Biomarkers for staging fibrosis and non-alcoholic steatohepatitis in non-alcoholic fatty liver disease (the LITMUS project): a comparative diagnostic accuracy study.

BACKGROUND: The reference standard for detecting non-alcoholic steatohepatitis (NASH) and staging fibrosis-liver biopsy-is invasive and resource intensive. Non-invasive biomarkers are urgently needed, but few studies have compared these biomarkers in a single cohort. As part of the Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS) project, we aimed to evaluate the diagnostic accuracy of 17 biomarkers and multimarker scores in detecting NASH and clinically significant fibrosis in patients with non-alcoholic fatty liver disease (NAFLD) and identify their optimal cutoffs as screening tests in clinical trial recruitment. METHODS: This was a comparative diagnostic accuracy study in people with biopsy-confirmed NAFLD from 13 countries across Europe, recruited between Jan 6, 2010, and Dec 29, 2017, from the LITMUS metacohort of the prospective European NAFLD Registry. Adults (aged ≥18 years) with paired liver biopsy and serum samples were eligible; those with excessive alcohol consumption or evidence of other chronic liver diseases were excluded. The diagnostic accuracy of the biomarkers was expressed as the area under the receiver operating characteristic curve (AUC) with liver histology as the reference standard and compared with the Fibrosis-4 index for liver fibrosis (FIB-4) in the same subgroup. Target conditions were the presence of NASH with clinically significant fibrosis (ie, at-risk NASH; NAFLD Activity Score ≥4 and F≥2) or the presence of advanced fibrosis (F≥3), analysed in all participants with complete data. We identified thres holds for each biomarker for reducing the number of biopsy-based screen failures when recruiting people with both NASH and clinically significant fibrosis for future trials. FINDINGS: Of 1430 participants with NAFLD in the LITMUS metacohort with serum samples, 966 (403 women and 563 men) were included after all exclusion criteria had been applied. 335 (35%) of 966 participants had biopsy-confirmed NASH and clinically significant fibrosis and 271 (28%) had advanced fibrosis. For people with NASH and clinically significant fibrosis, no single biomarker or multimarker score significantly reached the predefined AUC 0·80 acceptability threshold (AUCs ranging from 0·61 [95% CI 0·54-0·67] for FibroScan controlled attenuation parameter to 0·81 [0·75-0·86] for SomaSignal), with accuracy mostly similar to FIB-4. Regarding detection of advanced fibrosis, SomaSignal (AUC 0·90 [95% CI 0·86-0·94]), ADAPT (0·85 [0·81-0·89]), and FibroScan liver stiffness measurement (0·83 [0·80-0·86]) reached acceptable accuracy. With 11 of 17 markers, histological screen failure rates could be reduced to 33% in trials if only people who were marker positive had a biopsy for evaluating eligibility. The best screening performance for NASH and clinically significant fibrosis was observed for SomaSignal (number needed to test [NNT] to find one true positive was four [95% CI 4-5]), then ADAPT (six [5-7]), MACK-3 (seven [6-8]), and PRO-C3 (nine [7-11]). INTERPRETATION: None of the single markers or multimarker scores achieved the predefined acceptable AUC for replacing biopsy in detecting people with both NASH and clinically significant fibrosis. However, several biomarkers could be applied in a prescreening strategy in clinical trial recruitment. The performance of promising markers will be further evaluated in the ongoing prospective LITMUS study cohort. FUNDING: The Innovative Medicines Initiative 2 Joint Undertaking.

Systematic Review with Meta-Analysis: Diagnostic Accuracy of Pro-C3 for Hepatic Fibrosis in Patients with Non-Alcoholic Fatty Liver Disease.

The prevalence and severity of non-alcoholic fatty liver disease (NAFLD) is increasing, yet adequately validated tests for care paths are limited and non-invasive markers of disease progression are urgently needed. The aim of this work was to summarize the performance of Pro-C3, a biomarker of active fibrogenesis, in detecting significant fibrosis (F ≥ 2), advanced fibrosis (F ≥ 3), cirrhosis (F4) and non-alcoholic steatohepatitis (NASH) in patients with NAFLD. A sensitive search of five databases was performed in July 2021. Studies reporting Pro-C3 measurements and liver histology in adults with NAFLD without co-existing liver diseases were eligible. Meta-analysis was conducted by applying a bivariate random effects model to produce summary estimates of Pro-C3 accuracy. From 35 evaluated reports, eight studies met our inclusion criteria; 1568 patients were included in our meta-analysis of significant fibrosis and 2058 in that of advanced fibrosis. The area under the summary curve was 0.81 (95% CI 0.77-0.84) in detecting significant fibrosis and 0.79 (95% CI 0.73-0.82) for advanced fibrosis. Our results support Pro-C3 as an important candidate biomarker for non-invasive assessment of liver fibrosis in NAFLD. Further direct comparisons with currently recommended non-invasive tests will demonstrate whether Pro-C3 panels can outperform these tests, and improve care paths for patients with NAFLD.

