Assessing Methods for Evaluating the Number of Components in Non-Negative Matrix Factorization.

Non-negative matrix factorization is a relatively new method of matrix decomposition which factors an m×n data matrix X into an m×k matrix W and a k×n matrix H, so that X≈W×H. Importantly, all values in X, W, and H are constrained to be non-negative. NMF can be used for dimensionality reduction, since the k columns of W can be considered components into which X has been decomposed. The question arises: how does one choose k? In this paper, we first assess methods for estimating k in the context of NMF in synthetic data. Second, we examine the effect of normalization on this estimate's accuracy in empirical data. In synthetic data with orthogonal underlying components, methods based on PCA and Brunet's Cophenetic Correlation Coefficient achieved the highest accuracy. When evaluated on a well-known real dataset, normalization had an unpredictable effect on the estimate. For any given normalization method, the methods for estimating k gave widely varying results. We conclude that when estimating k, it is best not to apply normalization. If underlying components are known to be orthogonal, then Velicer's MAP or Minka's Laplace-PCA method might be best. However, when orthogonality of the underlying components is unknown, none of the methods seemed preferable.

Diabetes, medical comorbidities and couple fecundity.

STUDY QUESTION: What is the relationship between couple's health and fecundity in a preconception cohort? SUMMARY ANSWER: Somatic health may impact fecundity in men and women as couples whose male partner had diabetes or whose female partner had two or more medical conditions had a longer time-to-pregnancy (TTP). WHAT IS ALREADY KNOWN: The impact of somatic health on human fecundity is hypothesized given the reported declines in spermatogenesis and ovulation among individuals with certain medical comorbidities. STUDY DESIGN, SIZE, DURATION: A population-based prospective cohort study recruiting couples from 16 counties in Michigan and Texas (2005-2009) using sampling frameworks allowing for identification of couples planning pregnancy in the near future. Five hundred and one couples desiring pregnancy and discontinuing contraception were followed-up for 12 months or until a human chorionic gonadotropin pregnancy was detected. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: In all, 33 (21.4%) female and 41 (26.6%) male partners had medical conditions at baseline. MAIN RESULTS AND THE ROLE OF CHANCE: Couples' medical comorbidity was associated with pregnancy status. Diabetes in either partner was associated with diminished fecundity, as measured by a longer TTP. Specifically, fecundability odds ratios (FORs) were below 1, indicating a longer TTP, for male partners with diabetes (0.35, 95% confidence interval (CI): 0.14-0.86) even in adjusted models (0.35, 95% CI: 0.13-0.88). Female partners with diabetes had comparable reductions in FORs; however, the analyses did not reach statistical significance (0.26, 95% CI: 0.03-1.98). Female partners with two or more medical conditions had a significantly longer TTP compared with women with no health problems (0.36, 95% CI: 0.14-0.92). Importantly, the presence of medical conditions was not associated with sexual frequency. We cannot rule out residual confounding, Type 2 errors for less prevalent medical conditions, or chance findings in light of the multiple comparisons made in the analysis. LIMITATIONS, REASONS FOR CAUTION: The findings require cautious interpretation given that medical diagnoses are subject to possible reporting errors, although we are unaware of any potential biases that may have been introduced, as participants were unaware of how long it would take to become pregnant upon enrollment. WIDER IMPLICATIONS OF THE FINDINGS: The current report suggests a relationship between male and female diabetes and fecundity, and possibly somatic health more globally. Moreover, while the mechanism is uncertain, if corroborated, our data suggest that early evaluation and treatment may be warranted for diabetics prior to attempting to conceive. STUDY FUNDING/COMPETING INTERESTS: Intramural research of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Contract nos. #N01-HD-3-3355, N01-HD-3-3356 and N01-HD-3-3358). The authors have no conflicts of interest to declare.

Urinary paracetamol and time-to-pregnancy.

