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1.  Maternal Vitamin B12 Status and Risk of Neural Tube Defects in a Population With High Neural Tube Defect Prevalence and No Folic Acid Fortification 
Pediatrics  2009;123(3):917-923.
Folic acid fortification has reduced neural tube defect prevalence by 50% to 70%. It is unlikely that fortification levels will be increased to reduce neural tube defect prevalence further. Therefore, it is important to identify other modifiable risk factors. Vitamin B12 is metabolically related to folate; moreover, previous studies have found low B12 status in mothers of children affected by neural tube defect. Our objective was to quantify the effect of low B12 status on neural tube defect risk in a high-prevalence, unfortified population.
We assessed pregnancy vitamin B12 status concentrations in blood samples taken at an average of 15 weeks’ gestation from 3 independent nested case-control groups of Irish women within population-based cohorts, at a time when vitamin supplementation or food fortification was rare. Group 1 blood samples were from 95 women during a neural tube defect–affected pregnancy and 265 control subjects. Group 2 included blood samples from 107 women who had a previous neural tube defect birth but whose current pregnancy was not affected and 414 control subjects. Group 3 samples were from 76 women during an affected pregnancy and 222 control subjects.
Mothers of children affected by neural tube defect had significantly lower B12 status. In all 3 groups those in the lowest B12 quartiles, compared with the highest, had between two and threefold higher adjusted odds ratios for being the mother of a child affected by neural tube defect. Pregnancy blood B12 concentrations of <250 ng/L were associated with the highest risks.
Deficient or inadequate maternal vitamin B12 status is associated with a significantly increased risk for neural tube defects. We suggest that women have vitamin B12 levels of >300 ng/L (221 pmol/L) before becoming pregnant. Improving B12 status beyond this level may afford a further reduction in risk, but this is uncertain.
PMCID: PMC4161975  PMID: 19255021
vitamin B12; cobalamin; neural tube defects; folic acid fortification; folate
2.  Lack of Association between Folate-Receptor Autoantibodies and Neural-Tube Defects 
The New England journal of medicine  2009;361(2):152-160.
A previous report described the presence of autoantibodies against folate receptors in 75% of serum samples from women with a history of pregnancy complicated by a neural-tube defect, as compared with 10% of controls. We sought to confirm this finding in an Irish population, which traditionally has had a high prevalence of neuraltube defects.
We performed two studies. Study 1 consisted of analysis of stored frozen blood samples collected from 1993 through 1994 from 103 mothers with a history of pregnancy complicated by a neural-tube defect (case mothers), 103 mothers with a history of pregnancy but no complication by a neural-tube defect (matched with regard to number of pregnancies and sampling dates), 58 women who had never been pregnant, and 36 men. Study 2, conducted to confirm that the storage of samples did not influence the folate-receptor autoantibodies, included fresh samples from 37 case mothers, 22 control mothers, 10 women who had never been pregnant, and 9 men. All samples were assayed for blocking and binding autoantibodies against folate receptors.
In Study 1, blocking autoantibodies were found in 17% of case mothers, as compared with 13% of control mothers (odds ratio, 1.54; 95% confidence interval [CI], 0.70 to 3.39), and binding autoantibodies in 29%, as compared with 32%, respectively (odds ratio, 0.82; 95% CI, 0.44 to 1.50). Study 2 showed similar results, indicating that sample degradation was unlikely.
The presence and titer of maternal folate-receptor autoantibodies were not significantly associated with a neural-tube defect–affected pregnancy in this Irish population.
PMCID: PMC4149290  PMID: 19587340
3.  Correction for Multiplicity in Genetic Association Studies of Triads: The Permutational TDT 
Annals of human genetics  2010;75(2):284-291.