Systematic Review with Meta-Analyses: Diagnostic Accuracy of FibroMeter Tests in Patients with Non-Alcoholic Fatty Liver Disease.

Early detection of liver fibrosis is crucial to select the correct care path for patients with non-alcoholic fatty liver disease (NAFLD). Here, we systematically review the evidence on the performance of FibroMeter versions in detecting different levels of fibrosis in patients with NAFLD. We searched four databases (Medline, Embase, the Cochrane library, and Web of Science) to find studies that included adults with NAFLD and biopsy-confirmed fibrosis (F1 to F4), compared with any version of FibroMeter. Two independent researchers screened the references, collected the data, and assessed the methodological quality of the included studies. We used a bivariate logit-normal random effects model to produce meta-analyses. From 273 references, 12 studies were eligible for inclusion, encompassing data from 3425 patients. Meta-analyses of the accuracy in detecting advanced fibrosis (F ≥ 3) were conducted for FibroMeter Virus second generation (V2G), NAFLD, and vibration controlled transient elaFS3stography (VCTE). FibroMeter VCTE showed the best diagnostic accuracy in detecting advanced fibrosis (sensitivity: 83.5% (95%CI 0.58-0.94); specificity: 91.1% (95%CI 0.89-0.93)), followed by FibroMeter V2G (sensitivity: 83.1% (95%CI 0.73-0.90); specificity: 84.4% (95%CI 0.62-0.95)) and FibroMeter NAFLD (sensitivity: 71.7% (95%CI 0.63-0.79); specificity: 82.8% (95%CI 0.71-0.91)). No statistically significant differences were found between the different FibroMeter versions. FibroMeter tests showed acceptable sensitivity and specificity in detecting advanced fibrosis in patients with NAFLD, but an urge to conduct head-to-head comparison studies in patients with NAFLD of the different FibroMeter tests remains.

FibroTest for Evaluating Fibrosis in Non-Alcoholic Fatty Liver Disease Patients: A Systematic Review and Meta-Analysis.

(1) Background: FibroTest™ is a multi-marker panel, suggested by guidelines as one of the surrogate markers with acceptable performance for detecting fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). A number of studies evaluating this test have been published after publication of the guidelines. This study aims to produce summary estimates of FibroTest™ diagnostic accuracy. (2) Methods: Five databases were searched for studies that evaluated FibroTest™ against liver biopsy as the reference standard in NAFLD patients. Two authors independently screened the references, extracted data, and assessed the quality of included studies. Meta-analyses of the accuracy in detecting different levels of fibrosis were performed using the bivariate random-effects model and the linear mixed-effects multiple thresholds model. (3) Results: From ten included studies, seven were eligible for inclusion in our meta-analysis. Five studies were included in the meta-analysis of FibroTest™ in detecting advanced fibrosis and five in significant fibrosis, resulting in an AUC of 0.77 for both target conditions. The meta-analysis of three studies resulted in an AUC of 0.69 in detecting any fibrosis, while analysis of three other studies showed higher accuracy in cirrhosis (AUC: 0.92). (4) Conclusions: Our meta-analysis showed acceptable performance (AUC > 0.80) of FibroTest™ only in detecting cirrhosis. We observed more limited performance of the test in detecting significant and advanced fibrosis in NAFLD patients. Further primary studies with high methodological quality are required to validate the reliability of the test for detecting different fibrosis levels and to compare the performance of the test in different settings.

Diagnostic accuracy of elastography and magnetic resonance imaging in patients with NAFLD: A systematic review and meta-analysis.