STUDY QUESTION: Is preconception urinary paracetamol (acetaminophen) associated with time-to-pregnancy (TTP)? SUMMARY ANSWER: Higher urinary paracetamol concentrations among male partners were associated with a longer TTP. WHAT IS KNOWN ALREADY: Paracetamol is a commonly used analgesic among women and men of all ages. As metabolites of select chemicals used in the manufacturing of polyurethane foam, dyes and various industrial products, as well as a common medicinal product, paracetamol and its primary metabolite p-aminophenol, are ubiquitous in the environment. Studies investigating the relationship between adult urinary concentrations of paracetamol and TTP are lacking. STUDY DESIGN, SIZE, DURATION: This prospective cohort included 501 couples discontinuing contraception for the purposes of attempting conception during the years 2005-2009 and residing in Michigan or Texas, USA. PARTICIPANTS/MATERIALS, SETTING, METHODS: Total urinary paracetamol, its metabolite para-aminophenol (p-aminophenol), and a summary measure of both urinary biomarkers were quantified by ultra-performance liquid chromatography coupled with an electrospray triple quadrupole mass spectrometry (UPLC-ESI-MS/MS). Female partners used the Clearblue® digital home test to confirm pregnancy. Cox's proportional odds models for discrete survival time were used to estimate fecundability odds ratios (FORs) and 95% confidence intervals (CIs), adjusting for age, body mass index (BMI), urinary creatinine, preconception smoking status, race/ethnicity and household income. Models were further adjusted for hypothyroidism and hypertension as an attempt to account for possible indications of paracetamol medication use. FOR estimates <1.0 denote a longer TTP (diminished fecundity). Models were performed to examine urinary concentrations of paracetamol as a continuous and variable or categorized into quartiles. In light of TTP being a couple-dependent outcome, models were first performed for females and males, modeled separately, and then modeled for couples with each partner's concentrations being adjusted for the other. MAIN RESULTS AND THE ROLE OF CHANCE: Among the 501 enrolled couples, 347 (69%) had an human chorionic gonadotrophin confirmed pregnancy. Urinary concentrations of paracetamol were lowest among females and males who achieved pregnancy and p-aminophenol concentrations were lowest among those not achieving pregnancy. Urinary paracetamol concentrations were higher among female than male partners (Median = 26.6 and 13.2 ng/ml, respectively; P < 0.0001). After adjustment for age, BMI, urinary creatinine, preconception smoking status, race/ethnicity and household income, the highest quartile of male urinary paracetamol was associated with a longer TTP [FOR = 0.67; 95% CI = (0.47, 0.95)]. This association remained after adjustment for chronic health conditions, hypothyroidism and hypertension and female partner's urinary paracetamol concentration [FOR = 0.65; 95% CI = (0.45, 0.94)]. No associations were observed between female or male partners' urinary concentrations of paracetamol or of its metabolite p-aminophenol when urinary concentrations were modeled continuously. LIMITATIONS, REASONS FOR CAUTION: Only a single spot urine was available for analysis despite the short-lived nature of paracetamol. Additionally, participants were not asked to provide information on indication of use for paracetamol medications; any underlying conditions for the paracetamol use would have been potential confounders. WIDER IMPLICATIONS OF THE FINDINGS: If corroborated with more robust studies, findings from our exploratory analysis may have both clinical and public health relevance among reproductive aged individuals, including those trying for pregnancy, given the prevalent use of paracetamol/acetaminophen medications and the ubiquitous nature of paracetamol in the environment. STUDY FUNDING/COMPETING INTERESTS: This research was supported by the National Institutes of Health, Intramural Research Program, and Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts N01-HD-3-3355; N01-HD-3-3356; NOH-HD-3-3358; HHSN27500001/HHSN27500001). None of the authors have any conflicts to declare.

Time-to-Pregnancy Associated With Couples' Use of Tobacco Products.