New technology for large-scale genotyping has created new challenges for statistical analysis. Correcting for multiple comparison without discarding true positive results and extending methods to triad studies are among the important problems facing statisticians. We present a one-sample permutation test for testing transmission disequilibrium hypotheses in triad studies, and show how this test can be used for multiple single nucleotide polymorphism (SNP) testing. The resulting multiple comparison procedure is shown in the case of the transmission disequilibrium test to control the familywise error. Furthermore, this procedure can handle multiple possible modes of risk inheritance per SNP. The resulting permutational procedure is shown through simulation of SNP data to be more powerful than the Bonferroni procedure when the SNPs are in linkage disequilibrium. Moreover, permutations implicitly avoid any multiple comparison correction penalties when the SNP has a rare allele. The method is illustrated by analyzing a large candidate gene study of neural tube defects and an independent study of oral clefts, where the smallest adjusted p-values using the permutation procedure are approximately half those of the Bonferroni procedure. We conclude that permutation tests are more powerful for identifying disease-associated SNPs in candidate gene studies and are useful for analysis of triad studies.
PMCID: PMC3117224  PMID: 21108625
Exchangeable; familywise error rate; linkage disequilibrium; power
4.  Association analysis of complex diseases using triads, parent-child dyads and singleton monads 
BMC Genetics  2013;14:78.
Triad families are routinely used to test association between genetic variants and complex diseases. Triad studies are important and popular since they are robust in terms of being less prone to false positives due to population structure. In practice, one may collect not only complete triads, but also incomplete families such as dyads (affected child with one parent) and singleton monads (affected child without parents). Since there is a lack of convenient algorithms and software to analyze the incomplete data, dyads and monads are usually discarded. This may lead to loss of power and insufficient utilization of genetic information in a study.
We develop likelihood-based statistical models and likelihood ratio tests to test for association between complex diseases and genetic markers by using combinations of full triads, parent-child dyads, and affected singleton monads for a unified analysis. A likelihood is calculated directly to facilitate the data analysis without imputation and to avoid computational complexity. This makes it easy to implement the models and to explain the results.
By simulation studies, we show that the proposed models and tests are very robust in terms of accurately controlling type I error evaluations, and are powerful by empirical power evaluations. The methods are applied to test for association between transforming growth factor alpha (TGFA) gene and cleft palate in an Irish study.
PMCID: PMC3844511  PMID: 24007308
Association mapping of complex diseases; Likelihood ratio tests; Transmission disequilibrium tests
5.  Evaluation of 64 Candidate Single Nucleotide Polymorphisms as Risk Factors for Neural Tube Defects in a Large Irish Study Population 
Individual studies of the genetics of neural tube defects (NTDs) contain results on a small number of genes in each report. To identify genetic risk factors for NTDs, we evaluated potentially functional single nucleotide polymorphisms (SNPs) that are biologically plausible risk factors for NTDs but that have never been investigated for an association with NTDs, examined SNPs that previously showed no association with NTDs in published studies, and tried to confirm previously reported associations in folate-related and non-folate-related genes. We investigated 64 SNPs in 34 genes for association with spina bifida in up to 558 case-families (520 cases, 507 mothers, 457 fathers) and 994 controls in Ireland. Case-control and mother-control comparisons of genotype frequencies, tests of transmission disequilibrium, and log-linear regression models were used to calculate effect estimates. Spina bifida was associated with over-transmission of the LEPR (leptin receptor) rs1805134 minor C allele (genotype relative risk (GRR): 1.5; 95% confidence interval (CI): 1.0, 2.1; P = 0.0264) and the COMT (catechol-O-methyltransferase) rs737865 major T allele (GRR: 1.4; 95% CI: 1.1, 2.0; P = 0.0206). After correcting for multiple comparisons, these individual test P-values exceeded 0.05. Consistent with previous reports, spina bifida was associated with MTHFR 677C>T, T (Brachyury) rs3127334, LEPR K109R, and PDGFRA promoter haplotype combinations. The associations between LEPR SNPs and spina bifida suggest a possible mechanism for the finding that obesity is a NTD risk factor. The association between a variant in COMT and spina bifida implicates methylation and epigenetics in NTDs.
PMCID: PMC3503244  PMID: 21204206
congenital abnormalities; folic acid; neural tube defects; single nucleotide polymorphism; spina bifida
6.  Testing reported associations of genetic risk factors for oral clefts in a large Irish study population 
Suggestive, but not conclusive, studies implicate many genetic variants in oral cleft etiology. We used a large, ethnically homogenous study population to test whether reported associations between nonsyndromic oral clefts and 12 genes (CLPTM1, CRISPLD2, FGFR2, GABRB3, GLI2, IRF6, PTCH1, RARA, RYK, SATB2, SUMO1, TGFA) could be confirmed.