BACKGROUND AND AIMS: Vibration-controlled transient elastography (VCTE), point shear wave elastography (pSWE), 2-dimensional shear wave elastography (2DSWE), magnetic resonance elastography (MRE), and magnetic resonance imaging (MRI) have been proposed as non-invasive tests for patients with non-alcoholic fatty liver disease (NAFLD). This study evaluated their diagnostic accuracy for liver fibrosis and non-alcoholic steatohepatitis (NASH). METHODS: PubMED/MEDLINE, EMBASE and the Cochrane Library were searched for studies examining the diagnostic accuracy of these index tests, against histology as the reference standard, in adult patients with NAFLD. Two authors independently screened and assessed methodological quality of studies and extracted data. Summary estimates of sensitivity, specificity and area under the curve (sAUC) were calculated for fibrosis stages and NASH, using a random effects bivariate logit-normal model. RESULTS: We included 82 studies (14,609 patients). Meta-analysis for diagnosing fibrosis stages was possible in 53 VCTE, 11 MRE, 12 pSWE and 4 2DSWE studies, and for diagnosing NASH in 4 MRE studies. sAUC for diagnosis of significant fibrosis were: 0.83 for VCTE, 0.91 for MRE, 0.86 for pSWE and 0.75 for 2DSWE. sAUC for diagnosis of advanced fibrosis were: 0.85 for VCTE, 0.92 for MRE, 0.89 for pSWE and 0.72 for 2DSWE. sAUC for diagnosis of cirrhosis were: 0.89 for VCTE, 0.90 for MRE, 0.90 for pSWE and 0.88 for 2DSWE. MRE had sAUC of 0.83 for diagnosis of NASH. Three (4%) studies reported intention-to-diagnose analyses and 15 (18%) studies reported diagnostic accuracy against pre-specified cut-offs. CONCLUSIONS: When elastography index tests are acquired successfully, they have acceptable diagnostic accuracy for advanced fibrosis and cirrhosis. The potential clinical impact of these index tests cannot be assessed fully as intention-to-diagnose analyses and validation of pre-specified thresholds are lacking. LAY SUMMARY: Non-invasive tests that measure liver stiffness or use magnetic resonance imaging (MRI) have been suggested as alternatives to liver biopsy for assessing the severity of liver scarring (fibrosis) and fatty inflammation (steatohepatitis) in patients with non-alcoholic fatty liver disease (NAFLD). In this study, we summarise the results of previously published studies on how accurately these non-invasive tests can diagnose liver fibrosis and inflammation, using liver biopsy as the reference. We found that some techniques that measure liver stiffness had a good performance for the diagnosis of severe liver scarring.

Accuracy of cytokeratin 18 (M30 and M65) in detecting non-alcoholic steatohepatitis and fibrosis: A systematic review and meta-analysis.

INTRODUCTION: Association between elevated cytokeratin 18 (CK-18) levels and hepatocyte death has made circulating CK-18 a candidate biomarker to differentiate non-alcoholic fatty liver from non-alcoholic steatohepatitis (NASH). Yet studies produced variable diagnostic performance. We aimed to provide summary estimates with increased precision for the accuracy of CK-18 (M30, M65) in detecting NASH and fibrosis among non-alcoholic fatty liver disease (NAFLD) adults. METHODS: We searched five databases to retrieve studies evaluating CK-18 against a liver biopsy in NAFLD adults. Reference screening, data extraction and quality assessment (QUADAS-2) were independently conducted by two authors. Meta-analyses were performed for five groups based on the CK-18 antigens and target conditions, using one of two methods: linear mixed-effects multiple thresholds model or bivariate logit-normal random-effects model. RESULTS: We included 41 studies, with data on 5,815 participants. A wide range of disease prevalence was observed. No study reported a pre-defined cut-off. Thirty of 41 studies provided sufficient data for inclusion in any of the meta-analyses. Summary AUC [95% CI] were: 0.75 [0.69-0.82] (M30) and 0.82 [0.69-0.91] (M65) for NASH; 0.73 [0.57-0.85] (M30) for fibrotic NASH; 0.68 (M30) for significant (F2-4) fibrosis; and 0.75 (M30) for advanced (F3-4) fibrosis. Thirteen studies used CK-18 as a component of a multimarker model. CONCLUSIONS: For M30 we found lower diagnostic accuracy to detect NASH compared to previous meta-analyses, indicating a limited ability to act as a stand-alone test, with better performance for M65. Additional external validation studies are needed to obtain credible estimates of the diagnostic accuracy of multimarker models.

Enhanced liver fibrosis test for the non-invasive diagnosis of fibrosis in patients with NAFLD: A systematic review and meta-analysis.

