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1.  Circulating anti-angiogenic factors during hypertensive pregnancy and increased risk of respiratory distress syndrome in preterm neonates 
OBJECTIVE
To test the hypothesis that high circulating concentrations of maternal anti-angiogenic factors are associated with increased risk of respiratory distress syndrome (RDS).
STUDY DESIGN
This is a nested case-control study of nulliparous women who delivered less than 37 weeks of gestation within the Calcium for Preeclampsia Prevention (CPEP) trial. The study included 116 women with preeclampsia or gestational hypertension and 323 normotensive controls. Soluble fms-like tyrosine kinase 1 (sFlt1), placental growth factor [PlGF] and soluble endoglin [sEng] in maternal serum were measured at 21–32 weeks of gestation.
RESULTS
Preterm infants born to hypertensive mothers were more likely to develop RDS (22.5 % versus 20.9%, P=0.03). After adjustment for gestational age at delivery, the odds ratio for the relationship between hypertension in pregnancy and RDS was 2.18 (95% C.I. 1.08, 4.39). In hypertensive pregnancies women whose infants developed RDS had significantly higher circulating mean sFlt1 levels during mid-pregnancy (21–32 weeks of gestation) even after adjustment for gestational age at delivery (21,516 pg/mL versus 7,000 pg/mL, P = 0.01).
CONCLUSIONS
Preterm preeclampsia and gestational hypertension, characterized by high circulating levels of sFlt1, are associated with a twofold increased risk of RDS in infants delivered before 37 weeks. Among women with these hypertensive pregnancies circulating sFlt1 concentrations during mid-pregnancy were substantially higher in women whose infants developed RDS.
doi:10.3109/14767058.2011.640368
PMCID: PMC3414194  PMID: 22097923
anti-angiogenic; soluble fms-like tyrosine kinase 1; sVEGF R1; sFlt1; placental growth factor; PlGF; soluble endoglin; sEng; respiratory distress syndrome; RDS; neonate; preterm; preeclampsia; gestational hypertension
2.  Bacterial vaginosis assessed by Gram stain and diminished colonization resistance to incident gonococcal, chlamydial and trichomonal genital infection 
The Journal of infectious diseases  2010;202(12):1907-1915.
Background
We sought to assess the relationship between bacterial vaginosis (BV) assessed by Gram stain and incident trichomonal (TV), gonococcal (GC) and/or chlamydial (CT) genital infection.
Methods
3,620 non-pregnant women aged 15-44 presenting for routine care at 12 clinics in Birmingham, Alabama participated in a longitudinal study. Participants were assessed quarterly for one year. Vaginal smears were categorized by Nugent's Gram stain score (0-3 designated normal, 4-6 intermediate state, 7-10 BV). Pooled logistic regression was used to estimate the hazard ratios (HR) for the comparison of TV/GC/CT incidence in participants by Nugent category at the prior visit. Participants were censored at their first TV/GC/CT-positive visit.
Results
Of the 10,606 visits, 37.96% were classified as BV and 13.3% as TV/GC/CT-positive. Intermediate state or BV at the prior visit were associated with a 1.5-2-fold increased risk for incident TV/GC/CT infection (adjusted HR(aHR):1.41, 95% CI:1.12-1.76; aHR: 1.73, 95% CI: 1.42-2.11, respectively, test for trend p=.058). Estimates were similar for TV-only, GC-only and CT-only outcomes.
Conclusion
BV microbiota gauged by Gram's stain is associated with a significantly elevated risk for acquisition of TV/GC/CT genital infection.
doi:10.1086/657320
PMCID: PMC3053135  PMID: 21067371
bacterial vaginosis (BV); vaginal microbiota; sexually transmitted infection (STI); Neisseria gonorrhoeae (GC); Chlamydia trachomatis (CT); Trichomonas vaginalis (TV)
3.  Bacterial Vaginosis Assessed by Gram Stain and Diminished Colonization Resistance to Incident Gonococcal, Chlamydial, and Trichomonal Genital Infection 
The Journal of Infectious Diseases  2010;202(12):1907-1915.
