Statistical methods for clinical genome interpretation with specific application to inherited cardiac conditions

Background: While next-generation sequencing has enabled us to rapidly identify sequence variants, clinical application is limited by our ability to determine which rare variants impact disease risk. Aim: Developing computational methods to identify clinically important variants Methods and Results: (1) I built a disease-specific variant classifier for inherited cardiac conditions (ICCs), which outperforms genome-wide tools in a wide range of benchmarking. It discriminates pathogenic variants from benign variants with global accuracy improved by 4-24% over existing tools. Variants classified with >90% confidence are significantly associated with both disease status and clinical outcomes. (2) To better interpret missense variants, I examined evolutionarily equivalent residues across protein domain families, to identify positions intolerant of variations. Homologous residue constraint is a strong predictor of variant pathogenicity. It can identify a subset of de novo missense variants with comparable impact on developmental disorders as protein-truncating variants. Independent from existing approaches, it can also improve the prioritisation of disease-relevant gene for both developmental disorders and inherited hypertrophic cardiomyopathy. (3) TTN-truncating variants are known to cause dilated cardiomyopathy, but the effect of missense variants is poorly understood. Using the approach in (2), I studied the role of TTN missense variants on DCM. Our prioritised residues are enriched with known pathogenic variants, including the two known to cause DCM and others involved in skeletal myopathies. I also found a significant association between constrained variants of TTN I-set domains and DCM in a case-control burden test of Caucasian samples (OR=3.2, 95%CI=1.3-9.4). Within subsets of DCM, the association is replicated in alcoholic cardiomyopathy. (4) Finally, I also developed a tool to annotate 5’UTR variants creating or disrupting upstream open reading frames (uORF). Its utility is demonstrated to detect high-impact uORF-disturbing variants from ClinVar, gnomAD and Genomics England. Conclusion: These studies established broadly applicable methods and improved understanding of ICCs.Open Acces

Development of a CBM based service indicator for UFD replacements - An introductory study

Dialysis is a life-sustaining treatment for many people around the world. In or- der to meet the high demands on the dialysis machines, replaceable parts must be exchanged in proper time. Condition based maintenance (CBM) bases its service decisions on the actual health status of the component. The goal of this master’s thesis was to develop an algorithm based on machine learning, constituting the first step of a CBM based service indicator monitoring the dialysis ultra filter (UFD) of Baxter’s AK 98 dialysis machine. Real treatment data retrieved from ten dialysis machines have been an- alyzed. Signals believed to be relevant to the UFD status were preprocessed and analyzed. From them different features were extracted whereof some were found in CBM related literature. Two different feature selection methods were used to select 10 out of the 178 available features. Different labeling meth- ods were tested and evaluated together with other relevant parameters in the algorithm. The final algorithm used a k-nearest neighbors (kNN) classifier with k = 12. The classification accuracy was approximately twice as good as a ran- dom guess. The main reason for not achieving a better result was that only six features appeared to contain relevant information regarding the UFD status. Furthermore, these features were derived from the same signal and closely related. Despite this, the developed algorithm did show promising result in detecting the UFD degradation level but further development will be needed. The main focus should be to improve the signal quality and/or find more relevant signals and/or features.Utveckling av algoritm som avgör filterstatusen hos dialysmaskiner Många människor världen över dör för att de inte har råd med dialysbehandling. För att minska kostnaderna har det i detta exjobb utvecklats en algoritm som kan användas i en framtida serviceindikator för filter i dialysmaskiner. Resultaten ser lovande ut. Kronisk njursjukdom beskriver ett tillstånd av progressivt förlorad njurfunktion. När detta utvecklats tillräckligt långt krävs behandling, till exempel i form av dialys. Man räknar med att runt två miljoner människor världen över är i behov av regelbunden dialysbehandling för att överleva. Dock är mörkertalet stort vilket medför att siffran troligtvis är tio gånger så stor. Det dåliga allmäntillståndet hos dialyspatienter ställer stora krav på behandlingen. Inte minst i form av att se till att dialysvätskan är helt fri från bakterier och andra smittämnen vilket annars kan få katastrofala konsekvenser. Som en del i försvaret mot detta finns ett specifikt filter i vissa dialysmaskiner. De nuvarande rekommendationerna är att byta ut detta filter efter en viss tid alternativt efter att ett visst antal desinfektioner har utförts. Därmed tas ingen hänsyn till den faktiska statusen på filtret. För att inte riskera att filterna byts ut för sent är gränserna väl tilltagna. Tänk om det fanns ett sätt att optimera användandet av varje enskilt filter. Det skulle dels minska belastningen på miljön men framför allt leda till minskade kostnader för sjukvården. I slutändan skulle detta kunna leda till att dialysbehandlingen skulle kunna nå ut till fler drabbade personer även i den fattiga delen av världen och rädda liv. Ett sätt att optimera filteranvändningen skulle vara att utveckla en serviceindikator liknande den som finns i bilar som säger till när det är dags för service. Som ett första steg i att ta fram en sådan serviceindikator har vi i detta examensarbete utvecklat en algoritm som försöker avgöra statusen på filtret. Resultatet indikerar att möjligheterna att utveckla den önskade serviceindikatorn är mycket lovande, men det krävs fortsatta studier. Algoritmen var ungefär dubbelt så bra som en slumpmässig gissning på att avgöra filtrets status. Speciellt en signal som analyserades visade sig ha en väldigt nära koppling med tillståndet hos filtret. När denna signal studeras närmare gjordes en häpnadsväckande upptäckt. Den ursprungliga tanken var att filtret skulle sättas igen ju mer det användes och därmed få svårare att släppa igenom dialysvätskan. Vad resultatet däremot påvisade var motsatsen, nämligen att det blev lättare för dialysvätskan att passera filtret. Orsaken till detta var svår att finna då det inte fanns möjlighet att undersöka de studerade filterna. Dock fanns misstankar om att det kunde finnas ett samband med användandet av en viss typ av desinfektionsprogram