BACKGROUND & AIMS: The enhanced liver fibrosis (ELF) test has been proposed for the non-invasive assessment of advanced fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). We performed a systematic review to estimate the accuracy of this test against biopsy. METHODS: In this systematic review, we searched MEDLINE, Embase, Web of Science and the Cochrane Library for studies that included patients with NAFLD and that used both liver biopsy (as the reference standard) and the ELF test. Two authors independently screened the references, extracted the data and assessed the quality of included studies. Due to the variation in reported thresholds, we used a multiple thresholds random effects model for meta-analysis (diagmeta R-package). RESULTS: The meta-analysis of 11 studies reporting advanced fibrosis and 5 studies reporting significant fibrosis showed that the ELF test had a sensitivity of >0.90 for excluding fibrosis at a threshold of 7.7. However, as a diagnostic test at high thresholds, the test only achieved specificity and positive predictive value >0.80 in very high prevalence settings (>50%). To achieve a specificity of 0.90 for advanced and significant fibrosis, thresholds of 10.18 (sensitivity: 0.57) and 9.86 (sensitivity: 0.55) were required, respectively. CONCLUSION: The ELF test showed high sensitivity but limited specificity to exclude advanced and significant fibrosis at low cut-offs. The diagnostic performance of the test at higher thresholds was found to be more limited in low-prevalence settings. We conclude that clinicians should carefully consider the likely disease prevalence in their practice setting and adopt suitable test thresholds to achieve the desired performance. LAY SUMMARY: The enhanced liver fibrosis test has been suggested as a non-invasive blood test to aid the diagnosis of severe liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). Our study results showed that the test has a high negative predictive value, especially in populations with low disease prevalence (likely encountered in primary care); so, it can exclude advanced fibrosis in patients with NAFLD. However, when prevalence is low, the positive predictive value of the enhanced liver fibrosis test is low, suggesting that additional strategies may be needed to make a positive diagnosis in such settings.

Maternal environmental risk factors and the development of internalizing and externalizing problems in childhood: The complex role of genetic factors.

The development of problem behavior in children is associated with exposure to environmental factors, including the maternal environment. Both are influenced by genetic factors, which may also be correlated, that is, environmental risk and problem behavior in children might be influenced by partly the same genetic factors. In addition, environmental and genetic factors could interact with each other increasing the risk of problem behavior in children. To date, limited research investigated these mechanisms in a genome-wide approach. Therefore, the goal of this study was to investigate the association between genetic risk for psychiatric and related traits, as indicated by polygenetic risk scores (PRSs), exposure to previously identified maternal risk factors, and problem behavior in a sample of 1,154 children from the Amsterdam Born Children and their Development study at ages 5-6 and 11-12 years old. The PRSs were derived from genome-wide association studies (GWASs) on schizophrenia, major depressive disorder, neuroticism, and wellbeing. Regression analysis showed that the PRSs were associated with exposure to multiple environmental risk factors, suggesting passive gene-environment correlation. In addition, the PRS based on the schizophrenia GWAS was associated with externalizing behavior problems in children at age 5-6. We did not find any association with problem behavior for the other PRSs. Our results indicate that genetic predispositions for psychiatric disorders and wellbeing are associated with early environmental risk factors for children's problem behavior.

Influence of Dietary Approaches to Stop Hypertension-Type Diet, Known Genetic Variants and Their Interplay on Blood Pressure in Early Childhood: ABCD Study.

There is limited evidence on association between adherence to the Dietary Approaches to Stop Hypertension (DASH diet) and a lower blood pressure (BP) in children. In a population-based cohort study, among 1068 Dutch children aged 5 to 7, we evaluated the association between a DASH-type diet, 29 known genetic variants incorporated in a genetic risk score, and their interaction on BP. We calculated DASH score based on the food intake data measured through a validated 71-item food frequency questionnaire. In our sample, DASH score ranged from 9 (low adherence to the DASH diet) to 33 (median=21), and genetic score ranged from 18 (low genetic risk on high BP) to 41 (median=29). After adjustment for covariates, each 10 unit increase in DASH score was associated with a lower systolic BP of 0.7 mm Hg (P=0.033). DASH score was negatively associated with hypertension (odds ratio=0.96 [0.92-0.99], P=0.044). Similarly, each SD increment in genetic score was associated with 0.5 mm Hg higher diastolic BP (P=0.002). We found a positive interaction between low DASH score and high genetic score on diastolic BP adjusted for BP risk factors (ß=1.52, Pinteraction=0.019 in additive scale and ß=0.03, Pinteraction=0.021 in multiplicative scale). Our findings show that adherence to the DASH-type diet, as well as a low (adult-derived) genetic risk profile for BP, is associated with lower BP in children and that the genetic basis of BP phenotypes at least partly overlaps between adults and children. In addition, we found evidence of a gene-diet interaction on BP in children.