Background. We sought to assess the relationship between bacterial vaginosis (BV) assessed by Gram stain and incident trichomonal, gonococcal, and/or chlamydial genital infection.
Methods. This longitudinal study included 3620 nonpregnant women aged 15–44 years who presented for routine care at 12 clinics in Birmingham, Alabama. Participants were assessed quarterly for 1 year. Vaginal smears were categorized by the Nugent Gram stain score (0–3, normal; 4–6, intermediate state; 7–10, BV). Pooled logistic regression was used to estimate the hazard ratios for the comparison of trichomonal, gonococcal, and chlamydial infection incidence in participants by Nugent score at the prior visit. Participants were censored at their first visit with a positive test result for trichomonal, gonococcal, and/or chlamydial infection.
Results. Of the 10,606 eligible visits, 37.96% were classified by BV and 13.3% by positive detection of trichomonal, gonococcal, and/or chlamydial infection. An intermediate state or BV at the prior visit was associated with a 1.5–2-fold increased risk for incident trichomonal, gonococcal, and/or chlamydial infection (adjusted hazard ratio [AHR] for intermediate state, 1.41 [95% confidence interval {CI}, 1.12–1.76]; AHR for BV, 1.73 [95% CI, 1.42–2.11]; P=.058 for trend). Estimates were similar for trichomonal-only, gonococcal-only, and chlamydialonly infection outcomes.
Conclusion. BV microbiota as gauged by Gram stain is associated with a significantly elevated risk for acquisition of trichomonal, gonococcal, and/or chlamydial genital infection.
doi:10.1086/657320
PMCID: PMC3053135  PMID: 21067371
4.  A Rank-Based Test for Comparison of Multidimensional Outcomes 
For comparison of multiple outcomes commonly encountered in biomedical research, Huang et al. (2005) improved O’Brien’s (1984) rank-sum tests through the replacement of the ad hoc variance by the asymptotic variance of the test statistics. The improved tests control the Type I error rate at the desired level and gain power when the differences between the two comparison groups in each outcome variable fall into the same direction. However, they may lose power when the differences are in different directions (e.g., some are positive and some are negative). These tests and the popular Bonferroni correction failed to show important significant difference when applied to compare heart rates from a clinical trial to evaluate the effect of a procedure to remove the cardioprotective solution HTK. We propose an alternative test statistic, taking the maximum of the individual rank-sum statistics, which controls the type I error and maintains satisfactory power regardless of the directions of the differences. Simulation studies show the proposed test to be of higher power than other tests in certain alternative parameter space of interest. Furthermore, when used to analyze the heart rates data the proposed test yields more satisfactory results.
doi:10.1198/jasa.2010.ap09114
PMCID: PMC3102319  PMID: 21625372
Autism spectrum disorder; Behrens-Fisher problem; Cardioprotective solution; Case-control studies; Growth hormones; Multiple outcomes; Non-parametrics; Rank-sum statistics
5.  A threshold sample-enrichment approach in a clinical trial with heterogeneous subpopulations 
Background
Large comparative clinical trials usual target a wide-range of patients population in which subgroups exist according to certain patients’ characteristics. Often, scientific knowledge or existing empirical data support the assumption that patients’ improvement is larger among certain subgroups than the others. Such information can be used to design a more cost-effective clinical trial.
Purpose
The goal of the article is to use such information to design a more cost-effective clinical trial.
Method
A two-stage sample-enrichment design strategy is proposed that begins with enrollment from certain subgroup of patients and allows the trial to be terminated for futility in that subgroup.
Results
Simulation studies show that the two-stage sample-enrichment strategy is cost-effective if indeed the null hypothesis of no treatment improvement is true, as also so illustrated with data from a completed trial of calcium to prevent preeclampsia.