The Genomics of Human Local Adaptation

Modern humans inhabit a variety of environments and are exposed to a plethora of selective pressures, leading to multiple genetic adaptations to local environmental conditions. These include adaptations to climate, UV exposure, disease, diet, altitude, or cultural practice and have generated important genetic and phenotypic differences amongst populations. In recent years, new methods to identify the genomic signatures of natural selection underlying these adaptations, combined with novel types of genetic data (e.g., ancient DNA), have provided unprecedented insights into the origin of adaptive alleles and the modes of adaptation. As a result, numerous instances of local adaptation have been identified in humans. Here, we review the most exciting recent developments and discuss, in our view, the future of this field

Narcissistic rage and neoliberal reproduction

Combining political economy and depth psychology, this article seeks to elucidate the socio-psychical underpinnings of neoliberalism’s resilience following the global financial crisis. In explicating neoliberalism’s reproduction, the analysis employs self psychologist Heinz Kohut’s theorisation of narcissistic development. Kohut conceives narcissism as a normal condition driving self-formation, but claims that obstructions in its development result in impaired self-esteem and self-confidence, a lack of empathy and aggression against others and the self. The article argues that neoliberalism fosters and is reinforced by narcissistic configurations that impede the attainment of a more stable sense of self. The inability to attain narcissistic fulfilment through neoliberal sociality contributes to defensive and compensatory reactions that entrench neoliberalism’s logic and, through economic performativity, manifest in what Kohut termed narcissistic rage. As an exemplar of this phenomenon, the article examines the emergence of popular neoliberalism in the form of the Tea Party

Evidence in disease and non-disease contexts that nonsense mutations cause altered splicing via motif disruption