Is there an association between oocyte number and embryo quality? A systematic review and meta-analysis.

This systematic review and meta-analysis determined the association between aspirated after ovarian stimulation and top/good quality embryos obtained in women undergoing ovarian stimulation for IVF/intracytoplasmic sperm injection (ICSI). MEDLINE, EMBASE, Scopus, CINAHL and Web of Science were searched for English-language publications on top/good-quality embryos at cleavage (day 2/3) and/or blastocyst (day 5/6) developmental stages, up to 18 November 2017. Twenty-eight studies (three prospective and 25 retrospective) reporting data on 291,752 assisted reproductive technology (ART) cycles were considered eligible. We confirmed a strong positive association between oocytes retrieved and top/good-quality day 2/3 embryos (weighted correlation coefficient [rw] = 0.791), day 5/6 embryos (rw = 0.901), metaphase II oocytes (rw = 0.988), oocytes exhibiting two pronuclei (rw = 0.987) and euploid embryos (rw = 0.851); P < 0.001 for all correlations (evaluated in subsets of the 17 studies). Data from 5657 cycles showed that the group with the most oocytes aspirated had the most top/good-quality day 2/3 embryos (pooled standardized mean differences (high [>15] versus low [<4] 1.91, 95% confidence interval [CI] 1.05-2.77, P < 0.0001; high versus medium [4-15] 1.15, 95% CI 0.74-1.55, P < 0.0001; medium versus low 1.41, 95% CI 0.79-2.03, P < 0.0001). Individual participant meta-analysis would enable accurate determination of these associations and other outcomes.

Development and evaluating multimarker models for guiding treatment decisions.

BACKGROUND: Despite the growing interest in developing markers for predicting treatment response and optimizing treatment decisions, an appropriate methodology to identify, combine and evaluate such markers has been slow to develop. We propose a step-by-step strategy for analysing data from existing randomised trials with the aim of identifying a multi-marker model for guiding decisions about treatment. METHODS: We start with formulating the treatment selection problem, continue with defining the treatment threshold, prepare a list of candidate markers, develop the model, apply the model to estimate individual treatment effects, and evaluate model performance in the study group of patients who meet the trial eligibility criteria. In this process, we rely on some well-known techniques for multivariable prediction modelling, but focus on predicting benefit from treatment, rather than outcome itself. We present our approach using data from a randomised trial in which 808 women with multiple pregnancy were assigned to cervical pessary or control, to prevent adverse perinatal outcomes. Overall, cervical pessary did not reduce the risk of adverse perinatal outcomes. RESULTS: The treatment threshold was zero. We had a preselected list of 5 potential markers and developed a logistic model including the markers, treatment and all marker-by-treatment interaction terms. The model was well calibrated and identified 35% (95% confidence interval (CI) 32 to 39%) of the trial participants as benefitting from pessary insertion. We estimated that the risk of adverse outcome could be reduced from 13.5 to 8.1% (5.4% risk reduction; 95% CI 2.1 to 8.6%) through model-based selective pessary insertion. The next step is external validation upon existence of independent trial data. CONCLUSIONS: We suggest revisiting existing trials data to explore whether differences in treatment benefit can be explained by differences in baseline characteristics of patients. This could lead to treatment selection tools which, after validation in comparable existing trials, can be introduced into clinical practice for guiding treatment decisions in future patients.

Ideal cardiovascular health among Ghanaian populations in three European countries and rural and urban Ghana: the RODAM study.

