Importance of Different Types of Prior Knowledge in Selecting Genome-Wide Findings for Follow-Up

Genetics impacts sleep, yet, the molecular mechanisms underlying sleep regulation remain elusive. We built machine learning (ML) models to predict genes based on their similarity to known sleep genes. Our predictions fit with prior knowledge of sleep regulation and also identify several key genes/pathways to pursue in follow-up studies. We tested one of our findings, the NF-κB pathway, and showed that its genetic alteration affects sleep duration in mice. Our study highlights the power of ML to integrate prior knowledge and genome-wide data to study genetic regulation of sleep and other complex behaviors.

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Faculty Opinions recommendation of Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13345956.14715054 ◽

2011 ◽

Author(s):

Craig Hersh

Keyword(s):

Lung Function ◽

Large Scale ◽

Genome Wide Association ◽

Genome Wide

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Characteristics of Different Types of Childhood Violence and the Risk of Revictimization

Violence Against Women ◽

10.1177/1077801218818381 ◽

2019 ◽

Vol 25 (14) ◽

pp. 1696-1716 ◽

Cited By ~ 4

Author(s):

Ida Frugaard Stroem ◽

Helene Flood Aakvaag ◽

Tore Wentzel-Larsen

Keyword(s):

Childhood Abuse ◽

Telephone Survey ◽

Regression Analyses ◽

Multiple Forms ◽

Different Types ◽

Children And Young Adults ◽

Childhood Violence ◽

Forms Of Violence ◽

The Relationship

This study investigates the relationship between the characteristics of different types of childhood violence and adult victimization using two waves of data from a community telephone survey (T1) and a follow-up survey, including 505 cases and 506 controls, aged 17-35 years (T2). The logistic regression analyses showed that exposure to childhood abuse, regardless of type, was associated with adult victimization. Exposure to multiple types of abuse, victimization both in childhood and in young adulthood, and recency of abuse increased these odds. Our findings emphasize the importance of assessing multiple forms of violence when studying revictimization. Practitioners working with children and young adults should be attentive to the number of victimization types experienced and recent victimization to prevent further abuse.

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Cardiac Amyloidosis with Discordant QRS Voltage between Frontal and Precordial Leads

Medicina ◽

10.3390/medicina57070660 ◽

2021 ◽

Vol 57 (7) ◽

pp. 660

Author(s):

Csilla-Andrea Eötvös ◽

Roxana-Daiana Lazar ◽

Iulia-Georgiana Zehan ◽

Erna-Brigitta Lévay-Hail ◽

Giorgia Pastiu ◽

...

Keyword(s):

Left Ventricular Hypertrophy ◽

Cardiac Amyloidosis ◽

Ventricular Hypertrophy ◽

Low Voltage ◽

Disease Process ◽

Left Ventricular ◽

Clinical Suspicion ◽

Immunoglobulin Light Chain ◽

Different Types

Among the different types, immunoglobulin light chain (AL) cardiac amyloidosis is associated with the highest morbidity and mortality. The outcome, however, is significantly better when an early diagnosis is made and treatment initiated promptly. We present a case of cardiac amyloidosis with left ventricular hypertrophy criteria on the electrocardiogram. After 9 months of follow-up, the patient developed low voltage in the limb leads, while still maintaining the Cornell criteria for left ventricular hypertrophy as well. The relative apical sparing by the disease process, as well as decreased cancellation of the opposing left ventricular walls could be responsible for this phenomenon. The discordance between the voltage in the frontal leads and precordial leads, when present in conjunction with other findings, may be helpful in raising the clinical suspicion of cardiac amyloidosis.

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Joint association between education and polygenic risk score for incident coronary heart disease events: a longitudinal population-based study of 26 203 men and women

Journal of Epidemiology & Community Health ◽

10.1136/jech-2020-214358 ◽

2021 ◽

pp. jech-2020-214358

Author(s):

Pekka Martikainen ◽

Kaarina Korhonen ◽

Aline Jelenkovic ◽

Hannu Lahtinen ◽

Aki Havulinna ◽

...