Thirty-one single nucleotide polymorphisms (SNPs) in exons, splice sites, and conserved non-coding regions were studied in 509 patients with cleft lip with or without cleft palate (CLP), 383 with cleft palate only (CP), 838 mothers and 719 fathers of patients with oral clefts, and 902 controls from Ireland. Case-control and family-based statistical tests were performed using isolated oral clefts for the main analyses.
In case-control comparisons, the minor allele of PTCH1 A562A (rs2066836) was associated with reduced odds of CLP (OR: 0.29, 95% CI: 0.13–0.64 for homozygotes) whereas the minor allele of PTCH1 L1315P (rs357564) was associated with increased odds of CLP (OR: 1.36, 95% CI: 1.07–1.74 for heterozygotes and OR: 1.56, 95% CI: 1.09–2.24 for homozygotes). The minor allele of one SUMO1 SNP, rs3769817 located in intron 2, was associated with increased odds of CP (OR: 1.45, 95% CI: 1.06–1.99 for heterozygotes). Transmission disequilibrium was observed for the minor allele of TGFA V159V (rs2166975) which was over-transmitted to CP cases (P=0.041).
For 10 of the 12 genes, this is the largest candidate gene study of nonsyndromic oral clefts to date. The findings provide further evidence that PTCH1, SUMO1, and TGFA contribute to nonsyndromic oral clefts.
PMCID: PMC3503531  PMID: 19937600
cleft lip; cleft palate; congenital abnormalities
7.  Assessment of Intrapartum Antibiotic Prophylaxis for the Prevention of Early-onset Group B Streptococcal Disease 
Most early-onset group B streptococcal (GBS) disease in recent years has occurred in newborns of prenatally GBS–negative mothers who missed intrapartum antibiotic prophylaxis (IAP). We aimed to assess the accuracy of prenatal culture in predicting GBS carriage during labor, the IAP use and occurrence of early-onset GBS disease.
We obtained vaginal-rectal swabs at labor for GBS culture from 5497 women of ≥32 weeks gestation and surface cultures at birth from newborns during 2/5/08–2/4/09 at three hospitals in Houston Texas and Oakland California. Prenatal cultures were performed by health care provider during routine care, and culture results obtained from medical records. The accuracy of prenatal culture in predicting intrapartum GBS carriage was assessed by positive (PPV) and negative (NPV) predictive values. Mother-to-newborn transmission of GBS was assessed. Newborns were monitored for early-onset GBS disease.
GBS carriage was 24.5% by prenatal and 18.8% by labor cultures. Comparing prenatal with labor GBS cultures of 4696 women, the PPV was 50.5% and NPV 91.7%. IAP, administered to 93.3% of prenatally GBS-positive women, was 83.7% effective in preventing newborn’s GBS colonization. Mother-to-newborn transmission of GBS occurred in 2.6% of elective Cesarean deliveries. Two newborns developed early-onset GBS disease (0.36/1000 births): one’s prenatal GBS culture was negative, the other’s unknown.
IAP was effective in interrupting mother-to-newborn transmission of GBS. However, ~10% of prenatally GBS-negative women were positive during labor and missed IAP while ~50% of prenatally GBS-positive women were negative during labor and received IAP. These findings emphasize the need for rapid diagnostics during labor.
PMCID: PMC3158245  PMID: 21540758
group B streptococcus; early onset disease; predictive values; prenatal cultures; intrapartum antibiotic prophylaxis
8.  Evaluation of common genetic variants in 82 candidate genes as risk factors for neural tube defects 
BMC Medical Genetics  2012;13:62.
Neural tube defects (NTDs) are common birth defects (~1 in 1000 pregnancies in the US and Europe) that have complex origins, including environmental and genetic factors. A low level of maternal folate is one well-established risk factor, with maternal periconceptional folic acid supplementation reducing the occurrence of NTD pregnancies by 50-70%. Gene variants in the folate metabolic pathway (e.g., MTHFR rs1801133 (677 C > T) and MTHFD1 rs2236225 (R653Q)) have been found to increase NTD risk. We hypothesized that variants in additional folate/B12 pathway genes contribute to NTD risk.