INTRODUCTION: Previous studies suggest female smoking increases time-to-pregnancy (TTP), a couple-dependent reproductive outcome, while associations with male smoking are more ambiguous. Furthermore, despite small increases in smokeless tobacco use in the United States, no prior study has evaluated TTP among smokeless tobacco users. METHODS: Using population-based sampling in 16 counties in Michigan and Texas, 501 couples discontinuing contraception to become pregnant were followed until positive pregnancy test or 12 months of trying. Participants were interviewed on lifetime and current cigarette, cigar, and chew/snuff (smokeless) use and provided blood samples for quantification of heavy metals and cotinine. Fecundability odds ratios (FORs) and 95% confidence intervals (95% CIs) were estimated, adjusted for demographics/lifestyle. FORs less than 1 reflect longer TTP. RESULTS: Eleven percentage of females and 15% of males smoked cigarettes. Among men, 14% smoked cigars, 9% used snuff, and 2% used chew. Compared with never tobacco users, male (FOR: 0.41, 95% CI: 0.24, 0.68) and female (FOR: 0.53, 95% CI: 0.33, 0.85) smoking were individually associated with longer TTP; males' smoking remained significant (FOR: 0.46, 95% CI: 0.27, 0.79) when modeling partners together. Cadmium levels were higher in smokers than smokeless tobacco and never users; adjusting for cadmium attenuated the cigarette-TTP association, particularly among women. TTP was shorter among smokeless tobacco users relative to smokers (FOR: 2.86, 95% CI: 1.47, 5.57). CONCLUSIONS: Compared with never users, smokeless tobacco did not alter TTP in our cohort; however, TTP was shorter compared with smokers. We observed longer TTP in male and female smokers; cadmium may partially contribute. IMPLICATIONS: Both partners' preconception smoking contributed to longer TTP, highlighting the importance of both partners' lifestyles in healthy reproduction and underscores the need for couple-based preconception guidance. The male's contribution is a new finding. Higher cadmium levels may partially contribute to longer TTP in smokers, particularly among females. Though we do not observe longer TTP among a small sample of smokeless tobacco users compared with never tobacco users, we observe shorter TTP compared with smokers. Further work is needed to more thoroughly delineate the relationship between smokeless tobacco use and TTP and possible mechanisms of tobacco use's effects on reproduction.

Lifestyle and pregnancy loss in a contemporary cohort of women recruited before conception: The LIFE Study.

OBJECTIVE: To estimate pregnancy loss incidence in a contemporary cohort of couples whose lifestyles were measured during sensitive windows of reproduction to identify factors associated with pregnancy loss for the continual refinement of preconception guidance. DESIGN: Prospective cohort with preconception enrollment. SETTING: Sixteen counties in Michigan and Texas. PATIENT(S): Three hundred forty-four couples with a singleton pregnancy followed daily through 7 postconception weeks of gestation. INTERVENTION(S): None. Couples daily recorded use of cigarettes, caffeinated and alcoholic beverages, and multivitamins. Women used fertility monitors for ovulation detection and digital pregnancy tests. Pregnancy loss was denoted by conversion to a negative pregnancy test, onset of menses, or clinical confirmation depending upon gestation. Using proportional hazards regression and accounting for right censoring, we estimated adjusted hazard ratios and 95% confidence intervals (aHR, 95% CI) for couples' lifestyles (cigarette smoking, alcoholic and caffeinated drinks, multivitamins) during three sensitive windows: preconception, early pregnancy, and periconception. MAIN OUTCOME MEASURE(S): Incidence and risk factors for pregnancy loss. RESULT(S): Ninety-eight of 344 (28%) women with a singleton pregnancy experienced an observed pregnancy loss. In the preconception window, loss was associated with female age ≥35 years (1.96, 1.13-3.38) accounting for couples' ages, women's and men's consumption of >2 daily caffeinated beverages (1.74, 1.07-2.81; and 1.73, 1.10-2.72, respectively), and women's vitamin adherence (0.45, 0.25-0.80). The findings were similar for lifestyle during the early pregnancy and periconception windows. CONCLUSION(S): Couples' preconception lifestyle factors were associated with pregnancy loss, although women's multivitamin adherence dramatically reduced risk. The findings support continual refinement and implementation of preconception guidance.

Persistent organic pollutants and pregnancy complications.

We sought to investigate the relationship between maternal preconception exposures to persistent organic pollutants (POPs) and pregnancy complications, gestational diabetes (GDM) and gestational hypertension. Data from 258 (51%) women with human chorionic gonadotropin (hCG) confirmed pregnancies reaching ≥24weeks gestation, from a prospective cohort of 501 couples who discontinued contraception to attempt pregnancy, were analyzed. Preconception concentrations of 9 organochlorine pesticides (OCPs) and 10 polybrominated diphenyl ethers (PBDEs) were quantified in serum. In separate multiple logistic regression models of self-reported physician diagnosed outcomes: GDM (11%) and gestational hypertension (10%), chemicals were natural log-transformed and rescaled by their standard deviation (SD). Models were adjusted for serum lipids, and then adjusted for age, body mass index, race, and smoking. Models were additionally adjusted for the sum of the remaining POPs in each chemical class. Women's serum concentration of PBDE congener 153 (PBDE-153) was positively associated with an increased odds of GDM per SD increase in log-transformed concentration, for unadjusted (OR=1.36, 95%CI: 1.02-1.81), a priori adjusted (OR=1.38, 95% CI: 1.03-1.86) and with the sum of remaining PBDEs (OR=1.79, 95% CI: 1.18, 2.74) models. Our findings suggest that at environmentally relevant concentrations, maternal exposure to POPs prior to conception may contribute to increased chance of developing GDM.

