Genome-wide circadian rhythm detection methods: systematic evaluations and practical guidelines.
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ABSTRACT:
SUBMITTER: Mei W
PROVIDER: S-EPMC8138819 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Robust methods for identifying patterns of expression in genome-wide data are important for generating hypotheses regarding gene function. To this end, several analytic methods have been developed for detecting periodic patterns. We improve one such method, JTK_CYCLE, by explicitly calculating the null distribution such that it accounts for multiple hypothesis testing and by including non-sinusoidal reference waveforms. We term this method empirical JTK_CYCLE with asymmetry search, and we compare its performance to JTK_CYCLE with Bonferroni and Benjamini-Hochberg multiple hypothesis testing correction, as well as to five other methods: cyclohedron test, address reduction, stable persistence, ANOVA, and F24. We find that ANOVA, F24, and JTK_CYCLE consistently outperform the other three methods when data are limited and noisy; empirical JTK_CYCLE with asymmetry search gives the greatest sensitivity while controlling for the false discovery rate. Our analysis also provides insight into experimental design and we find that, for a fixed number of samples, better sensitivity and specificity are achieved with higher numbers of replicates than with higher sampling density. Application of the methods to detecting circadian rhythms in a metadataset of microarrays that quantify time-dependent gene expression in whole heads of Drosophila melanogaster reveals annotations that are enriched among genes with highly asymmetric waveforms. These include a wide range of oxidation reduction and metabolic genes, as well as genes with transcripts that have multiple splice forms.
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Project description:Detection of individual body time (BT) via a single-time-point assay has been a longstanding unfulfilled dream in medicine, because BT information can be exploited to maximize potency and minimize toxicity during drug administration and thus will enable highly optimized medication. To achieve this dream, we created a "molecular timetable" composed of >100 "time-indicating genes," whose gene expression levels can represent internal BT. Here we describe a robust method called the "molecular-timetable method" for BT detection from a single-time-point expression profile. The power of this method is demonstrated by the sensitive and accurate detection of BT and the sensitive diagnosis of rhythm disorders. These results demonstrate the feasibility of BT detection based on single-time-point sampling, suggest the potential for expression-based diagnosis of rhythm disorders, and may translate functional genomics into chronotherapy and personalized medicine.
| S-EPMC509173 | biostudies-literature
Project description:BackgroundCircadian variation of gene expression is often neglected when ionizing radiation-induced effects are studied, whether in animal models or in cell culture. This study characterized diurnal variation of genome-wide transcriptional regulation and responses of potential biomarkers and signature genes in normal mouse tissues at 24 h after i.v. administration of (131)I.MethodsFemale BALB/c nude mice were i.v. injected with 90 kBq (131)I at 9:00 a.m., 12:00 p.m., or 3:00 p.m. and killed after 24 h (n?=?4/group). Paired control groups were mock-treated (n?=?3-4/group). The kidneys, liver, lungs, spleen, and thyroid were excised, snap-frozen, and stored at -80 °C until extraction of total RNA. RNA microarray technology was used for genome-wide expression analysis. Enriched biological processes were categorized after cellular function. Signature genes for ionizing radiation and thyroid hormone-induced responses were taken from the literature. Absorbed dose was estimated using the Medical Internal Radiation Dose (MIRD) formalism.ResultsThe thyroid received an absorbed dose of 5.9 Gy and non-thyroid tissues received 0.75-2.2 mGy over 24 h. A distinct peak in the total number of significantly regulated transcripts was observed at 9:00 a.m. in the thyroid, but 3 h later in the kidney cortex, kidney medulla, and liver. Transcriptional regulation in the lungs and spleen was marginal. Associated cellular functions generally varied in quality and response strength between morning, noon, and afternoon. In the thyroid, 25 genes were significantly regulated at all investigated times of day, and 24 thereof showed a distinct pattern of pronounced down-regulation at 9:00 a.m. and comparatively weak up-regulation at later times. Eleven of these genes belonged to the species-specific kallikrein subfamily Klk1b. Responses in signature genes for thyroid hormone-induced responses were more frequent than for ionizing radiation, and trends persisted irrespective of time of day.ConclusionDiurnal variation of genome-wide transcriptional responses to 90 kBq (131)I was demonstrated for the thyroid, kidney cortex and medulla, and liver, whereas variation was only marginal in the lungs and spleen. Overall, significant detection of potential biomarkers and signature genes was validated at each time of day, although direction of regulation and fold-change differed between morning, noon, and afternoon. These findings suggest that circadian rhythm should be considered in radiation research and that biological and analytical endpoints should be validated for circadian robustness.