Limitations
Feasibility of the proposed enrichment design relies on the knowledge prior to the start of the trial that certain patients can benefit more than others from the treatment.
Conclusions
The two-stage sample-enrichment approach borrows strength from treatment heterogeneity among target patients in a large scale comparative clinical trial, and is more cost-effective if the treatment are of no difference.
doi:10.1177/1740774510378695
PMCID: PMC2995455  PMID: 20685769
Sample size and power; stopping for futility; subgroup analysis; treatment heterogeneity
6.  Testing for Genetic Association With Constrained Models Using Triads 
Annals of human genetics  2009;73(2):225-230.
Wang and Sheffield (2005) showed that it is preferable to use a robust model that incorporated constraints on the genotype relative risk rather than rely on a model that assumes the disease operates in a recessive or dominant fashion. Wang and Sheffield’s method is applicable to case-control studies, but not to family based studies of case children along with their parents (triads). We show here how to implement analogous constraints while analyzing triad data. The likelihood, conditional on the parents genotype, is maximized over the appropriately constrained parameter space. The asymptotic distribution for the maximized likelihood ratio statistic is found and used to estimate the null distribution of the test statistics. The properties of several methods of testing for association are compared by simulation. The constrained method provides higher power across a wide range of genetic models with little cost when compared to methods that restrict to a dominant, recessive, or multiplicative model, or make no modeling restriction. The methods are applied to two SNPs on the methylenetetrahy-drofolate reductase (MTHFR) gene with neural tube defect (NTD) triads.
doi:10.1111/j.1469-1809.2008.00494.x
PMCID: PMC2657230  PMID: 19178434
conditional distribution; genetic risk model; likelihood ratio test; power
7.  Exact inference on contrasts in means of intraclass correlation models with missing responses 
Intraclass correlation models with missing data at random are considered. With a properly reduced model, a general method, which allows repeated observations with missing in non-monotone pattern, is proposed to construct exact test statistics and simultaneous confidence intervals for linear contrasts in the means. Simulation results are given to compare exact and asymptotic simultaneous confidence intervals. A real example is provided for illustration of the proposed method.
doi:10.1016/j.jmva.2008.05.002
PMCID: PMC2659342  PMID: 20126283
Contrast; Exact test; Intraclass correlation model; Linear mixed model; Simultaneous confidence intervals
8.  Pre-eclampsia, soluble fms-like tyrosine kinase 1, and the risk of reduced thyroid function: nested case-control and population based study 
Objective To determine if pre-eclampsia is associated with reduced thyroid function during and after pregnancy.
Design Nested case-control study during pregnancy and population based follow-up study after pregnancy.
Setting Calcium for Pre-eclampsia Prevention trial of healthy pregnant nulliparous women in the United States during 1992-5, and a Norwegian population based study (Nord-Trondelag Health Study or HUNT-2) during 1995-7 with linkage to the medical birth registry of Norway.
Participants All 141 women (cases) in the Calcium for Pre-eclampsia Prevention trial with serum measurements before 21 weeks’ gestation (baseline) and after onset of pre-eclampsia (before delivery), 141 normotensive controls with serum measurements at similar gestational ages, and 7121 women in the Nord-Trondelag Health Study whose first birth had occurred in 1967 or later and in whom serum levels of thyroid stimulating hormone had been subsequently measured.
Main outcome measures Thyroid function tests and human chorionic gonadotrophin and soluble fms-like tyrosine kinase 1 concentrations in the Calcium for Pre-eclampsia Prevention cohort and odds ratios for levels of thyroid stimulating hormone above the reference range, according to pre-eclampsia status in singleton pregnancies before the Nord-Trondelag Health Study.