Cardiovascular health (CVH) is a construct defined by the American Heart Association (AHA) as part of its 2020 Impact Goal definition. CVH has, until now, not been evaluated in Sub-Saharan African populations. The aim of this study was to investigate differences in the prevalence of ideal CVH and its constituent metrics among Ghanaians living in rural and urban Ghana and Ghanaian migrants living in three European countries. The AHA definition of CVH is based on 7 metrics: smoking, body mass index, diet, physical activity, blood pressure, total cholesterol, and fasting plasma glucose. These were evaluated among 3510 Ghanaian adults (aged 25-70 years) residing in rural and urban Ghana and three European cities (Amsterdam, London and Berlin) in the multi-centre RODAM study. Differences between groups were assessed using logistic regression with adjustments for gender, age, and education. Only 0.3% of all participants met all 7 metrics of the AHA's definition of ideal CVH. Compared to rural Ghana (25.7%), the proportions and adjusted odds ratio (OR) of individuals who had 6-7 CVH metrics in the ideal category were substantially lower in urban Ghana, (7.5%; OR 0.204, 95% CI 0.15-0.29), Amsterdam (4.4%; 0.13, 0.08-0.19), Berlin (2.7%; 0.06, 0.03-0.11), and London (1.7%; 0.04, 0.02-0.09), respectively. The proportion of ideal CVH for the various metrics ranged from 96% for all sites in the smoking metric to below 6% in the diet metric. The proportion of ideal CVH is extremely low in Ghanaians, especially among those living in urban Ghana and Ghanaian migrants in Europe.

Heritability and Genome-Wide Association Analyses of Sleep Duration in Children: The EAGLE Consortium.

STUDY OBJECTIVES: Low or excessive sleep duration has been associated with multiple outcomes, but the biology behind these associations remains elusive. Specifically, genetic studies in children are scarce. In this study, we aimed to: (1) estimate the proportion of genetic variance of sleep duration in children attributed to common single nucleotide polymorphisms (SNPs), (2) identify novel SNPs associated with sleep duration in children, and (3) investigate the genetic overlap of sleep duration in children and related metabolic and psychiatric traits. METHODS: We performed a population-based molecular genetic study, using data form the EArly Genetics and Life course Epidemiology (EAGLE) Consortium. 10,554 children of European ancestry were included in the discovery, and 1,250 children in the replication phase. RESULTS: We found evidence of significant but modest SNP heritability of sleep duration in children (SNP h2 0.14, 95% CI [0.05, 0.23]) using the LD score regression method. A novel region at chromosome 11q13.4 (top SNP: rs74506765, P = 2.27e-08) was associated with sleep duration in children, but this was not replicated in independent studies. Nominally significant genetic overlap was only found (rG = 0.23, P = 0.05) between sleep duration in children and type 2 diabetes in adults, supporting the hypothesis of a common pathogenic mechanism. CONCLUSIONS: The significant SNP heritability of sleep duration in children and the suggestive genetic overlap with type 2 diabetes support the search for genetic mechanisms linking sleep duration in children to multiple outcomes in health and disease.

Which intrauterine growth restricted fetuses at term benefit from early labour induction? A secondary analysis of the DIGITAT randomised trial.

OBJECTIVE: The Disproportionate Intrauterine Growth Intervention Trial at Term (DIGITAT trial) showed that in women with suspected intrauterine growth restriction (IUGR) at term, there were no substantial outcome differences between induction of labour and expectant monitoring. The objective of the present analysis is to evaluate whether maternal or fetal markers could identify IUGR fetuses who would benefit from early labour induction. STUDY DESIGN: The DIGITAT trial was a multicenter, parallel and open-label randomised controlled trial in women who had a singleton pregnancy beyond 36+0 weeks' gestation with suspected IUGR (n=650). Women had been randomly allocated to either labour induction or expectant monitoring. The primary outcome was a composite measure of adverse neonatal outcome, defined as neonatal death before hospital discharge, Apgar score <7, umbilical artery pH <7.05, or admission to neonatal intensive care. Using logistic regression modelling, we investigated associations between outcome and 17 markers, maternal characteristics and fetal sonographic and Doppler velocimetry measurements, all collected at study entry. RESULTS: 17 (5.3%) infants in the induction group had an adverse neonatal outcome compared to 20 (6.1%) in the expectant monitoring group. The only potentially informative marker for inducing labour was maternal pre-pregnancy body mass index (BMI). Otherwise, we observed at best weak associations between a benefit from labour induction and maternal age, ethnicity, smoking, parity, pregnancy-induced hypertension or preeclampsia, Bishop score and gestational age, or fetal sonographic markers (gender, estimated fetal weight, body measurements, oligohydramnios, or umbilical artery pulsatility index and end diastolic flow). CONCLUSION: In late preterm and term pregnancies complicated by suspected intrauterine growth restriction, most of the known prognostic markers seem unlikely to be helpful in identifying women who could benefit from labour induction, except for maternal pre-pregnancy BMI.

The M235T variant of the angiotensinogen gene is related to development of self-reported hypertension during pregnancy: the Prospect-EPIC cohort study.