Keyword(s):

Coronary Heart Disease ◽

Heart Disease ◽

Risk Score ◽

Density Lipoprotein ◽

Population Based ◽

Polygenic Risk Score ◽

Genome Wide ◽

Increased Risk ◽

Region Of Residence

BackgroundGenetic vulnerability to coronary heart disease (CHD) is well established, but little is known whether these effects are mediated or modified by equally well-established social determinants of CHD. We estimate the joint associations of the polygenetic risk score (PRS) for CHD and education on CHD events.MethodsThe data are from the 1992, 1997, 2002, 2007 and 2012 surveys of the population-based FINRISK Study including measures of social, behavioural and metabolic factors and genome-wide genotypes (N=26 203). Follow-up of fatal and non-fatal incident CHD events (N=2063) was based on nationwide registers.ResultsAllowing for age, sex, study year, region of residence, study batch and principal components, those in the highest quartile of PRS for CHD had strongly increased risk of CHD events compared with the lowest quartile (HR=2.26; 95% CI: 1.97 to 2.59); associations were also observed for low education (HR=1.58; 95% CI: 1.32 to 1.89). These effects were largely independent of each other. Adjustment for baseline smoking, alcohol use, body mass index, igh-density lipoprotein (HDL) and total cholesterol, blood pressure and diabetes attenuated the PRS associations by 10% and the education associations by 50%. We do not find strong evidence of interactions between PRS and education.ConclusionsPRS and education predict CHD events, and these associations are independent of each other. Both can improve CHD prediction beyond behavioural risks. The results imply that observational studies that do not have information on genetic risk factors for CHD do not provide confounded estimates for the association between education and CHD.

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FRI0046 PHARMACOGENOMICS-DRIVEN INDIVIDUALIZED PREDICTION OF TREATMENT RESPONSE TO METHOTREXATE IN PATIENTS WITH RHEUMATOID ARTHRITIS: A MACHINE LEARNING APPROACH

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.4993 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 598.2-598

Author(s):

E. Myasoedova ◽

A. Athreya ◽

C. S. Crowson ◽

R. Weinshilboum ◽

L. Wang ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Machine Learning ◽

Supervised Machine Learning ◽

Research Support ◽

Eular Response ◽

Learning Methods ◽

Machine Learning Methods ◽

Early Ra ◽

Genome Wide

Background:Methotrexate (MTX) is the most common anchor drug for rheumatoid arthritis (RA), but the risk of missing the opportunity for early effective treatment with alternative medications is substantial given the delayed onset of MTX action and 30-40% inadequate response rate. There is a compelling need to accurately predicting MTX response prior to treatment initiation, which allows for effectively identifying patients at RA onset who are likely to respond to MTX.Objectives:To test the ability of machine learning approaches with clinical and genomic biomarkers to predict MTX response with replications in independent samples.Methods:Age, sex, clinical, serological and genome-wide association study (GWAS) data on patients with early RA of European ancestry from 647 patients (336 recruited in United Kingdom [UK]; 307 recruited across Europe; 70% female; 72% rheumatoid factor [RF] positive; mean age 54 years; mean baseline Disease Activity Score with 28-joint count [DAS28] 5.65) of the PhArmacogenetics of Methotrexate in RA (PAMERA) consortium was used in this study. The genomics data comprised 160 genome-wide significant single nucleotide polymorphisms (SNPs) with p<1×10-5 associated with risk of RA and MTX metabolism. DAS28 score was available at baseline and 3-month follow-up visit. Response to MTX monotherapy at the dose of ≥15 mg/week was defined as good or moderate by the EULAR response criteria at 3 months’ follow up visit. Supervised machine-learning methods were trained with 5-repeats and 10-fold cross-validation using data from PAMERA’s 336 UK patients. Class imbalance (higher % of MTX responders) in training was accounted by using simulated minority oversampling technique. Prediction performance was validated in PAMERA’s 307 European patients (not used in training).Results:Age, sex, RF positivity and baseline DAS28 data predicted MTX response with 58% accuracy of UK and European patients (p = 0.7). However, supervised machine-learning methods that combined demographics, RF positivity, baseline DAS28 and genomic SNPs predicted EULAR response at 3 months with area under the receiver operating curve (AUC) of 0.83 (p = 0.051) in UK patients, and achieved prediction accuracies (fraction of correctly predicted outcomes) of 76.2% (p = 0.054) in the European patients, with sensitivity of 72% and specificity of 77%. The addition of genomic data improved the predictive accuracies of MTX response by 19% and achieved cross-site replication. Baseline DAS28 scores and following SNPs rs12446816, rs13385025, rs113798271, and rs2372536 were among the top predictors of MTX response.Conclusion:Pharmacogenomic biomarkers combined with DAS28 scores predicted MTX response in patients with early RA more reliably than using demographics and DAS28 scores alone. Using pharmacogenomics biomarkers for identification of MTX responders at early stages of RA may help to guide effective RA treatment choices, including timely escalation of RA therapies. Further studies on personalized prediction of response to MTX and other anti-rheumatic treatments are warranted to optimize control of RA disease and improve outcomes in patients with RA.Disclosure of Interests:Elena Myasoedova: None declared, Arjun Athreya: None declared, Cynthia S. Crowson Grant/research support from: Pfizer research grant, Richard Weinshilboum Shareholder of: co-founder and stockholder in OneOme, Liewei Wang: None declared, Eric Matteson Grant/research support from: Pfizer, Consultant of: Boehringer Ingelheim, Gilead, TympoBio, Arena Pharmaceuticals, Speakers bureau: Simply Speaking