Results In predelivery specimens of the Calcium for Pre-eclampsia Prevention cohort after the onset of pre-eclampsia, thyroid stimulating hormone levels increased 2.42 times above baseline compared with a 1.48 times increase in controls. The ratio of the predelivery to baseline ratio of cases to that of the controls was 1.64 (95% confidence interval 1.29 to 2.08). Free triiodothyronine decreased more in the women with pre-eclampsia than in the controls (case ratio to control ratio 0.96, 95% confidence interval 0.92 to 0.99). The predelivery specimens but not baseline samples from women with pre-eclampsia were significantly more likely than those from controls to have concentrations of thyroid stimulating hormone above the reference range (adjusted odds ratio 2.2, 95% confidence interval 1.1 to 4.4). Both in women who developed pre-eclampsia and in normotensive controls the increase in thyroid stimulating hormone concentration between baseline and predelivery specimens was strongly associated with increasing quarters of predelivery soluble fms-like tyrosine kinase 1 (P for trend 0.002 and <0.001, respectively). In the Nord-Trondelag Health Study, women with a history of pre-eclampsia in their first pregnancy were more likely than other women (adjusted odds ratio 1.7, 95% confidence interval 1.1 to 2.5) to have concentrations of thyroid stimulating hormone above the reference range (>3.5 mIU/l). In particular, they were more likely to have high concentrations of thyroid stimulating hormone without thyroid peroxidase antibodies (adjusted odds ratio 2.6, 95% confidence interval 1.3 to 5.0), suggesting hypothyroid function in the absence of an autoimmune process. This association was especially strong (5.8, 1.3 to 25.5) if pre-eclampsia had occurred in both the first and the second pregnancies.
Conclusion Increased serum concentration of soluble fms-like tyrosine kinase 1 during pre-eclampsia is associated with subclinical hypothyroidism during pregnancy. Pre-eclampsia may also predispose to reduced thyroid function in later years.
doi:10.1136/bmj.b4336
PMCID: PMC2778749  PMID: 19920004
9.  A Weighted Rank-Sum Procedure for Comparing Samples with Multiple Endpoints 
Statistics and its interface  2009;2(2):197-201.
Summary
For comparing the distribution of two samples with multiple endpoints, O’Brien (1984) proposed rank-sum-type test statistics. Huang et al. (2005) extended these statistics to the general nonparametric Behrens-Fisher hypothesis problem and obtained improved test statistics by replacing the ad hoc variance with the asymptotic variance of the rank-sum statistics. In this paper we generalize the work of O’Brien (1984) and Huang et al. (2005) and propose a weighted rank-sum statistic. We show that the weighted rank-sum statistic is asymptotically normally distributed, permitting the computation of power, p-values and confidence intervals. We further demonstrate via simulation that the weighted rank-sum statistic is efficient in controlling the type I error rate and under certain alternatives, is more powerful than the statistics of O’Brien (1984) and Huang et al.(2005).
PMCID: PMC2759535  PMID: 19823699
Asymptotic normality; Behrens-Fisher problem; Case-Control; Clinical trials; Multiple endpoints; Rank-sum statistics; Weights
10.  CIRCULATING SOLUBLE ENDOGLIN AND PLACENTAL ABRUPTION 
Prenatal diagnosis  2008;28(9):852-858.
Objective
Our objective was to investigate whether serum concentrations of a novel anti-angiogenic factor, soluble endoglin (sEng), could predict placental abruption.
Methods
In a nested case control study of nulliparous pregnancies, we examined levels of sEng in serum collected prospectively from 31 women who later developed placental abruption and from 31 normal controls. All serum specimens were collected before the onset of hypertension or abruption and before labor or delivery. Serum sEng was compared within three gestational age intervals: early- (<20 weeks), mid- (21–32 weeks), and late (≥33 weeks) pregnancy.
Results
There was no significant difference in sEng between abruption cases and controls in early pregnancy. sEng was significantly elevated among abruption cases at 21–32 weeks (10.7 versus 5.9 ng/mL, P<0.01). Subgroup analyses revealed no differences in sEng concentrations at any gestational age interval between cases with abruption without hypertension and healthy controls. Among women who developed hypertension and placental abruption, sEng was not significantly increased in early pregnancy, but was in mid-pregnancy (19.3 versus 5.5 ng/mL, P=0.002) and in late pregnancy (15.6 versus 9.5 ng/mL, P=0.04).
