social groups, with individuals belonging to socially disadvantaged communities in India lagging behind in social progress. Multigenerational mobility for Muslims in education and occupation have decreased in comparison to Hindus over the three generations. While we find that there is an increase in educational mobility for other disadvantaged groups such as Scheduled Castes, Scheduled Tribes, and Other Backward Classes compared to General Castes, we do not find evidence of increased occupational mobility over the three generations

INTERPRETING GENETIC VARIANTS FOR DISCOVERING DISEASE ETIOLOGY AND MECHANISMS

High-throughput sequencing methods now provide extensive data on disease-related human genetic variants. New methods are required to maximally utilize these data for enhanced understanding and treatment of human diseases. This dissertation describes my work in addressing three aspects of this challenge: Determining disease-causative variants; representing mechanisms by which genetic variant(s) cause disease phenotypes; and quantitatively analyzing genetic disease mechanisms. First, I developed a variant prioritization algorithm, VarP, and objectively tested it in CAGI (Critical Assessment of Genome Interpretation). It was ranked best in the CAGI challenge on interpreting panel sequencing data for 106 patients, determining which disease class each patient has and the corresponding causative variant(s). VarP correctly identified the disease class for 36 cases, including 10 where the original clinical pipeline failed, and found seven cases with strong evidence of an alternative disease to that tested. Over-reliance on pathogenicity annotations in the HGMD mutation database led to several incorrect cases. Post analysis showed that protein structure data could have helped to interpret the impact of many prioritized missense variants. Next, I co-developed and implemented MecCog, a web-based graphical framework to represent mechanisms by which genetic variants cause disease phenotypes. A MecCog mechanism schema displays the propagation of system perturbations across stages of biological organization, using graphical notations to symbolize perturbed entities and activities, knowledge gaps, ambiguities and uncertainties, and hyperlinked evidence. The web platform enables a user to construct, store, publish, browse, query, and comment on schemas. MecCog facilitates better comprehension of disease mechanisms, identification of critical unanswered questions on causal relationships, and possible new sites of therapeutic intervention. Finally, I developed a framework to quantitatively represent and analyze mechanisms relating genetic variants to complex trait disease. It involves generating a computable circuit from MecCog schemas by assigning node functions and parameters to represent the behavior of the schema components. I demonstrate that such a circuit can be used to analyze the effect size of a variant contributing to disease risk as a function of the genetic background in an individual and the extent to which epistatic effects may be masked in population averages. I also show that the circuit functions and parameters can be learned in a data-driven manner using a hybrid neural network approach

Multigenerational Mobility Among Males in India

Most studies of intergenerational mobility focus on adjacent generations, and there is limited knowledge about multigenerational mobility—status transmission across three generations. We examine multigenerational educational and occupational mobility in India, using a nationally representative data set the India Human Development Survey that contains information about education and occupation for three generations. We find that mobility has increased over generations for education, but not for occupation. We also find that there are stark differences across social groups, with individuals belonging to socially disadvantaged communities lagging behind in social progress. Multigenerational mobility for Muslims in education and occupation has decreased in comparison to Hindus over the three generations. While we find that there is an increase in educational mobility for other disadvantaged groups such as Scheduled Castes, Scheduled Tribes, and Other Backward Classes compared to General Castes, we do not find evidence of increased occupational mobility over the three generations.Peer reviewe