Nationwide study on development and validation of a risk prediction model for CIN3+ and cervical cancer in Estonia.

Transitioning to an individualized risk-based approach can significantly enhance cervical cancer screening programs. We aimed to derive and internally validate a prediction model for assessing the risk of cervical intraepithelial neoplasia grade 3 or higher (CIN3+) and cancer in women eligible for screening. This retrospective study utilized data from the Estonian electronic health records, including 517,884 women from the health insurance database and linked health registries.

Rare copy-number variants as modulators of common disease susceptibility.

Background: Copy-number variations (CNVs) have been associated with rare and debilitating genomic disorders (GDs) but their impact on health later in life in the general population remains poorly described.

Methods: Assessing four modes of CNV action, we performed genome-wide association scans (GWASs) between the copy-number of CNV-proxy probes and 60 curated ICD-10 based clinical diagnoses in 331,522 unrelated white British UK Biobank (UKBB) participants with replication in the Estonian Biobank.

Results: We identified 73 signals involving 40 diseases, all of which indicating that CNVs increased disease risk and caused earlier onset.

Polygenic risk scores for cervical HPV infection, neoplasia and cancer show potential for personalised screening: comparison of two methods.

The era of precision medicine requires the achievement of accurate risk assessment. Polygenic risk scores (PRSs) have strong potential for increasing the benefits of nationwide cancer screening programs. The current pool of evidence on the role of a PRS as a risk stratification model in actual practice and implementation is limited.

Incarceration history is associated with HIV infection among community-recruited people who inject drugs in Europe: A propensity-score matched analysis of cross-sectional studies.

Aims: We measured the association between a history of incarceration and HIV positivity among people who inject drugs (PWID) across Europe.

Design, Setting And Participants: This was a cross-sectional, multi-site, multi-year propensity-score matched analysis conducted in Europe. Participants comprised community-recruited PWID who reported a recent injection (within the last 12 months).

Genetic insights into the age-specific biological mechanisms governing human ovarian aging.

There is currently little evidence that the genetic basis of human phenotype varies significantly across the lifespan. However, time-to-event phenotypes are understudied and can be thought of as reflecting an underlying hazard, which is unlikely to be constant through life when values take a broad range. Here, we find that 74% of 245 genome-wide significant genetic associations with age at natural menopause (ANM) in the UK Biobank show a form of age-specific effect.

Liability-scale heritability estimation for biobank studies of low-prevalence disease.

Theory for liability-scale models of the underlying genetic basis of complex disease provides an important way to interpret, compare, and understand results generated from biological studies. In particular, through estimation of the liability-scale heritability (LSH), liability models facilitate an understanding and comparison of the relative importance of genetic and environmental risk factors that shape different clinically important disease outcomes. Increasingly, large-scale biobank studies that link genetic information to electronic health records, containing hundreds of disease diagnosis indicators that mostly occur infrequently within the sample, are becoming available.

Haematological changes from conception to childbirth: An indicator of major pregnancy complications.

Background: About 800 women die every day worldwide from pregnancy-related complications, including excessive blood loss, infections and high-blood pressure (World Health Organization, 2019). To improve screening for high-risk pregnancies, we set out to identify patterns of maternal hematological changes associated with future pregnancy complications.

Methods: Using mixed effects models, we established changes in 14 complete blood count (CBC) parameters for 1710 healthy pregnancies and compared them to measurements from 98 pregnancy-induced hypertension, 106 gestational diabetes and 339 postpartum hemorrhage cases.

Improving GWAS discovery and genomic prediction accuracy in biobank data.

Genetically informed, deep-phenotyped biobanks are an important research resource and it is imperative that the most powerful, versatile, and efficient analysis approaches are used. Here, we apply our recently developed Bayesian grouped mixture of regressions model (GMRM) in the UK and Estonian Biobanks and obtain the highest genomic prediction accuracy reported to date across 21 heritable traits. When compared to other approaches, GMRM accuracy was greater than annotation prediction models run in the LDAK or LDPred-funct software by 15% (SE 7%) and 14% (SE 2%), respectively, and was 18% (SE 3%) greater than a baseline BayesR model without single-nucleotide polymorphism (SNP) markers grouped into minor allele frequency-linkage disequilibrium (MAF-LD) annotation categories.

Probabilistic inference of the genetic architecture underlying functional enrichment of complex traits.

We develop a Bayesian model (BayesRR-RC) that provides robust SNP-heritability estimation, an alternative to marker discovery, and accurate genomic prediction, taking 22 seconds per iteration to estimate 8.4 million SNP-effects and 78 SNP-heritability parameters in the UK Biobank. We find that only ≤10% of the genetic variation captured for height, body mass index, cardiovascular disease, and type 2 diabetes is attributable to proximal regulatory regions within 10kb upstream of genes, while 12-25% is attributed to coding regions, 32-44% to introns, and 22-28% to distal 10-500kb upstream regions.

Enteral nutrition and dynamics of citrulline and intestinal fatty acid-binding protein in adult ICU patients.

Background And Aims: Plasma citrulline and intestinal fatty acid binding protein (I-FABP) are biomarkers reflecting enterocyte function and intestinal mucosal injury. The aim was to describe daily dynamics of citrulline and I-FABP concentrations in association with enteral nutrition (EN) in adult ICU patients. We hypothesized that success or failure of EN is reflected by differences in citrulline and I-FABP levels at admission, as well as in daily dynamics over the first week.

Genomic architecture and prediction of censored time-to-event phenotypes with a Bayesian genome-wide analysis.

While recent advancements in computation and modelling have improved the analysis of complex traits, our understanding of the genetic basis of the time at symptom onset remains limited. Here, we develop a Bayesian approach (BayesW) that provides probabilistic inference of the genetic architecture of age-at-onset phenotypes in a sampling scheme that facilitates biobank-scale time-to-event analyses. We show in extensive simulation work the benefits BayesW provides in terms of number of discoveries, model performance and genomic prediction.

Cervical cancer screening patterns among HIV-positive women in Estonia: a population-based retrospective cohort study.

Background: The World Health Organisation (WHO) calls for the elimination of cervical cancer (CC) as a public health issue. To achieve elimination, efforts must be aligned and accelerated. Women living with HIV (WLWH) have excess risk for developing, and dying from, CC over the general population.

Multi-method genome- and epigenome-wide studies of inflammatory protein levels in healthy older adults.

Background: The molecular factors which control circulating levels of inflammatory proteins are not well understood. Furthermore, association studies between molecular probes and human traits are often performed by linear model-based methods which may fail to account for complex structure and interrelationships within molecular datasets.

Methods: In this study, we perform genome- and epigenome-wide association studies (GWAS/EWAS) on the levels of 70 plasma-derived inflammatory protein biomarkers in healthy older adults (Lothian Birth Cohort 1936; n = 876; Olink® inflammation panel).