A central question in molecular biology is how transcriptional regulatory elements (TREs) act in combination. Recent high-throughput data provide us with the location of multiple regulatory regions ...for multiple regulators, and thus with the possibility of analyzing the multivariate distribution of the occurrences of these TREs along the genome.
We present a model of TRE occurrences known as the Hawkes process. We illustrate the use of this model by analyzing two different publically available data sets. We are able to model, in detail, how the occurrence of one TRE is affected by the occurrences of others, and we can test a range of natural hypotheses about the dependencies among the TRE occurrences. In contrast to earlier efforts, pre-processing steps such as clustering or binning are not needed, and we thus retain information about the dependencies among the TREs that is otherwise lost. For each of the two data sets we provide two results: first, a qualitative description of the dependencies among the occurrences of the TREs, and second, quantitative results on the favored or avoided distances between the different TREs.
The Hawkes process is a novel way of modeling the joint occurrences of multiple TREs along the genome that is capable of providing new insights into dependencies among elements involved in transcriptional regulation. The method is available as an R package from http://www.math.ku.dk/~richard/ppstat/.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background Evidence linking individual-level maternal folic acid supplementation to offspring risk of congenital heart defects is lacking. We investigated whether folic acid supplementation in early ...pregnancy reduces offspring risk of heart defects in 2 large birth cohort studies. Methods and Results Women recruited in early pregnancy within the DNBC (Danish National Birth Cohort), 1996-2003, and MoBa (Norwegian Mother and Child Cohort Study), 2000-2009, were followed until delivery. Information on periconceptional intake of folic acid and other supplements was linked with information on heart defects from national registers. Among 197 123 births, we identified 2247 individuals with heart defects (114/10 000). Periconceptional (4 weeks before through 8 weeks after conception) use of folic acid plus other supplements (54.8%), folic acid only (12.2%), and non-folic acid supplements (5.0%) were compared with no supplement use (28.0%); the adjusted relative risks of heart defects were 0.99 (95% CI, 0.80-1.22), 1.08 (95% CI , 0.93-1.25), and 1.07 (95% CI , 0.97-1.19), respectively. For initiation of folic acid in the preconception period weeks -4 to -1 (33.7%) and the postconception periods 0 to 4 weeks (15.5%), 5 to 8 weeks (17.8%), and 9 to 12 weeks (4.6%), compared with no or late folic acid intake (29.1%), relative risks of heart defect were 1.11 (95% CI , 1.00-1.25), 1.09 (95% CI , 0.95-1.25), 0.98 (95% CI , 0.86-1.12), and 0.97 (95% CI , 0.78-1.20), respectively. Relative risks of severe defects, conotruncal defects, and septal defects showed similar results. Conclusions Folic acid was not associated with offspring risk of heart defects, including severe defects, conotruncal defects, or septal defects.
Objectives The purpose of this study was to examine the effect of a family history of premature death, cardiovascular death in particular, on the risk of early cardiovascular disease. Background ...Studies suggest that fatal cardiovascular events and less severe cardiovascular diseases may co-occur in families. Consequently, a family history of premature death may indicate a familial cardiac frailty that predisposes to early cardiovascular disease. Methods We ascertained family history of premature death (age <60 years) in all individuals born in Denmark from 1950 to 2008 and followed this cohort for early cardiovascular disease (age <50 years). Using Poisson regression, we estimated incidence rate ratios (IRRs) reflecting the effect of premature death in the family on early cardiovascular disease risk. Results Among 3,985,301 persons followed up for 89,294,258 person-years, 129,825, 31,172, and 5,214 were diagnosed with any early cardiovascular disease, ischemic heart disease, and ventricular arrhythmia, respectively. IRRs for these conditions given a history of premature cardiovascular death in first-degree relatives were 1.72 (95% confidence interval CI: 1.68 to 1.77), 2.21 (95% CI: 2.11 to 2.31), and 1.94 (95% CI: 1.70 to 2.20), respectively. With ≥2 cardiovascular deaths in a family, corresponding IRRs were 3.30 (95% CI: 2.77 to 3.94), 5.00 (95% CI: 3.87 to 6.45), and 6.18 (95% CI: 3.32 to 11.50). The IRR for any early cardiovascular disease given a family history of premature noncardiovascular death was significantly lower, 1.12 (95% CI: 1.10 to 1.14) (pcardiac vs. noncardiac < 0.0001). Conclusions Family history of premature cardiovascular death was consistently and significantly associated with a risk of early cardiovascular disease, suggesting an inherited cardiac vulnerability. These results should be kept in mind when assessing cardiovascular disease risk in persons with a family history of premature cardiovascular death.