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Midterm follow-up results of two different types of implants in opening wedge high tibia osteotomy

The Knee ◽

10.1016/j.knee.2021.05.006 ◽

2021 ◽

Vol 31 ◽

pp. 11-21

Author(s):

Simo Miettinen ◽

Henrik Nyländen ◽

Jussi Jalkanen ◽

Hannu Miettinen ◽

Heikki Kröger ◽

...

Keyword(s):

Opening Wedge ◽

Different Types ◽

Tibia Osteotomy

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DNA Methylation at ATP11A cg11702988 Is a Biomarker of Lung Disease Severity in Cystic Fibrosis: A Longitudinal Study

Genes ◽

10.3390/genes12030441 ◽

2021 ◽

Vol 12 (3) ◽

pp. 441

Author(s):

Fanny Pineau ◽

Davide Caimmi ◽

Sylvie Taviaux ◽

Maurane Reveil ◽

Laura Brosseau ◽

...

Keyword(s):

Cystic Fibrosis ◽

Dna Methylation ◽

Clinical Trials ◽

Lung Disease ◽

Disease Severity ◽

Genome Wide ◽

A Genome ◽

Lung Disease Severity ◽

Epigenetic Biomarker

Cystic fibrosis (CF) is a chronic genetic disease that mainly affects the respiratory and gastrointestinal systems. No curative treatments are available, but the follow-up in specialized centers has greatly improved the patient life expectancy. Robust biomarkers are required to monitor the disease, guide treatments, stratify patients, and provide outcome measures in clinical trials. In the present study, we outline a strategy to select putative DNA methylation biomarkers of lung disease severity in cystic fibrosis patients. In the discovery step, we selected seven potential biomarkers using a genome-wide DNA methylation dataset that we generated in nasal epithelial samples from the MethylCF cohort. In the replication step, we assessed the same biomarkers using sputum cell samples from the MethylBiomark cohort. Of interest, DNA methylation at the cg11702988 site (ATP11A gene) positively correlated with lung function and BMI, and negatively correlated with lung disease severity, P. aeruginosa chronic infection, and the number of exacerbations. These results were replicated in prospective sputum samples collected at four time points within an 18-month period and longitudinally. To conclude, (i) we identified a DNA methylation biomarker that correlates with CF severity, (ii) we provided a method to easily assess this biomarker, and (iii) we carried out the first longitudinal analysis of DNA methylation in CF patients. This new epigenetic biomarker could be used to stratify CF patients in clinical trials.

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O21 The incidence of COVID-19 among children with rheumatic diseases receiving biological agents

Rheumatology ◽

10.1093/rheumatology/keab246.020 ◽

2021 ◽

Vol 60 (Supplement_1) ◽

Author(s):

Nadezhda Tsurikova ◽

Elena Ligostaeva ◽

Vadim Avdeenko ◽

Nataliya Kobzeva ◽

Irina Tsiganok ◽

...

Keyword(s):