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Project description:A symposium at the 2014 European Society of Cardiology (ESC) congress reviewed the 2012 update of the ESC guideline on rhythm management of atrial fibrillation (AF) patients. The guidelines now include catheter ablation of AF as first-line therapy in selected patients with symptomatic, paroxysmal AF. A panel comprising electrophysiologists and cardiologists discussed four clinical cases that illustrated the challenges faced in the day-to-day treatment of AF patients and how these guidelines can help inform treatment decisions. Among the key discussions were the importance of early treatment of AF and the dilemma faced in treating AF patients with recently implanted stent, where the risk of stroke must be balanced against the risk of stent thrombosis. The panel considered that among selected patients with paroxysmal AF and no structural heart disease, catheter ablation is reasonable as first-line therapy.
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Project description:BackgroundIndividuals with typical circadian rhythm sleep-wake disorders (CRSWDs) have a habitual sleep timing that is desynchronized from social time schedules. However, it is possible to willfully force synchronisation against circadian-driven sleepiness, which causes other sleep problems. This pathology is distinguishable from typical CRSWDs and is referred to here as latent CRSWD (LCRSWD). Conventional diagnostic methods for typical CRSWDs are insufficient for detecting LCRSWD because sufferers have an apparently normal habitual sleep timing.MethodsWe first evaluated the reliability of circadian phase estimation based on clock gene expression using hair follicles collected at three time points without sleep interruption. Next, to identify detection criteria for LCRSWD, we compared circadian and sleep parameters according to estimated circadian phases, at the group and individual level, between subjects with low and high Pittsburgh Sleep Quality Index (PSQI) scores. To validate the reliability of identified detection criteria, we investigated whether the same subjects could be reproducibly identified at a later date and whether circadian amelioration resulted in sleep improvement.FindingsWe successfully validated the reliability of circadian phase estimation at three time points and identified potential detection criteria for individuals with LCRSWD attributed to delayed circadian-driven sleepiness. In particular, a criterion based on the interval between the times of the estimated circadian phase of clock gene expression and getting out of bed on work or school days was promising. We also successfully confirmed the reproducibility of candidate screening and sleep improvement by circadian amelioration, supporting the reliability of the detection criteria.InterpretationAlthough several limitations remain, our present study demonstrates a promising prototype of a detection method for LCRSWD attributed to delayed circadian-driven sleepiness. More extensive trials are needed to further validate this method.FundingThis study was supported mainly by JSPS, Japan.
| S-EPMC7653065 | biostudies-literature
Project description:BACKGROUND:The deployment of Genome-wide association studies (GWASs) requires genomic information of a large population to produce reliable results. This raises significant privacy concerns, making people hesitate to contribute their genetic information to such studies. RESULTS:We propose two provably secure solutions to address this challenge: (1) a somewhat homomorphic encryption (HE) approach, and (2) a secure multiparty computation (MPC) approach. Unlike previous work, our approach does not rely on adding noise to the input data, nor does it reveal any information about the patients. Our protocols aim to prevent data breaches by calculating the ?2 statistic in a privacy-preserving manner, without revealing any information other than whether the statistic is significant or not. Specifically, our protocols compute the ?2 statistic, but only return a yes/no answer, indicating significance. By not revealing the statistic value itself but only the significance, our approach thwarts attacks exploiting statistic values. We significantly increased the efficiency of our HE protocols by introducing a new masking technique to perform the secure comparison that is necessary for determining significance. CONCLUSIONS:We show that full-scale privacy-preserving GWAS is practical, as long as the statistics can be computed by low degree polynomials. Our implementations demonstrated that both approaches are efficient. The secure multiparty computation technique completes its execution in approximately 2 ms for data contributed by one million subjects.