Conclusion
Serum levels of the anti-angiogenic factor sEng are elevated prior to the development of hypertension and placental abruption. These elevations are not apparent until the late second trimester (26 – 27 weeks, on average), but they persist from this time in gestation onward. sEng may be useful for identifying pregnant women at risk for abruption and hypertension.
doi:10.1002/pd.2065
PMCID: PMC2574843  PMID: 18702104
Abruptio placentae; preeclampsia; gestational hypertension; endoglin; angiogenic factors
11.  A Longitudinal Study of Vaginal Douching and Bacterial Vaginosis—A Marginal Structural Modeling Analysis 
American Journal of Epidemiology  2008;168(2):188-196.
The etiology of bacterial vaginosis is unknown, and there are no long-term therapies for preventing this frequently recurring condition. Vaginal douching has been reported to be associated with bacterial vaginosis in observational studies. However, this association may be due to confounding by indication—that is, confounding by women douching in response to vaginal symptoms associated with bacterial vaginosis. The authors used marginal structural modeling to estimate the causal effect of douching on bacterial vaginosis risk while controlling for this confounding effect. In 1999–2002, nonpregnant women (n = 3,620) were recruited into a prospective study when they visited one of 12 public health clinics in Birmingham, Alabama, for routine care. Participants were assessed quarterly for 1 year. Bacterial vaginosis was based on a Nugent's Gram stain score of 7 or higher. Thirty-two percent of participants douched in every study interval, and 43.0% never douched. Of the 12,349 study visits, 40.2% were classified as involving bacterial vaginosis. The relative risk for regular douching as compared with no douching was 1.21 (95% confidence interval: 1.08, 1.38). These findings indicate that douching confers increased risk of disruption of vaginal flora. In the absence of a large randomized trial, these findings provide the best evidence to date for a risk of bacterial vaginosis associated with douching.
doi:10.1093/aje/kwn103
PMCID: PMC2574994  PMID: 18503038
confounding factors (epidemiology); epidemiologic methods; longitudinal studies; models, structural; vaginal douching; vaginosis, bacterial
12.  Two-stage procedures for selecting the best diagnostic biomarkers 
Considered in the paper is the problem of selecting a diagnostic biomarker that has the highest classification rate among several candidate markers with dichotomous outcomes. The probability of correct selection depends on a number of nuisance parameters from the joint distribution of the biomarkers and thus can be substantially affected if these nuisance parameters are misspecified. A two-stage procedure is proposed to compute the needed sample size that achieves the desired level of correct selection, as so confirmed by simulation results.
doi:10.1098/rsta.2008.0032
PMCID: PMC3227145  PMID: 18407902
classification rate; diagnosis; nuisance parameters; probability of correct selection; sensitivity; specificity
13.  A longitudinal study of vaginal douching and bacterial vaginosis — A marginal structural modeling analysis 
American journal of epidemiology  2008;168(2):188-196.
The etiology of bacterial vaginosis (BV) is unknown and there are no long-term therapies for preventing this frequently recurring condition. Vaginal douching has been reported to be associated with BV in observational studies. However, this association may be due to confounding by indication-- women douching in response to vaginal symptoms associated with BV. Marginal structural modeling was used to estimate the causal effect of douching on risk for BV controlling for this confounding effect. From 1999-2002, non-pregnant women (n=3620) were recruited into a prospective study when presenting for routine care at 12 public health clinics in Birmingham, Alabama. Participants were assessed quarterly for one year. BV was based on Nugent’s Gram stain score ≥ 7. Thirty-two percent of participants douched in every interval and 43.0% never douched. Of the 12,349 visits, 40.2% were classified as having BV. The relative risk for regular douching practice compared with no douching practice was 1.21 (95% CI: 1.08, 1.38). Our findings indicate that douching confers an increased risk for disruption of vaginal flora. In the absence of a large randomized trial, these findings provide the best evidence to date for the risk of douching on BV.