Angiotensinogen gene (AGT) M235T polymorphism is associated with an increased risk of hypertension. It is unknown whether this mutation also leads to an increased risk of development of high blood pressure (BP) in pregnancy. The aim of this study was to investigate the association of this polymorphism with elevated blood pressure during pregnancy in a population of healthy Dutch women. We studied a randomly selected sample of 1,736 middle-aged women who participated in a prospective cohort study of 17,357 Dutch women. After excluding those who had never been pregnant or those with missing data, 429 women with and 921 women without a history of elevated BP during pregnancy remained for further analyses. History of hypertension in pregnancy was assessed using a questionnaire, and confirmed cases varied in severity from mild blood pressure elevation to pre-eclampsia. Individuals with the TT genotype were more likely to have had a history of elevated BP during pregnancy than those with the MM genotype (odds ratio [OR] = 1.43; 95% confidence interval [CI], 1.02-2.01; p = 0.04). In heterozygote individuals (MT) an increased risk was found, which did not reach statistical significance (OR = 1.24; 95% CI, 0.96-1.60; p = 0.11). Under both dominant and additive genetic models, the M235T polymorphism was associated with a history of elevated blood pressure during pregnancy, with ORs of 1.29 (95% CI, 1.01-1.64; p = 0.04) and 1.20 (95% CI, 1.02-1.42; p = 0.03), respectively. The findings of this study among Caucasian Dutch women, aged 49 to 70 years, demonstrated that the presence of the T allele of the M235T polymorphism in the AGT is associated with self-reported hypertensive disorders in pregnancy.

The angiotensinogen gene M235T polymorphism and development of preeclampsia/eclampsia: a meta-analysis and meta-regression of observational studies.

OBJECTIVE: The angiotensinogen gene M235T polymorphism is related to an increased risk of hypertension. Hypertension and pregnancy-induced hypertension have been suggested to share common etiologic factors. We examined whether this mutation also increases the risk of preeclampsia/eclampsia. METHODS: Pubmed/Medline, Web of Science and EMBASE were searched and a hand search of bibliographies was conducted. In all, 17 studies (including 1446 cases and 3829 controls) published in English between 1993 and October 2006 on the association of angiotensinogen gene M235T polymorphism with preeclampsia/eclampsia were selected. RESULTS: The overall odds ratio (OR) under a random effects model revealed that individuals homozygous for the T allele were 1.62 times more likely to develop preeclampsia/eclampsia [95% confidence interval (CI), 1.12 to 2.33; P = 0.01) compared to individuals homozygous for the M allele. The relation in Caucasians (OR = 1.99; 95% CI, 1.18-3.36; P = 0.01) was similar to that in East Asian populations (OR = 1.74; 95% CI, 0.92-3.28; P = 0.09), although the latter was not statistically significant due to lower numbers of studies. Under additive, recessive and dominant genetic models positive associations were also found. A meta-regression analysis showed that ethnic background was a significant source of between-study heterogeneity (P = 0.04) but design of the study, study size and Hardy-Weinberg equilibrium deviation were not. There was a low probability of publication bias. CONCLUSION: Our meta-analysis expands the findings on hypertension by showing that the presence of the T allele of the angiotensinogen gene is associated with an increased risk to develop preeclampsia/eclampsia.

Peroxisome proliferator-activated receptor gamma-2 P12A polymorphism and risk of acute myocardial infarction, coronary heart disease and ischemic stroke: a case-cohort study and meta-analyses.

BACKGROUND: The alanine allele of P12A polymorphism in PPARG gene in a few studies has been associated with a reduced or increased risk of acute myocardial infarction (AMI). Yet, the risk relation has not been confirmed, and data on ischemic stroke (IS) is scarce. We therefore investigated the role of this polymorphism on occurrence of AMI, coronary heart disease (CHD) and IS. METHODS AND FINDINGS: We performed a case-cohort study in 15,236 initially healthy Dutch women and applied a Cox proportional hazards model to study the relation of the P12A polymorphism and AMI (n = 71), CHD (n = 211), and IS (n = 49) under different inheritance models. In addition, meta-analyses of published studies were performed. Under the dominant inheritance model, carriers of the alanine allele compared with those with the more common genotype were not at increased or decreased risk of CHD (hazard ratio [HR] = 0.82; 95% confidence interval [CI], 0.58 to 1.17) and of IS (HR = 1.03; 95% CI, 0.14 to 7.74). In addition no relations were found under the recessive and additive models. Our meta-analyses corroborated these findings by showing no significant association. For AMI we found a borderline significant association under dominant (HR = 0.49; 95% CI, 0.26 to 0.94), and additive (HR = 0.51; 95% CI, 0.26 to 1.00) models which could be due to chance, because of small cases in this subgroup. The meta-analysis did not show any association between the polymorphism and risk of AMI under the different genetic models. CONCLUSIONS: Our study in healthy Dutch women in combination with the meta-analyses of previous reports does not provide support for a role of P12A polymorphism in PPARG gene in MI and CHD risk. Also our study shows that the polymorphism has no association with IS risk.