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Project description:ObjectivesBenchmarking is common in clinical registries to support the improvement of health outcomes by identifying underperforming clinician or health service providers. Despite the rise in clinical registries and interest in publicly reporting benchmarking results, appropriate methods for benchmarking and outlier detection within clinical registries are not well established, and the current application of methods is inconsistent. The aim of this review was to determine the current statistical methods of outlier detection that have been evaluated in the context of clinical registry benchmarking.DesignA systematic search for studies evaluating the performance of methods to detect outliers when benchmarking in clinical registries was conducted in five databases: EMBASE, ProQuest, Scopus, Web of Science and Google Scholar. A modified healthcare modelling evaluation tool was used to assess quality; data extracted from each study were summarised and presented in a narrative synthesis.ResultsNineteen studies evaluating a variety of statistical methods in 20 clinical registries were included. The majority of studies conducted application studies comparing outliers without statistical performance assessment (79%), while only few studies used simulations to conduct more rigorous evaluations (21%). A common comparison was between random effects and fixed effects regression, which provided mixed results. Registry population coverage, provider case volume minimum and missing data handling were all poorly reported.ConclusionsThe optimal methods for detecting outliers when benchmarking clinical registry data remains unclear, and the use of different models may provide vastly different results. Further research is needed to address the unresolved methodological considerations and evaluate methods across a range of registry conditions.Prospero registration numberCRD42022296520.
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Project description:More and more genome-wide association studies are being designed to uncover the full genetic basis of common diseases. Nonetheless, the resulting loci are often insufficient to fully recover the observed heritability. Epistasis, or gene-gene interaction, is one of many hypotheses put forward to explain this missing heritability. In the present work, we propose epiGWAS, a new approach for epistasis detection that identifies interactions between a target SNP and the rest of the genome. This contrasts with the classical strategy of epistasis detection through exhaustive pairwise SNP testing. We draw inspiration from causal inference in randomized clinical trials, which allows us to take into account linkage disequilibrium. EpiGWAS encompasses several methods, which we compare to state-of-the-art techniques for epistasis detection on simulated and real data. The promising results demonstrate empirically the benefits of EpiGWAS to identify pairwise interactions.
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Project description:ObjectiveOsteoarthritis (OA) is the most common age-related joint disease. With aging and in OA, the expression of FoxO transcription factors is reduced, diminishing their chondroprotective actions. In order to elucidate the molecular mechanisms by which FoxO1 protects chondrocytes, we sought to identify the genome-wide occupancy profile of FoxO1.MethodsWe performed FoxO1 chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-Seq) on human primary chondrocytes. ChIP-Seq data were integrated with RNA sequencing (RNA-Seq) data sets. Bioinformatics results were confirmed in primary chondrocytes that were treated with a FoxO1 inhibitor.ResultsAnalysis of FoxO1 ChIP-Seq on human primary chondrocytes showed that pathways implicated in OA pathogenesis are mainly regulated by FoxO1 binding to tissue-specific enhancers with suboptimal binding sites (20% of the peaks), while more ubiquitous FoxO1 pathways are regulated at the promoter level through interaction with its canonical binding motif (7% of the peaks). Integrating FoxO1 occupancy data with RNA-Seq data comparing OA and healthy human cartilage revealed 428 putative FoxO1 target genes that are dysregulated in OA. Pathway analysis showed enrichment for genes belonging to the senescence pathway (logP = -6.73), extracellular matrix (ECM) pathway (logP = -12.97), and circadian clock pathway (logP = -6.30), which suggests that FoxO1 dysregulation plays an important role in their abnormal expression in OA. Using an inhibitor of FoxO1, we confirmed that FoxO1 regulates these pathways in cultured human chondrocytes.ConclusionFoxO1 regulates ubiquitous and cartilage-specific genes in chondrocytes by using different mechanisms. The FoxO1 transcriptional network is a key player in regulating homeostasis, ECM, and circadian clock genes and plays an important role in the abnormal expression of these pathways observed in OA pathogenesis.
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Project description:Gut Microbe-Targeted Choline Trimethylamine Lyase Inhibition Improves Obesity Via Rewiring of Host Circadian Rhythms.
| PRJEB48232 | ENA