Pre-pregnancy maternal exposure to polybrominated and polychlorinated biphenyls and gestational diabetes: a prospective cohort study.

BACKGROUND: While several studies have shown an association between environmental pollutants and diabetes among non-pregnant adults, few studies have prospectively assessed the association among pregnant women. We estimated the association between maternal pre-pregnancy levels of a polybrominated biphenyl (PBB 153) and 36 polychlorinated biphenyls (PCBs) with gestational diabetes (GDM). METHODS: Data are from women (18-40 years) participating in a prospective cohort who achieved pregnancy lasting ≥24 weeks gestation and completed monthly pregnancy journals (n = 258). Women were recruited between 2005 and 2007 from 16 counties in Michigan and Texas. Women who ever reported a physician diagnosis of high blood glucose in monthly pregnancy journals were categorized as having gestational diabetes (n = 28; 10.9 %). Multivariable binary logistic regression was used to estimate odds ratios (OR) and 95 % confidence intervals (CIs). RESULTS: There was no association between PBB 153 and GDM or any of the PCB congeners and GDM in unadjusted models. All associations remained non-significant with stepwise adjustment for age and waist-to-height ratio. Only with further adjustment for total serum lipids did the associations become significant, with lower levels of nine PCB congeners associated with GDM: 138, 153, 156, 167, 170, 172, 178, 180, and 194. The adjusted ORs for PCBs 170 and 180 were the strongest: 0.40 (0.18, 0.88) and 0.41 (0.19, 0.87), respectively. CONCLUSIONS: Pre-pregnancy levels of PCBs were not consistently associated with development of GDM in this prospective cohort of U.S. women. Interestingly, we found that although women with GDM had higher mean pre-pregnancy circulating lipid levels compared to women without GDM, they had lower wet weight circulating levels of many PCBs. More research is needed to understand the dynamic fluctuations of PCBs and other persistent organic pollutants between lipid compartments in women preparing to conceive and throughout pregnancy.

Parental urinary biomarkers of preconception exposure to bisphenol A and phthalates in relation to birth outcomes.

BACKGROUND: Bisphenol A (BPA) and phthalates are ubiquitous non-persistent endocrine disrupting chemicals whose relation with infant birth size is not clearly understood. METHODS: We examined associations between maternal and paternal preconception urinary concentrations of total BPA and 14 phthalate metabolites and birth size for 233 infants. Multiple linear regression models were used to estimate parental quartiles of BPA and phthalates in relation to birth weight, length, head circumference, and ponderal index with separate models run for each parent adjusting for age, smoking, body mass index, education, alcohol, parity, and creatinine. Models also included an interaction term for each chemical and infant sex and were further adjusted to include the other partner's chemical concentrations. RESULTS: In maternal models adjusted for partner's exposure and covariates, reductions in birth weight (range: 178-215 g; p < 0.05) were observed for the 2nd quartile of maternal monomethyl phthalate, mono-[(2-carboxymethyl) hexyl] phthalate and mono-n-octyl phthalate when compared with the 1st quartiles. The 3rd quartile of monoethylhexyl phthalate (mEHP) was also associated with a 200.16 g (95 % CI: -386.90, -13.42) reduction. Similar reductions in birth weight were observed for the 2(nd) quartile of paternal mEHP (ß = -191.93 g; 95 % CI: -381.61, -2.25). Additionally, select maternal urinary metabolites were associated with decreased head circumference, birth length and gestational age. However, paternal concentrations were generally associated with increased birth length and gestational age. CONCLUSIONS: We observed some suggestion that preconception maternal and paternal urinary concentration of BPA and specific phthalate metabolites may be associated with smaller birth size and increased gestational age, though the findings appeared to be parent and chemical specific.