A tagSNP approach was used to screen common variation in 82 candidate genes selected from the folate/B12 pathway and NTD mouse models. We initially genotyped polymorphisms in 320 Irish triads (NTD cases and their parents), including 301 cases and 341 Irish controls to perform case–control and family based association tests. Significantly associated polymorphisms were genotyped in a secondary set of 250 families that included 229 cases and 658 controls. The combined results for 1441 SNPs were used in a joint analysis to test for case and maternal effects.
Nearly 70 SNPs in 30 genes were found to be associated with NTDs at the p < 0.01 level. The ten strongest association signals (p-value range: 0.0003–0.0023) were found in nine genes (MFTC, CDKN2A, ADA, PEMT, CUBN, GART, DNMT3A, MTHFD1 and T (Brachyury)) and included the known NTD risk factor MTHFD1 R653Q (rs2236225). The single strongest signal was observed in a new candidate, MFTC rs17803441 (OR = 1.61 [1.23-2.08], p = 0.0003 for the minor allele). Though nominally significant, these associations did not remain significant after correction for multiple hypothesis testing.
To our knowledge, with respect to sample size and scope of evaluation of candidate polymorphisms, this is the largest NTD genetic association study reported to date. The scale of the study and the stringency of correction are likely to have contributed to real associations failing to survive correction. We have produced a ranked list of variants with the strongest association signals. Variants in the highest rank of associations are likely to include true associations and should be high priority candidates for further study of NTD risk.
PMCID: PMC3458983  PMID: 22856873
Neural tube defects; Spina bifida; Folic acid; One-carbon metabolism; Candidate gene
9.  Maternal vitamin levels in pregnancies affected by congenital malformations other than neural tube defects 
Periconceptional use of folic acid prevents most neural tube defects (NTDs). Whether folic acid and/or multivitamins can prevent other congenital anomalies is not clear. This study tested whether maternal blood levels of folate and vitamin B12 in pregnancies affected by congenital malformations excluding NTDs are lower when compared to non-affected pregnancies.
We measured pregnancy red cell folate (RCF), vitamin B12, and homocysteine (tHcy) concentrations in blood samples taken at the first antenatal clinic in Dublin maternity hospitals in 1986–1990 when vitamin supplementation was rare. The cases were mothers who delivered a baby with a congenital malformation other than NTD identified by the Dublin EUROCAT Registry; controls were a systematic sample of mothers of offspring without congenital malformations from the same hospitals in the same time period.
The median maternal levels of RCF and tHcy did not differ significantly between cases and controls for any of the congenital malformation groups examined (RCF: all malformations 275.9 ug/L v controls 271.2; p=0.77; tHcy: all malformations 7.5 umol/L v controls 7.6; p=0.57). In an unadjusted analysis vitamin B12 was significantly higher in case-mothers whose babies had cleft palate only (p=0.006), musculoskeletal malformations (p=0.034) and midline defects (p=0.039) but not after adjustment for multiple testing.
Our data suggest that low maternal folate and B12 levels or high tHcy levels in early pregnancy are not associated with all congenital malformations excluding NTDs. Fortification with folic acid or B12 may not have a beneficial effect in the prevention of these anomalies.
PMCID: PMC3372895  PMID: 21591245
10.  Permutational Multiple Testing Adjustments With Multivariate Multiple Group Data 
We consider the multiple comparison problem where multiple outcomes are each compared among several different collections of groups in a multiple group setting. In this case there are several different types of hypotheses, with each specifying equality of the distributions of a single outcome over a different collection of groups. Each type of hypothesis requires a different permutational approach. We show that under a certain multivariate condition it is possible to use closure over all hypotheses, although intersection hypotheses are tested using Boole’s inequality in conjunction with permutation distributions in some cases. Shortcut tests are then found so that the resulting testing procedure is easily performed. The error rate and power of the new method is compared to existing competitors through simulation of correlated data. An example is analyzed, consisting of multiple adverse events in a clinical trial.
PMCID: PMC3080701  PMID: 21516184
Adverse Events; Closed Testing; Exchangeability; Familywise Error Rate; Power
11.  Multiple McNemar Tests 
Biometrics  2010;66(4):1185-1191.