Transcripts containing premature termination codons (PTCs) can be subject to nonsense-associated alternative splicing (NAS). Two models have been evoked to explain this, scanning and splice motif disruption. The latter postulates that exonic cis motifs, such as exonic splice enhancers (ESEs), are disrupted by nonsense mutations. We employ genome-wide transcriptomic and k-mer enrichment methods to scrutinize this model. First, we show that ESEs are prone to disruptive nonsense mutations owing to their purine richness and paucity of TGA, TAA and TAG. The motif model correctly predicts that NAS rates should be low (we estimate 5–30%) and approximately in line with estimates for the rate at which random point mutations disrupt splicing (8–20%). Further, we find that, as expected, NAS-associated PTCs are predictable from nucleotide-based machine learning approaches to predict splice disruption and, at least for pathogenic variants, are enriched in ESEs. Finally, we find that both in and out of frame mutations to TAA, TGA or TAG are associated with exon skipping. While a higher relative frequency of such skip-inducing mutations in-frame than out of frame lends some credence to the scanning model, these results reinforce the importance of considering splice motif modulation to understand the etiology of PTC-associated disease

2007 Annual Research Symposium Abstract Book

2007 annual volume of abstracts for science research projects conducted by students at Trinity College

Tracing the Performance of Law in Indonesia (A Perspective of Thomas Kuhn’s "Normal Science")

The hustle and bustle of ’unique’ legal decisions in Indonesian posed by  the positivistic approach of law performance, this is because the approach has been in the phase of normal science of law paradigm. This assumption is quite reasonable considering the justification of legal reasoning has somehow negated human values, or justice. The continuum of legal positivism should be given an alternative through the Progressive Law approach, which focuses on the spirit to break, or to conduct a ”Law Breaking”. Moral awareness and soul conscience should be treated as the foundation for the Progressive Law since the approach is conducted holistically and comprehensively. The law is not only seen from the outside and on the surface level but also from the the substance of legal existence among the society, so that the law really meets the thirst of order of justice in the Indonesia today. Keywords : Law Positivism, Normal Science, Progressive Law

An Occupational Hygiene and Safety Primer, Volume 2

Intended to teach the basic tenets of occupational hygiene and safety to a wide variety of undergraduate college students with quite diverse backgrounds, the information in these volumes is open-sourced from a variety of experts on the subject.https://ohioopen.library.ohio.edu/opentextbooks/1006/thumbnail.jp

Subfunctionalization reduces the fitness cost of gene duplication in humans by buffering dosage imbalances

<p>Abstract</p> <p>Background</p> <p>Driven essentially by random genetic drift, subfunctionalization has been identified as a possible non-adaptive mechanism for the retention of duplicate genes in small-population species, where widespread deleterious mutations are likely to cause complementary loss of subfunctions across gene copies. Through subfunctionalization, duplicates become indispensable to maintain the functional requirements of the ancestral locus. Yet, gene duplication produces a dosage imbalance in the encoded proteins and thus, as investigated in this paper, subfunctionalization must be subject to the selective forces arising from the fitness bottleneck introduced by the duplication event.</p> <p>Results</p> <p>We show that, while arising from random drift, subfunctionalization must be inescapably subject to selective forces, since the diversification of expression patterns across paralogs mitigates duplication-related dosage imbalances in the concentrations of encoded proteins. Dosage imbalance effects become paramount when proteins rely on obligatory associations to maintain their structural integrity, and are expected to be weaker when protein complexation is ephemeral or adventitious. To establish the buffering effect of subfunctionalization on selection pressure, we determine the packing quality of encoded proteins, an established indicator of dosage sensitivity, and correlate this parameter with the extent of paralog segregation in humans, using species with larger population -and more efficient selection- as controls.</p> <p>Conclusions</p> <p>Recognizing the role of subfunctionalization as a dosage-imbalance buffer in gene duplication events enabled us to reconcile its mechanistic nonadaptive origin with its adaptive role as an enabler of the evolution of genetic redundancy. This constructive role was established in this paper by proving the following assertion: <it>If subfunctionalization is indeed adaptive, its effect on paralog segregation should scale with the dosage sensitivity of the duplicated genes</it>. Thus, subfunctionalization becomes adaptive in response to the selection forces arising from the fitness bottleneck imposed by gene duplication.</p