Approaches for monitoring time trends in couples' fecundity and for studying its sensitivity to environmental factors are needed. Two approaches rely on the inclusion of a cross-sectional sample of ...couples currently "at risk" of pregnancy either with follow up (prevalent cohort) or without follow up (current-duration design). To illustrate the feasibility of the current-duration design, we contacted a random sample of 1204 French women age 18 to 44 years in 2004 and recruited those who were currently having unprotected sexual intercourse. The current duration since the beginning of unprotected intercourse was defined for 69 women (5.7%). An additional 15 women (1.2%) were planning to start trying to become pregnant within the next 6 months. Parametric methods allowed, based on current duration of unprotected intercourse, estimation of fecundity as if the couples had been followed prospectively. The estimated proportion of couples not pregnant after 12 months of unprotected intercourse was 34% (95% confidence interval CI = 15-54%). The accelerated-failure time model allows study of the influence of environmental factors on fecundity. As an illustration, tobacco smoking by the woman was associated with a doubling in the median duration of unprotected intercourse before pregnancy (adjusted time ratio = 2.4; 95% CI = 1.1-5.2). We quantified the influence of time trends in the prevalence of smoking on this estimate. We suggest ways to quantify or avoid other potential bias. In conclusion, it is possible to recruit a sample of couples currently having unprotected intercourse. The current-duration design appears feasible with approximately 5 times as many women eligible for study as for an incident cohort design.
Introduction & Objective: ONWARDS 6 compared the efficacy and safety of once-weekly insulin icodec (icodec) and once-daily insulin degludec (degludec) in adults with T1D. This post hoc analysis ...examined physical activity-related hypoglycemia in ONWARDS 6. Methods: During the trial, participants experiencing hypoglycemic episodes were asked to indicate any relationship to physical activity in a digital diary. Overall hypoglycemia rate was also assessed based on baseline physical activity level recorded using the International Physical Activity Questionnaire. Results: The proportion of physical activity-related hypoglycemic episodes relative to overall hypoglycemic episodes was similar or lower for icodec vs degludec (Figure A); odds of having physical activity-related level 2 or level 3 hypoglycemia were similar between groups (OR: 1.04; 95% CI: 0.75-1.46; p = 0.8060). Most physical activity-related level 2 or level 3 hypoglycemic episodes did not lead to further hypoglycemic episodes within 24 hrs in either group (Figure B). Overall hypoglycemia rates (including those unrelated to physical activity) were comparable within each group regardless of baseline physical activity level (data not shown). Conclusion: There was no evidence of increased risk of physical activity-related hypoglycemic episodes with icodec versus degludec in adults with T1D. Disclosure H. Sourij: Advisory Panel; Amarin Corporation. Speaker's Bureau; Amgen Inc., Amarin Corporation, Bayer Inc. Advisory Panel; Boehringer-Ingelheim. Speaker's Bureau; Boehringer-Ingelheim. Research Support; Boehringer-Ingelheim. Advisory Panel; Eli Lilly and Company. Research Support; Eli Lilly and Company. Speaker's Bureau; Eli Lilly and Company. Advisory Panel; Novartis AG. Speaker's Bureau; Novartis AG. Advisory Panel; Novo Nordisk. Research Support; Novo Nordisk. Speaker's Bureau; Novo Nordisk. Research Support; Sanofi. Speaker's Bureau; Sanofi. Consultant; K:Businesscom. R.M. Bracken: None. M. Asong: Employee; Novo Nordisk A/S. Stock/Shareholder; Novo Nordisk A/S. L. Carstensen: Employee; Novo Nordisk A/S. Stock/Shareholder; Novo Nordisk A/S. S.K. Watt: Employee; Novo Nordisk. A. Philis-Tsimikas: Advisory Panel; Dexcom, Inc., Lilly Diabetes, Novo Nordisk, Sanofi, Medtronic, Bayer Inc. Funding Novo Nordisk A/S