The M235T polymorphism in the AGT gene and CHD risk: evidence of a Hardy-Weinberg equilibrium violation and publication bias in a meta-analysis.

BACKGROUND: The M235T polymorphism in the AGT gene has been related to an increased risk of hypertension. This finding may also suggest an increased risk of coronary heart disease (CHD). METHODOLOGY/PRINCIPAL FINDINGS: A case-cohort study was conducted in 1,732 unrelated middle-age women (210 CHD cases and 1,522 controls) from a prospective cohort of 15,236 initially healthy Dutch women. We applied a Cox proportional hazards model to study the association of the polymorphism with acute myocardial infarction (AMI) (n = 71) and CHD. In the case-cohort study, no increased risk for CHD was found under the additive genetic model (hazard ratio [HR] = 1.20; 95% confidence interval [CI], 0.86 to 1.68; P = 0.28). This result was not changed by adjustment (HR = 1.17; 95% CI, 0.83 to 1.64; P = 0.38) nor by using dominant, recessive and pairwise genetic models. Analyses for AMI risk under the additive genetic model also did not show any statistically significant association (crude HR = 1.14; 95% CI, 0.93 to 1.39; P = 0.20). To evaluate the association, a comprehensive systematic review and meta-analysis were undertaken of all studies published up to February 2007 (searched through PubMed/MEDLINE, Web of Science and EMBASE). The meta-analysis (38 studies with 13284 cases and 18722 controls) showed a per-allele odds ratio (OR) of 1.08 (95% CI, 1.01 to 1.15; P = 0.02). Moderate to large levels of heterogeneity were identified between studies. Hardy-Weinberg equilibrium (HWE) violation and the mean age of cases were statistically significant sources of the observed variation. In a stratum of non-HWE violation studies, there was no effect. An asymmetric funnel plot, the Egger's test (P = 0.066), and the Begg-Mazumdar test (P = 0.074) were all suggestive of the presence of publication bias. CONCLUSIONS/SIGNIFICANCE: The pooled OR of the present meta-analysis, including our own data, presented evidence that there is an increase in the risk of CHD conferred by the M235T variant of the AGT gene. However, the relevance of this weakly positive overall association remains uncertain because it may be due to various residual biases, including HWE-violation and publication biases.

Alpha-adducin Gly460Trp variant increases the risk of stroke in hypertensive Dutch women.

The Gly460Trp variant of the alpha-adducin gene has been associated with renal sodium retention and salt-sensitive hypertension. Independent of blood pressure, salt sensitivity has been related to cerebrovascular events. We studied the risk of stroke, coronary heart disease (CHD), and myocardial infarction (MI) associated with the alpha-adducin variant and examined the extent to which this risk is modified by the presence of hypertension. We performed a case-cohort study in a prospective cohort of 15,236 initially healthy Dutch women. We applied a Cox proportional hazards model with an estimation procedure adapted for case-cohort designs to study the relation of the polymorphism and CHD (n=210), MI (n=71), any stroke (n=74), and ischemic stroke (n=49). Subjects with the Gly460Trp variant had a 2.8 times higher risk of stroke (95% confidence intervals [CI] 1.3 to 5.8) under the dominant genetic model, which did not attenuate after adjustment. The same pattern was found under per-allele comparison. Risk of ischemic stroke in the variant allele carriers was 3.9 times higher than in subjects with the common genotype (95% CI 1.7 to 8.6) using dominant inheritance model. The same patterns were found under per-allele comparison. CHD and MI were not related to the variant. The risk of ischemic stroke was more pronounced among women with systolic hypertension (10.9; 95% CI 3.6 to 31.5). The findings in this prospective study in a population based cohort of Dutch women strongly suggest that presence of the alpha-adducin Gly460Trp polymorphism increases the risk of stroke. This risk is particularly elevated in the presence of systolic hypertension.