Methods for performing multiple tests of paired proportions are described. A broadly applicable method using McNemar's exact test and the exact distributions of all test statistics is developed; the method controls the familywise error rate in the strong sense under minimal assumptions. A closed form (not simulation-based) algorithm for carrying out the method is provided. A bootstrap alternative is developed to account for correlation structures. Operating characteristics of these and other methods are evaluated via a simulation study. Applications to multiple comparisons of predictive models for disease classification and to post-market surveillance of adverse events are given.
PMCID: PMC2902578  PMID: 20345498
Bonferroni-Holm; Bootstrap; Discreteness; Exact Tests; Multiple Comparisons; Post-Market Surveillance; Predictive Model
12.  A prospective evaluation of antral follicle function in women with 46,XX spontaneous primary ovarian insufficiency 
Fertility and sterility  2009;94(5):1769-1774.
To assess ovarian follicle function in women with 46,XX spontaneous primary ovarian insufficiency
Case-control with nested prospective cohort
Clinical Research Center, National Institutes of Health
Women with primary ovarian insufficiency without estrogen replacement for two weeks (N=97) and regularly menstruating control women (N=42)
Single injection of 300 IU hrFSH
Main outcome measures
Change in serum estradiol at 24 hours
Antral follicles ≥ 3 mm were detected in 73% (69/95) of patients; both serum estradiol and progesterone levels correlated significantly with maximum follicle diameter in these women. Patients with a maximum follicle diameter ≥ 8 mm had significantly higher serum estradiol and progesterone levels and significantly lower FSH and LH levels as compared to patients without such follicles. In controls estradiol levels increased significantly after FSH administration but in patients this was not the case despite the presence of an antral follicle ≥ 8 mm.
Most women with 46,XX spontaneous primary ovarian insufficiency have antral follicles detectable by ultrasound, suggesting that down-regulation of FSH receptors is not the predominant mechanism of follicle dysfunction. Evidence of progesterone secretion by antral follicles ≥ 8 mm in these patients is consistent with prior histologic evidence that follicle luteinization is the predominant mechanism of follicle dysfunction in this condition. Prospective controlled investigation designed to improve ovulatory function and fertility in these women is indicated.
PMCID: PMC2888894  PMID: 19939372
Primary ovarian insufficiency; hypergonadotropic hypogonadism; premature ovarian failure; premature menopause; lutienized Graafian follicle
13.  Multiple Testing with Minimal Assumptions 
Resampling-based multiple testing methods that control the Familywise Error Rate in the strong sense are presented. It is shown that no assumptions whatsoever on the data-generating process are required to obtain a reasonably powerful and flexible class of multiple testing procedures. Improvements are obtained with mild assumptions. The methods are applicable to gene expression data in particular, but more generally to any multivariate, multiple group data that may be character or numeric. The role of the disputed “subset pivotality” condition is clarified.
PMCID: PMC3117234  PMID: 18932134
Bootstrap; Exchangeability; Permutation; Resampling; Subset pivotality
14.  Women with spontaneous 46,XX primary ovarian insufficiency (hypergonadotropic hypogonadism) have lower perceived social support than control women 
Fertility and sterility  2008;92(2):688-693.
To test the hypothesis that women with spontaneous primary ovarian insufficiency differ from control women with regard to perceived social support and to investigate the relationship between perceived social support and self-esteem.
Mark O. Hatfield Clinical Research Center, National Institutes of Health.
Women diagnosed with spontaneous primary ovarian insufficiency (N=154) at a mean age of 27 years and healthy control women (N=63).
Administration of validated self-reporting instruments.
Main Outcome Measure(s)
Personal Resource Questionnaire-85 (PRQ85), Rosenberg Self-Esteem Scale
Women with primary ovarian insufficiency had significantly lower scores than controls on the perceived social support scale and the self-esteem scale. The findings remained significant after modeling with multivariate regression for differences in age, marital status, and having children. In patients there was a significant positive correlation between self-esteem scores and perceived social support. We found no significant differences in perceived social support or self-esteem related to marital status, whether or not they had children, or time since diagnosis.
This evidence supports the need for prospective controlled studies. Strategies to improve social support and self-esteem might provide a therapeutic approach to reduce the emotional suffering that accompanies the life-altering diagnosis of spontaneous primary ovarian insufficiency.