Rheumatic Diseases ◽

Lupus Erythematosus ◽

Biological Agents ◽

Tnf Receptor ◽

The Past ◽

Different Types ◽

Mediterranean Fever ◽

Positive Results ◽

Single Center Observational Study

Abstract Background/Aims During the COVID-19 pandemic, analysis of the incidence of COVID-19 among patients suffering from rheumatic diseases and receiving therapy with biological agents remains relevant. Methods This single-center observational study included 118 children suffering from various rheumatic diseases and receiving therapy with anti-rheumatic drugs and biological agents. In this research, we analyzed the incidence of CIVID-19 and the frequency of documented contact with SARS-CoV-2 in the period from 01.03.2020 to 11.10.2020 (32 weeks). The results were analyzed using descriptive statistics. Results Among 118 children, there were 28 (24%) boys and 90 (76%) girls, average age 10.3±4.2. 104 (88.2%) patients had different types of juvenile idiopathic arthritis (JIA), 2 (1.6%) children had systemic lupus erythematosus (SLE), 2 (1.6%) patients had juvenile dermatomyositis (JDM), 1 (1%) child had ANCA-associated vasculitis, 6 (5%) patients had familial Mediterranean fever (FMF), 2 (1.6%) children had deficiency of adenosine deaminase 2 (DADA2), 1 (1%) child had TNF receptor-associated periodic syndrome (TRAPS). In this group of patients 94 (79%) patients were treated with methotrexate, 1 (1%) - azathioprine, 3 (2%) patients received hydroxychloroquine, 6(5%) - mycophenolate mofetil, 4 (3%) - sulfasalazine, 14(11%) children received prednisone, 6(5%) - cyclosporine A. All children included in this study received biological agents for more than 1 year, the distribution of biological agents among patients was as follows: 41(34%) - etanercept, 33(28%) - adalimumab, 24 (20%) - tocilizumab, 7 (6%) - canakinumab, 3 (2%) - abatacept, 4 (3%) - golimumab, 6 (5%) - rituximab. Out of 118 children, 4 (3%) patients had flu-like symptoms and positive results of PCR tests for COVID-19 (1 patient was treated with etanercept, 1 - adalimumab, 1 - tocilizumab, 1 - rituximab), none of the patients had signs of SARS-CoV-2 pneumonia. 10 (8%) patients had documented contact with COVID-19: among this patients 2 children had flu-like symptoms, positive results of PCR tests and absence of COVID-19 pneumonia (one of this patient was treated with adalimumab, another one - with rituximab), one more patient was treated with tocilizumab and had positive PCR test without any symptoms of COVID-19; other 7 children had negative PCR tests and didn’t have any signs of COVID-19. Conclusion Among our patients with various rheumatic diseases treated with biological agents there were no registered severe cases of COVID-19. Over the past period (32 weeks of follow-up) 3% of children with COVID-19 were identified and 8% patients had documented contact with COVID-19, but we suppose it is too early to make conclusions about the degree and severity of COVID-19 among children suffering from rheumatic diseases and receiving various biological agents. Further follow-up is needed to better understand the risk and impact of COVID-19 among children with rheumatic diseases and receiving therapy with biological agents. Disclosure N. Tsurikova: None. E. Ligostaeva: None. V. Avdeenko: None. N. Kobzeva: None. I. Tsiganok: None. K. Skorobogatova: None. A. Motkina: None.

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Incidence and Characteristics of Retinoblastoma in Poland: The First Nationwide Study 2010–2017

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18126539 ◽

2021 ◽

Vol 18 (12) ◽

pp. 6539

Author(s):

Michał S. Nowak ◽

Bożena Romanowska-Dixon ◽

Iwona Grabska-Liberek ◽

Michał Żurek

Keyword(s):

Western Europe ◽

External Beam Radiotherapy ◽

Cohort Analysis ◽

Developed Countries ◽

Live Births ◽

Focal Treatment ◽

Different Types ◽

The Mean ◽

Birth Cohort Analysis

Background: The present study aimed to investigate the incidence and characteristics of retinoblastoma in the overall population of Poland. Methods: The retrospective survey of both National Health Fund (NHF) and National Cancer Registry (NCR) databases were performed to identify all retinoblastoma cases in Poland in the years 2010–2017. Results: During 2010–2017, the mean age-standardised incidence of retinoblastoma (the unit of incidence is per 1,000,000 person-years) was 10.15 (95% CI 7.23–13.08) among children aged 0 to 4 years and 5.39 (95% CI 4.18–6.60) in those aged 0 to 9 years. During 2010–2014 (to allow 5 years of follow-up), the mean incidence of retinoblastoma by birth cohort analysis in Poland was 4.89 (95% CI 4.04–5.74) per 100,000 live births, corresponding to an incidence of 1 per 20,561 (95% CI 15,855–25,267) live births. In Poland, 14.6% of children with retinoblastoma had enucleation of the eye globe, 76.8% received different types of chemotherapy combined with focal treatment, 5.9% were treated with external beam radiotherapy, and 2.7% were treated with focal treatments only. Conclusions: The incidence of retinoblastoma and the pattern of medical management of retinoblastoma in Poland was similar to that reported in developed countries in Western Europe, Asia, and North America.

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