Clustering of retrospectively reported and prospectively observed time-to-pregnancy.

PURPOSE: Given reportedly high clustering but limited validity of retrospectively reported time-to-pregnancy (TTP), we assessed within-woman clustering for retrospectively reported TTPs alone and including gold-standard prospectively observed TTPs among women with 2 or more retrospectively reported and 1 or more prospectively observed TTPs. We further investigated whether past trying times inform future trying time among women with 1 or more retrospectively reported and 1 or more prospectively observed TTPs. METHODS: Five hundred one couples attempting pregnancy were prospectively observed until human chorionic gonadotropin pregnancy or 12 months of trying. Women reported TTP for past planned pregnancies. Clustering as measured by the frailty variance was estimated using discrete Cox frailty models, adjusted for age, body mass index, smoking at each attempt. Utility of past attempts to inform future attempts was assessed with discrete Cox models and relative risk regression, adjusted for enrollment age, body mass index, smoking. RESULTS: Seventy-five women with 2 or more prior pregnancies contributed 180 retrospective and 91 prospective TTPs for frailty modeling. Retrospectively reported TTP clustering was high (frailty variance = 0.89) but substantially lower when including prospectively observed TTPs (frailty variance = 0.42). Among 202 women with 1 or more prior pregnancies, past trying times did not inform future trying time. CONCLUSIONS: TTP recall rather than TTP may account for clustering. Past trying times may not inform future trying times.

Birth outcomes and background exposures to select elements, the Longitudinal Investigation of Fertility and the Environment (LIFE).

Evidence suggests that trace exposures to select elements may increase the risk for adverse birth outcomes. To investigate further, we used multiple regression to assess associations between preconception parental exposures to Pb, Cd, and total Hg in blood, and 21 elements in urine, with n=235 singleton birth outcomes, adjusted for confounders and partner's exposure. Earlier gestational age at delivery (GA) was associated with higher tertiles of urine maternal W (-1.22 days) and paternal U (-1.07 days), but GA was later for higher tertiles of maternal (+1.11 days) and paternal (+1.30 days) blood Hg. Additional analysis indicated shorter GA associated with higher paternal urine Ba, W, and U, and with higher maternal blood Pb for boys, but GA was longer in association with higher maternal urine Cr. Birth weight (BW) was lower for higher tertiles of paternal urine Cs (-237.85g), U (-187.34g), and Zn (-209.08g), and for higher continuous Cr (P=0.021). In contrast, BW was higher for higher tertiles of paternal urine As (+194.71g) and counterintuitively for maternal blood Cd (+178.52g). Birth length (BL) was shorter for higher tertiles of urine maternal W (-1.22cm) and paternal U (-1.10cm). Yet, higher tertiles of maternal (+1.11cm) and paternal (+1.30) blood Hg were associated with longer BL. Head circumference at delivery was lower for higher tertiles of paternal urine U (-0.83cm), and for higher continuous Mo in boys (-0.57cm). Overall, associations were most consistently indicated for GA and measures of birth size with urine W and U, and paternal exposures were more frequently associated than maternal. Though limited by several factors, ours is the largest multi-element investigation of prospective couple-level trace exposures and birth outcomes to date; the novel observations for W and U merit further investigation.

Preconception maternal and paternal exposure to persistent organic pollutants and birth size: the LIFE study.