doi:10.1093/aje/kwn103
PMCID: PMC2574994  PMID: 18503038
Vaginosis, Bacterial; Vaginal Douching; epidemiologic methods; Longitudinal Studies; Models, Structural; Confounding Factor; Epidemiologic; time-dependent confounding
14.  BLOOD PRESSURE DYNAMICS DURING PREGNANCY AND SPONTANEOUS PRETERM BIRTH 
Objective
To examine whether blood pressure in early pregnancy and its rise in second half of gestation are associated with spontaneous preterm birth in healthy, normotensive, nulliparous women.
Methods
We included 5,167 women with singleton gestation who participated in the World Health Organization Calcium Supplementation for the Prevention of Preeclampsia Trial. Systolic, diastolic, mean arterial blood pressure and pulse pressure at baseline (12 – 19 weeks of gestation) and mid 3rd trimester (30 – 34 weeks) were calculated. Rise in blood pressure was the difference between the mid 3rd trimester and baseline. Preterm birth was defined as early preterm (< 34 completed weeks) and late preterm birth (34 – 36 weeks).
Results
Women experiencing early or late preterm birth had over 10 mmHg and 3 mmHg higher rise, respectively, in systolic, diastolic and mean arterial blood pressure than women delivering at term. A rise in systolic pressure over 30 mmHg or diastolic pressure over 15 mmHg was associated with a statistically significant 2 – 3-fold increase in risk of spontaneous preterm birth.
Conclusion
An excessive rise in either systolic or diastolic blood pressures from early pregnancy to mid 3rd trimester is associated with spontaneous preterm birth in a dose-response pattern.
doi:10.1016/j.ajog.2007.03.053
PMCID: PMC2033381  PMID: 17689635
blood pressure; preeclampsia; preterm birth
15.  Circulating anti-angiogenic factors during hypertensive pregnancy and increased risk of respiratory distress syndrome in preterm neonates 
Objective: To test the hypothesis that high circulating concen-trations of maternal anti-angiogenic factors are associated with increased risk of respiratory distress syndrome (RDS). Study Design: This is a nested case-control study of nulliparous women who delivered less than 37 weeks of gestation within the Calcium for Preeclampsia Prevention (CPEP) trial. The study included 116 women with preeclampsia or gestational hyperten-sion and 323 normotensive controls. Soluble fms-like tyrosine kinase 1 (sFlt1), placental growth factor (PlGF) and soluble endo-glin (sEng) in maternal serum were measured at 21–32 weeks of gestation. Results: Preterm infants born to hypertensive mothers were more likely to develop RDS (22.5% vs. 20.9%, p =0.03). After adjustment for gestational age at delivery, the odds ratio for the relationship between hypertension in pregnancy and RDS was 2.18 (95% CI 1.08–4.39). In hypertensive pregnancies women whose infants developed RDS had significantly higher circulating mean sFlt1 levels during midpregnancy (21–32 weeks of gestation) even after adjustment for gestational age at delivery (21,516 pg/mL vs. 7,000 pg/mL, p =0.01). Conclusions: Preterm preeclampsia and gestational hypertension, charac-terized by high circulating levels of sFlt1, are associated with a twofold increased risk of RDS in infants delivered before 37 weeks. Among women with these hypertensive pregnancies circulating sFlt1 concentrations during midpregnancy were substantially higher in women whose infants developed RDS.
doi:10.3109/14767058.2011.640368
PMCID: PMC3414194  PMID: 22097923
Anti-angiogenic; soluble fms-like tyrosine kinase 1; sVEGF R1; sFlt1; placental growth factor; PlGF; soluble endoglin; sEng; respiratory distress syndrome; RDS; neonate; preterm; preeclampsia; gestational hypertension

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