Introduction & Objective: The ONWARDS (ON) phase 3a trials showed the efficacy and safety of once-weekly (OW) basal insulin icodec (icodec) vs once-daily (OD) basal insulin comparators. This post hoc ...analysis examined physical activity (PA)-related hypoglycemia, based on self-reported data, in adults with T2D in ON 1-5. Methods: Hypoglycemia occurrence was evaluated in insulin-naive (ON 1, 3, 5) and insulin-treated (ON 2, 4) adults with T2D receiving icodec vs OD comparators. In each trial, participants who experienced hypoglycemic episodes were instructed to note any relation to PA in a digital diary. Results: The number of PA-related level 2 or level 3 hypoglycemic episodes was low in all trials, except ON 4 (basal-bolus trial). The proportion of hypoglycemic episodes that were related to PA trended higher or was comparable with icodec vs OD comparators in insulin-naive T2D and trended lower or was comparable in insulin-treated T2D (Table). There were no statistically significant differences in the odds of experiencing a PA-related level 2 or level 3 hypoglycemia for icodec vs OD comparators. Conclusion: The incidence of PA-related level 2 or level 3 hypoglycemia in T2D was low in these trials of basal insulins and was not worsened by treatment with icodec vs OD basal insulin comparators. Despite some uncertainty due to low incidences, these data are reassuring. Disclosure M.C. Riddell: Consultant; Eli Lilly and Company. Speaker's Bureau; Novo Nordisk. Advisory Panel; Supersapiens. Consultant; Dexcom, Inc. Speaker's Bureau; Sanofi. Advisory Panel; Zealand Pharma A/S. Speaker's Bureau; Dexcom, Inc. Stock/Shareholder; Zucara Therapeutics. S.R. Heller: Research Support; Dexcom, Inc. Speaker's Bureau; Novo Nordisk. Other Relationship; Eli Lilly and Company. Speaker's Bureau; Medtronic. Advisory Panel; Zealand Pharma A/S, Zucara Therapeutics, Vertex Pharmaceuticals Incorporated. M. Asong: Employee; Novo Nordisk A/S. Stock/Shareholder; Novo Nordisk A/S. L. Carstensen: Employee; Novo Nordisk A/S. Stock/Shareholder; Novo Nordisk A/S. S.K. Watt: Employee; Novo Nordisk. V.C. Woo: Advisory Panel; Novo Nordisk. Speaker's Bureau; Abbott. Advisory Panel; Boehringer-Ingelheim, Lilly Diabetes. Funding Novo Nordisk A/S
This post hoc analysis assessed continuous glucose monitoring (CGM)-based metrics and hypoglycemia duration with once-weekly insulin icodec versus once-daily basal insulin analogs in ...insulin-experienced individuals with long-standing type 2 diabetes from two 26-week phase 3a trials (ONWARDS 2 and ONWARDS 4).
Time in range (TIR) (3.9-10.0 mmol/L), time above range (TAR) (>10.0 mmol/L), and time below range (TBR) (<3.9 mmol/L and <3.0 mmol/L) were assessed during three CGM time periods (switch weeks 0-4, end of treatment weeks 22-26, and follow-up weeks 27-31) for icodec versus comparators (ONWARDS 2, insulin degludec basal regimen; ONWARDS 4, insulin glargine U100 basal-bolus regimen) using double-blind CGM data. CGM-derived hypoglycemic episode duration (<3.9 mmol/L) was assessed.
In both trials, there were no statistically significant differences in TIR, TAR, or TBR (<3.0 mmol/L) for icodec versus comparators across all time periods. In the end-of-treatment period, mean TIR was 63.1% (icodec) vs. 59.5% (degludec) in ONWARDS 2 and 66.9% (icodec) vs. 66.4% (glargine U100) in ONWARDS 4. Mean TBR <3.9 mmol/L and <3.0 mmol/L remained within recommended targets (<4% and <1%, respectively) across time periods and treatment arms. Hypoglycemic episode duration (<3.9 mmol/L) was comparable across time periods and treatment arms (median duration ≤40 min).
In insulin-experienced participants with long-standing type 2 diabetes, CGM-based TIR, TAR, and CGM-derived hypoglycemia duration (<3.9 mmol/L) were comparable for icodec and once-daily basal insulin analogs during all time periods. TBR remained within recommended targets.