BACKGROUND: Persistent organic pollutants (POPs) are developmental toxicants, but the impact of both maternal and paternal exposures on offspring birth size is largely unexplored. OBJECTIVE: We examined associations between maternal and paternal serum concentrations of 63 POPs, comprising five major classes of pollutants, with birth size measures. METHODS: Parental serum concentrations of 9 organochlorine pesticides, 1 polybrominated biphenyl (PBB), 7 perfluoroalkyl chemicals (PFCs), 10 polybrominated diphenyl ethers (PBDEs), and 36 polychlorinated biphenyls (PCBs) were measured before conception for 234 couples. Differences in birth weight, length, head circumference, and ponderal index were estimated using multiple linear regression per 1-SD increase in natural log-transformed (ln-transformed) chemicals. Models were estimated separately for each parent and adjusted for maternal age, maternal prepregnancy body mass index (kilograms per meter squared) and other confounders, and all models included an interaction term between infant sex and each chemical. RESULTS: Among girls (n = 117), birth weight was significantly lower (range, 84-195 g) in association with a 1-SD increase in ln-transformed maternal serum concentrations of DDT, PBDE congeners 28 and 183, and paternal serum concentrations of PBDE-183 and PCB-167. Among boys (n = 113), maternal (PCBs 138, 153, 167, 170, 195, and 209 and perfluorooctane sulfonamide) and paternal (PCBs 172 and 195) serum concentrations of several POPs were statistically associated with lower birth weight (range, 98-170 g), whereas paternal concentrations of PBDEs (66, 99) were associated with higher birth weight. Differences in offspring head circumference, length, and ponderal index were also associated with parental exposures. CONCLUSIONS: Preconceptional maternal and paternal concentrations of several POPs were associated with statistically significant differences in birth size among offspring.

A prospective study of prepregnancy serum concentrations of perfluorochemicals and the risk of gestational diabetes.

OBJECTIVE: To examine preconception serum concentrations of perfluorooctanoic acid (PFOA) and six other PFCs in relation to gestational diabetes (GDM) risk. DESIGN: Prospective cohort with longitudinal follow-up. SETTING: Not applicable. PATIENT(S): Among 501 women recruited upon discontinuing contraception for the purpose of becoming pregnant, 258 (51%) became pregnant and were eligible for the study, of which 28 (11%) reported having physician-diagnosed GDM during follow-up. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The odds ratios (ORs) and 95% confidence intervals (CIs) of GDM associated with each standard deviation (SD) increment of preconception serum PFOA concentration (ng/mL, log-transformed) and six other PFCs were estimated with the use of logistic regression after adjusting for age, prepregnancy body mass index, smoking, and parity conditional on gravidity. RESULT(S): Preconception geometric mean (95% CI) PFOA concentrations (in ng/mL) were higher for women with than without GDM (3.94 [3.15-4.93] vs. 3.07 [2.83-3.12], respectively). Each SD increment in PFOA was associated with a 1.87-fold increased GDM risk (adjusted OR 1.86 [95% CI 1.14-3.02]). A slightly increased risk associated with each SD increment for the six other PFCs was observed as well (all ORs >1.0, range 1.06-1.27), although the associations were not statistically significant. CONCLUSION(S): Our findings suggested that higher environmentally relevant concentrations of PFOA were significantly associated with an increased risk of GDM. If corroborated, these findings may be suggestive of a possible environmental etiology for GDM.

Urinary concentrations of benzophenone-type ultraviolet radiation filters and couples' fecundity.

Concern has arisen about benzophenone (BP) ultraviolet (UV) radiation filters, given their use in sunscreen and personal-care products and their reported estrogenic and antiandrogenic activity. We recruited 501 couples who were discontinuing use of contraceptives in order to become pregnant for the Longitudinal Investigation of Fertility and the Environment (LIFE) Study (Michigan and Texas, 2005-2009). Couples provided urine specimens and completed daily journals until they either achieved pregnancy or had tried for 12 months. Women used fertility monitors to time sexual intercourse and digital pregnancy tests. Urinary concentrations of 5 UV filters (ng/mL) were determined using triple-quadrupole mass spectrometry: 2,4-dihydroxybenzophenone (also called BP-1); 2,2',4,4'-tetrahydroxybenzophenone (BP-2); 2-hydroxy-4-methoxybenzophenone (BP-3); 2,2'-dihydroxy-4-methoxybenzophenone (BP-8); and 4-hydroxybenzophenone. Fecundability odds ratios were estimated for each UV filter (dichotomized at the 75th percentile) and adjusted for age, creatinine concentration, body mass index (weight (kg)/height (m)(2)), cotinine concentration, season, and site, while accounting for time off contraception. Separate models were fitted for each UV filter and partner; final models included partners' concentrations. Male partners' concentrations of BP-2 and 4-hydroxybenzophenone were associated with reduced fecundity in adjusted models (fecundability odds ratio (FOR) = 0.69 (95% confidence interval (CI): 0.50, 0.95) and FOR = 0.74 (95% CI: 0.54, 1.00), respectively). In models adjusting for both partners' concentrations, male BP-2 concentration remained associated with reduced fecundity (FOR = 0.69, 95% CI: 0.49, 0.97). These data suggest that male exposure to select UV filters may diminish couples' fecundity, resulting in a longer time to pregnancy.