PMCID: PMC2734403  PMID: 18829005
Primary ovarian insufficiency; hypergonadotropic hypogonadism; premature ovarian failure; premature menopause; infertility; coping; perceived social support; self-esteem
15.  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.
PMCID: PMC2657230  PMID: 19178434
conditional distribution; genetic risk model; likelihood ratio test; power
16.  Sexual function in young women with spontaneous 46,XX primary ovarian insufficiency 
Fertility and sterility  2007;90(5):1805-1811.
To assess sexual function in women with spontaneous 46,XX primary ovarian insufficiency after at least 3 months of a standardized hormone replacement regimen.
Cross-sectional cohort, controlled
National Institutes of Health Clinical Research Center
Women with primary ovarian insufficiency (N=143) and regularly menstruating controls (N=70).
Self-administered questionnaires; 100 micrograms/day estradiol patch, oral medroxyprogesterone acetate 10 mg for 12 days each month for patients
Main Outcome Measure(s)
Derogatis Interview for Sexual Function Self Report (DISF-SR)
Women with primary ovarian insufficiency had significantly lower DISF-SR composite scores as compared to control women. Their serum total testosterone levels were significantly correlated with DISF-SR composite score (r=0.20, P=0.03), although this accounted for only 4% of the variance in this measure. Patients with testosterone levels below normal tended to have lower DISF-SR composite scores. Of patients with primary ovarian insufficiency 9/127 (7%) scored below the 2nd centile on the composite sexual function score compared to 1/49 (2%) of control women (difference not statistically significant).
As assessed by the DISF-SR, sexual function is in the normal range for most young women with 46,XX spontaneous primary ovarian insufficiency who are receiving physiologic estradiol replacement. However, as a group, these young women score significantly lower on this sexual function scale than control women.
Sexual function is in the normal range for most young women with 46,XX spontaneous primary ovarian insufficiency who are receiving physiologic estradiol replacement.
PMCID: PMC2592535  PMID: 17961560
sexual function; primary ovarian insufficiency; premature ovarian failure; premature menopause; primary hypogonadism; hypergonadotropic hypogonadism; hypergonadotropic amenorrhea; hormone replacement therapy; estrogen; testosterone
17.  Eye Malformations in Children with Heavy Alcohol Exposure in Utero 
The Journal of pediatrics  2008;153(3):391-395.
To determine whether children who do not develop fetal alcohol syndrome (FAS) despite heavy alcohol exposure are at risk for eye abnormalities
Study design
We screened 9628 pregnant women and identified 101 women who were drinking ≥ 2 ounces of absolute alcohol per day and 101 non-drinking control women. We followed 43 exposed and 55 control offspring ages 4 to 9 years and performed masked, standardized ophthalomologic exams.
The groups did not differ in their rates of impaired visual acuity, refractory errors, ptosis, epicanthal folds, or short palpebral fissures. Biomicroscopy examinations were normal in all exposed subjects; two (4%) controls and no exposed had cataracts. Seven (16%) exposed subjects versus 8 (15%) controls had arterial tortuosity. No subjects had optic nerve hypoplasia.
Previous research has reported that children with FAS have a high incidence of serious ophthalmologic defects; our data show that the risk is limited to children with FAS, not children exposed to high levels of alcohol prenatally but who do not develop FAS. Eye examinations are unlikely to clarify the diagnosis in children suspected of having alcohol related damage.
PMCID: PMC2570183  PMID: 18571671
Fetal Alcohol Syndrome; visual acuity; ocular malformations; birth defects; alcohol; eye; optic nerve hypoplasia
18.  Testing for Group Effect in a 2 × k Heteroscedastic ANOVA Model 
It is natural to want to relax the assumption of homoscedasticity and Gaussian error in ANOVA models. For a two-way ANOVA model with 2 × k cells, one can derive tests of main effect for the factor with two levels (referred to as group) without assuming homoscedasticity or Gaussian error. Empirical likelihood can be used to derive testing procedures. An approximate empirical likelihood ratio test (AELRT) is derived for the test of group main effect. To approximate the distributions of the test statistics under the null hypothesis, simulation from the approximate empirical maximum likelihood estimate (AEMLE) restricted by the null hypothesis is used. The homoscedastic ANOVA F-test and a Box-type approximation to the distribution of the heteroscedastic ANOVA F-test are compared to the AELRT in level and power. The AELRT procedure is shown by simulation to have appropriate type I error control (although possibly conservative) when the distribution of the test statistics are approximated by simulation from the constrained AEMLE. The methodology is motivated and illustrated by an analysis of folate levels in the blood among two alcohol intake groups while accounting for gender.
