ShrinkCRISPR: a flexible method for differential fitness analysis of CRISPR-Cas9 screen data - BMC Bioinformatics

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An article published in BMCBioInformatics presents ShrinkCRISPR: a robust and flexible approach to incorporate different sources of variations and test for differential effect on cell fitness at the gene level.

illustrates the agreement between the 3 model results. The longitudinal model yielded many more hits: 781 genes compared to 337 and 234 for, respectively. Only 101 genes were selected between all model fits. This is mostly due to the disagreement between results using only 1 time point, as only 49 genes from each of the single time point models are not recovered by the longitudinal model.

In a simulation study, ShrinkCRISPR yielded similar ROC curves to those produced by a another method, drugZ, for drug sensitizing screens using paired designs. However, ShrinkCRISPR yields much less false positives in general. It also outperforms both drugZ and another method, MAGeCK, in the context of independent designs, used e.g. for isogenic screens, as it is the only approach to take into account initial sgRNA abundance.

ShrinkCRISPR is the best approach in terms of controlling the proportion of false positive hits, while it is able to find all hits with strong differential effect. However, ShrinkCRISPR is conservative: the false discovery rate is under the desired level, and the method is not able to detect hits with small effect sizes.

 

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Monocyte, neutrophil, and whole blood transcriptome dynamics following ischemic stroke - BMC MedicineBackground After ischemic stroke (IS), peripheral leukocytes infiltrate the damaged region and modulate the response to injury. Peripheral blood cells display distinctive gene expression signatures post-IS and these transcriptional programs reflect changes in immune responses to IS. Dissecting the temporal dynamics of gene expression after IS improves our understanding of immune and clotting responses at the molecular and cellular level that are involved in acute brain injury and may assist with time-targeted, cell-specific therapy. Methods The transcriptomic profiles from peripheral monocytes, neutrophils, and whole blood from 38 ischemic stroke patients and 18 controls were analyzed with RNA-seq as a function of time and etiology after stroke. Differential expression analyses were performed at 0–24 h, 24–48 h, and |48 h following stroke. Results Unique patterns of temporal gene expression and pathways were distinguished for monocytes, neutrophils, and whole blood with enrichment of interleukin signaling pathways for different time points and stroke etiologies. Compared to control subjects, gene expression was generally upregulated in neutrophils and generally downregulated in monocytes over all times for cardioembolic, large vessel, and small vessel strokes. Self-organizing maps identified gene clusters with similar trajectories of gene expression over time for different stroke causes and sample types. Weighted Gene Co-expression Network Analyses identified modules of co-expressed genes that significantly varied with time after stroke and included hub genes of immunoglobulin genes in whole blood. Conclusions Altogether, the identified genes and pathways are critical for understanding how the immune and clotting systems change over time after stroke. This study identifies potential time- and cell-specific biomarkers and treatment targets.
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Perinatal and pediatric outcomes associated with the use of fertility treatment: a population-based retrospective cohort study in Ontario, Canada - BMC Pregnancy and ChildbirthBackground Around 2% of births in Ontario, Canada involve the use of assisted reproductive technology (ART), and it is rising due to the implementation of a publicly funded ART program in 2016. To better understand the impact of fertility treatments, we assessed perinatal and pediatric health outcomes associated with ART, hormonal treatments, and artificial insemination compared with spontaneously conceived births. Methods This population-based retrospective cohort study was conducted using provincial birth registry data linked with fertility registry and health administrative databases in Ontario, Canada. Live births and stillbirths from January 2013 to July 2016 were included and followed to age one. The risks of adverse pregnancy, birth and infant health outcomes were assessed by conception method (spontaneous conception, ART – in vitro fertilization and non-ART – ovulation induction, intra-uterine or vaginal insemination) using risk ratios and incidence rate ratios with 95% confidence intervals (CI). Propensity score weighting using a generalized boosted model was applied to adjust for confounding. Result(s) Of 177,901 births with a median gestation age of 39 weeks (IQR 38.0–40.0), 3,457 (1.9%) were conceived via ART, and 3,511 (2.0%) via non-ART treatments. There were increased risks (adjusted risk ratio [95% CI]) of cesarean delivery (ART: 1.44 [1.42–1.47]; non-ART: 1.09 [1.07–1.11]), preterm birth (ART: 2.06 [1.98–2.14]; non-ART: 1.85 [1.79–1.91]), very preterm birth (ART: 2.99 [2.75–3.25]; non-ART: 1.89 [1.67–2.13]), 5-min Apgar | 7 (ART: 1.28 [1.16–1.42]; non-ART: 1.62 [1.45–1.81]), and composite neonatal adverse outcome indicator (ART: 1.61 [1.55–1.68]; non-ART: 1.29 [1.25–1.34]). Infants born after fertility treatments had increased risk of admission to neonatal intensive care unit (ART: 1.98 [1.84–2.13]; non-ART: 1.59 [1.51–1.67]) and prolonged birth admission (≥ 3 days) (ART: 1.60 [1.54–1.65]; non-ART: 1.42 [1.39–1.45]). The rate of emergency and in-hos
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Variety and quantity of dietary insoluble fiber intake from different sources and risk of new-onset hypertension - BMC MedicineBackground The relations of the variety and quantity of different sources of dietary insoluble fibers and hypertension remain uncertain. We aimed to investigate the associations between the variety and quantity of insoluble fibers intake from six major food sources and new-onset hypertension, using data from the China Health and Nutrition Survey (CHNS). Methods Twelve thousand one hundred thirty-one participants without hypertension at baseline from CHNS were included. Dietary intake was measured by three consecutive 24-h dietary recalls combined with a household food inventory. The variety score of insoluble fiber sources was defined as the number of insoluble fiber sources consumed at the appropriate level, accounting for both types and quantities of insoluble fibers. The study outcome was new-onset hypertension, defined as blood pressure ≥ 140/90 mmHg, or physician-diagnosed hypertension or receiving antihypertensive treatments during the follow-up. Results During a median follow-up of 6.1 years, 4252 participants developed hypertension. There were L-shaped associations of dietary insoluble fibers derived from vegetables, beans, tubers, and fruits with new-onset hypertension; a reversed J-shaped association of whole grain-derived insoluble fiber with new-onset hypertension; and no obvious association of refined grain-derived insoluble fiber with new-onset hypertension. Therefore, refined grain was not included in the insoluble fiber variety score calculation. More importantly, a higher insoluble fiber variety score was significantly associated with lower risks of new-onset hypertension (per score increment, hazard ratio, 0.50; 95% CI, 0.45–0.55). Conclusions There was an inverse association between the variety of insoluble fibers with appropriate quantity from different food sources and new-onset hypertension.
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