Urinary bisphenol A, phthalates, and couple fecundity: the Longitudinal Investigation of Fertility and the Environment (LIFE) Study.

OBJECTIVE: To assess the relationship between environmental chemicals and couple fecundity or time to pregnancy (TTP). DESIGN: Prospective cohort. SETTING: Communities of targeted populations with reported exposure. PATIENT(S): 501 couples recruited upon discontinuing contraception to become pregnant, 2005-2009. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Fecundability odds ratios (FORs) and 95% confidence intervals (CIs) estimated for each partner's chemical concentrations adjusted for age, body mass index, cotinine, creatinine, and research site while accounting for time off contraception. RESULT(S): Couples completed interviews and anthropometric assessments and provided the urine specimens for quantification of bisphenol A (BPA) and 14 phthalate metabolites, which were measured using high-performance liquid chromatography with electrospray triple-quadrupole mass spectrometer. Women recorded menstruation and pregnancy test results in daily journals. Couples were evaluated until a positive human-chorionic gonadotropin pregnancy test or 12 cycles without pregnancy. Neither female nor male BPA concentration was associated with TTP (FOR 0.98; 95% CI, 0.86, 1.13 and FOR 1.04; 95% CI, 0.91, 1.18, respectively). Men's urinary concentrations of monomethyl, mono-n-butyl, and monobenzyl phthalates were associated with a longer TTP (FOR 0.80; 95% CI, 0.70, 0.93; FOR 0.82, 95% CI, 0.70, 0.97; and FOR 0.77, 95% CI, 0.65 0.92, respectively). CONCLUSION(S): Select male but not female phthalate exposures were associated with an approximately 20% reduction in fecundity, underscoring the importance of assessing both partners' exposure to minimize erroneous conclusions.

Higher urinary lignan concentrations in women but not men are positively associated with shorter time to pregnancy.

Phytoestrogens have been associated with subtle hormonal changes, although effects on fecundity are unknown. Our objective was to evaluate the association between male and female urinary phytoestrogen (isoflavone and lignan) concentrations and time to pregnancy (TTP) in a population-based cohort of 501 couples desiring pregnancy and discontinuing contraception. Couples were followed for 12 mo or until pregnancy. Fecundability ORs (FORs) and 95% CIs were estimated after adjusting for age, body mass index, race, site, creatinine, supplement use, and physical activity in relation to female, male, and joint couple concentrations. Models included the phytoestrogen of interest and the sum of the remaining individual phytoestrogens. FORs <1 denote a longer TTP and FORs >1 a shorter TTP. Urinary lignan concentrations were higher, on average, among female partners of couples who became pregnant during the study compared with women who did not become pregnant (median enterodiol: 118 vs. 80 nmol/L; P < 0.10; median enterolactone: 990 vs. 412 nmol/L; P < 0.05) and were associated with significantly shorter TTP in models based on both individual and couples' concentrations (couples' models: enterodiol FOR, 1.13; 95% CI: 1.02, 1.26; enterolactone FOR, 1.11; 95% CI: 1.01, 1.21). Male lignan concentrations were not associated with TTP, nor were isoflavone concentrations. Sensitivity analyses showed that associations observed are unlikely to be explained by potential unmeasured confounding by lifestyle or other nutrients. Our results suggest that female urinary lignan concentrations at levels characteristic of the U.S. population are associated with a shorter TTP among couples who are attempting to conceive, highlighting the importance of dietary influences on fecundity.

Semen quality and time to pregnancy: the Longitudinal Investigation of Fertility and the Environment Study.