Once weekly (OW) icodec is a basal insulin in development. Hypoglycemia duration during the switch (weeks 0-4) and steady state (weeks 22-26) periods from two phase 3, randomized, treat-to-target ...trials in T2D was investigated, using double-blinded Dexcom G6 CGM. Insulin-treated individuals were randomized to OW icodec or once-daily (OD) degludec (ONWARDS 2), or OW icodec or OD glargine U100 with mealtime insulin aspart (ONWARDS 4). When switching, a one-time only additional 50% icodec dose was administered. Basal insulins were titrated weekly. Median hypoglycemia <70 mg/dL duration for episodes lasting ≥ 15 minutes and the proportion of such episodes spent <54 mg/dL were assessed. Median duration of hypoglycemia <70 mg/dL was similar between icodec and comparators during switch and at steady state (Figure), with no apparent clustering in either time-period. At steady state (icodec/degludec and icodec/glargine U100), of the episodes <70 mg/dL, 66.6/63.9% and 60.4/60.0% spent no time <54 mg/dL; 23.2/26.6% and 29.2/28.8% included episodes <54 mg/dL for ≥15 minutes; and 10.2/9.5% and 10.4/11.2% included episodes <54 mg/dL for <15 minutes, respectively. In insulin-treated T2D, the duration of hypoglycemic episodes <70 mg/dL was similar, with no apparent clustering, during switch and at steady state for OW icodec versus OD degludec or glargine U100.
Disclosure
H.S.Bajaj: Research Support; Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Anji Pharmaceuticals, Eli Lilly and Company, Kowa Company, Ltd., Novo Nordisk, Pfizer Inc., Sanofi, Tricida, Inc. B.Ásbjörnsdóttir: Employee; Novo Nordisk. L.Carstensen: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. L.Lang lehrskov: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. C.Mathieu: Advisory Panel; Novo Nordisk A/S, Boehringer Ingelheim Inc., Eli Lilly and Company, Medtronic, Vertex Pharmaceuticals Incorporated, Roche Diabetes Care, Imcyse, Speaker's Bureau; Novo Nordisk A/S, AstraZeneca, Boehringer Ingelheim Inc., Eli Lilly and Company, Medtronic, Vertex Pharmaceuticals Incorporated. A.Philis-tsimikas: Advisory Panel; Dexcom, Inc., Novo Nordisk A/S, Sanofi, Other Relationship; Medtronic, Research Support; Novo Nordisk A/S, Lilly, Viking Therapeutics, NIH - National Institutes of Health. T.Battelino: Advisory Panel; Eli Lilly and Company, Novo Nordisk, Sanofi, Medtronic, Abbott Diabetes, Consultant; Indigo Diabetes, Research Support; Novo Nordisk, Sanofi, Medtronic, Novartis, Speaker's Bureau; Eli Lilly and Company, Novo Nordisk, Sanofi, Medtronic, Abbott Diabetes, Dexcom, Inc.
Funding
Novo Nordisk A/S
Febrile seizures represent a serious adverse event following measles, mumps and rubella (MMR) vaccination. We conducted a series of genome-wide association scans comparing children with MMR-related ...febrile seizures, children with febrile seizures unrelated to vaccination and controls with no history of febrile seizures. Two loci were distinctly associated with MMR-related febrile seizures, harboring the interferon-stimulated gene IFI44L (rs273259: P = 5.9 × 10(-12) versus controls, P = 1.2 × 10(-9) versus MMR-unrelated febrile seizures) and the measles virus receptor CD46 (rs1318653: P = 9.6 × 10(-11) versus controls, P = 1.6 × 10(-9) versus MMR-unrelated febrile seizures). Furthermore, four loci were associated with febrile seizures in general, implicating the sodium channel genes SCN1A (rs6432860: P = 2.2 × 10(-16)) and SCN2A (rs3769955: P = 3.1 × 10(-10)), a TMEM16 family gene (ANO3; rs114444506: P = 3.7 × 10(-20)) and a region associated with magnesium levels (12q21.33; rs11105468: P = 3.4 × 10(-11)). Finally, we show the functional relevance of ANO3 (TMEM16C) with electrophysiological experiments in wild-type and knockout rats.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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