PMCID: PMC2662692  PMID: 18663763
Empirical likelihood; Likelihood ratio test; Power; Simulation
19.  Folate-Related Gene Polymorphisms as Risk Factors for Cleft Lip and Cleft Palate 
Cleft lip with or without cleft palate (CLP) and cleft palate only (CPO) have an inherited component and, many studies suggest, a relationship with folate. Attempts to find folate-related genes associated with clefts have, however, often been inconclusive. This study examined four SNPs related to folate metabolism (MTHFR 677 C→T, MTHFR 1298 A→C, MTHFD1 1958 G→A, and TC II 776 C→G) in a large Irish population to clarify their relationship with clefts.
Cases and their parents were recruited from major surgical centers performing cleft repairs in Ireland and a support organization. Data on risk factors, medical history, and DNA were collected. Controls were pregnant women from the greater Dublin area (n = 1,599).
CLP cases numbered 536 and CPO cases 426 after exclusions. CPO mothers were significantly more likely than controls to be MTHFR 677 TT, OR 1.50 (95% CI: 1.05–2.16; p = .03). Log-linear analysis showed a borderline association (p = .07). Isolated CPO case mothers were significantly more likely than controls to be homozygous for the MTHFD1 1958 G→A variant, OR 1.50 (95%CI: 1.08–2.09; p = .02). When multiple cases were added, both CPO cases and case mothers were significantly more likely to be AA (p = .02 and p = .007, respectively). The CLP case-control and mother-control analyses also showed significant effects, ORs 1.38 (95% CI: 1.05–1.82; p = .03) and 1.39 (95% CI: 1.04–1.85; p = .03), respectively.
Associations were found for both CPO and CLP and MTHFD1 1958 G→A in cases and case mothers. MTHFR 677 C→T could be a maternal risk factor for clefts but the association was not strong. Because multiple comparisons were made, these findings require additional investigation. Given the known association between MTHFD1 1958 G→A and NTDs, these findings should be explored in more detail.
PMCID: PMC2670560  PMID: 18661527
cleft lip; cleft palate; oral clefts; folate; folate genes; vitamin B12; transcobalamin gene
20.  Normalization of serum LH levels in women with 46,XX spontaneous primary ovarian insufficiency 
Fertility and sterility  2007;89(2):429-433.
To determine the proportion of women with primary ovarian insufficiency who achieve normal serum LH levels on transdermal estradiol therapy.
National Institutes of Health Clinical Center
Women with spontaneous primary ovarian insufficiency (N=137) and 70 regularly menstruating control women (N=70).
Main Outcome Measure(s)
Serum LH
Blood sampled from controls in the mid-follicular phase and from patients while off estradiol for 2 weeks, then again 3 months later during the estradiol-only phase of replacement (100 micrograms/day estradiol patch, oral medroxyprogesterone acetate 10 mg for 12 days each month).
While on transdermal estradiol therapy significantly more women (51.1%, 70/137, 95% confidence interval 42%, 60%) had serum LH levels in the normal range (5/137, 3.9% at baseline). Mean (SD) serum estradiol level significantly increased on therapy to 95.4 (84.9) pg/mL.
A regimen of 100 microgram per day of transdermal estradiol replacement achieves normal serum LH levels in approximately one-half of women with spontaneous primary ovarian insufficiency. Theoretically, by avoiding inappropriate luteinization, physiologic estradiol replacement therapy might improve follicle function in these women. Controlled studies to assess the effect of transdermal estradiol replacement on follicle function in these women are warranted.
PMCID: PMC2350200  PMID: 17509587
transdermal estradiol therapy; premature ovarian failure; premature menopause; primary ovarian insufficiency; primary hypogonadism; hypergonadotropic hypogonadism; LH; FSH; hormone replacement therapy

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