OBJECTIVE: To assess semen parameters and couple fecundity as measured by time to pregnancy (TTP). DESIGN: Observational prospective cohort with longitudinal measurement of TTP. SETTING: Sixteen Michigan/Texas counties. PATIENT(S): A total of 501 couples discontinuing contraception were followed for 1 year while trying to conceive; 473 men (94%) provided one semen sample, and 80% provided two samples. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Using prospectively measured TTP, fecundability odds ratios (FORs) and 95% confidence intervals (CIs) were estimated for 36 individual semen quality parameters accounting for repeated semen samples, time off contraception, abstinence, enrollment site, and couples' ages, body mass indices, and serum cotinine concentrations. RESULT(S): In adjusted models, semen quality parameters were associated with significantly shorter TTP as measured by FORs >1: percent motility, strict and traditional morphology, sperm head width, elongation factor, and acrosome area. Significantly longer TTPs or FORs <1 were observed for morphologic categories amorphous and round sperm heads and neck/midpiece abnormalities. No semen quality parameters achieved significance when simultaneously modeling all other significant semen parameters and covariates, except for percent coiled tail when adjusting for sperm concentration (FOR 0.99; 95% CI 0.99-1.00). Male age was consistently associated with reduced couple fecundity (FOR 0.96; 95% CI 0.93-0.99), reflecting a longer TTP across all combined models. Female but not male body mass index also conferred a longer TTP (FOR 0.98; 95% CI 0.96-0.99). CONCLUSION(S): Several semen measures were significantly associated with TTP when modeled individually but not jointly and in the context of relevant couple-based covariates.

Persistent environmental pollutants and couple fecundity: the LIFE study.

BACKGROUND: Evidence suggesting that persistent environmental pollutants may be reproductive toxicants underscores the need for prospective studies of couples for whom exposures are measured. OBJECTIVES: We examined the relationship between selected persistent pollutants and couple fecundity as measured by time to pregnancy. METHODS: A cohort of 501 couples who discontinued contraception to become pregnant was prospectively followed for 12 months of trying to conceive or until a human chorionic gonadotrophin (hCG) test confirmed pregnancy. Couples completed daily journals on lifestyle and provided biospecimens for the quantification of 9 organochlorine pesticides, 1 polybrominated biphenyl, 10 polybrominated diphenyl ethers, 36 polychlorinated biphenyls (PCBs), and 7 perfluorochemicals (PFCs) in serum. Using Cox models for discrete time, we estimated fecundability odds ratios (FORs) and 95% CIs separately for each partner's concentrations adjusting for age, body mass index, serum cotinine, serum lipids (except for PFCs), and study site (Michigan or Texas); sensitivity models were further adjusted for left truncation or time off of contraception (≤ 2 months) before enrollment. RESULTS: The adjusted reduction in fecundability associated with standard deviation increases in log-transformed serum concentrations ranged between 18% and 21% for PCB congeners 118, 167, 209, and perfluorooctane sulfonamide in females; and between 17% and 29% for p,p´-DDE and PCB congeners 138, 156, 157, 167, 170, 172, and 209 in males. The strongest associations were observed for PCB 167 (FOR 0.79; 95% CI: 0.64, 0.97) in females and PCB 138 (FOR = 0.71; 95% CI: 0.52, 0.98) in males. CONCLUSIONS: In this couple-based prospective cohort study with preconception enrollment and quantification of exposures in both female and male partners, we observed that a subset of persistent environmental chemicals were associated with reduced fecundity.

Strength of default mode resting-state connectivity relates to white matter integrity in children.

A default mode network of brain regions is known to demonstrate coordinated activity during the resting state. While the default mode network is well characterized in adults, few investigations have focused upon its development. We scanned 9-13-year-old children with diffusion tensor imaging and resting-state functional magnetic resonance imaging. We identified resting-state networks using Independent Component Analysis and tested whether the functional connectivity between the medial prefrontal cortex (mPFC) and posterior cingulate cortex (PCC) depends upon the maturation of the underlying cingulum white matter tract. To determine the generalizability of this relationship, we also tested whether functional connectivity depends on white matter maturity between bilateral lateral prefrontal cortex (lateral PFC) within the executive control network. We found a positive relationship between mPFC-PCC connectivity and fractional anisotropy of the cingulum bundle; this positive relationship was moderated by the age of the subjects such that it was stronger in older children. By contrast, no such structure-function relationship emerged between right and left lateral PFC. However, functional and structural connectivity of this tract related positively with cognitive speed, fluency, and set-switching neuropsychological measures.

Document classification for mining host pathogen protein-protein interactions.

OBJECTIVE: Scientific findings regarding human pathogens and their host responses are buried in the growing volume of biomedical literature and there is an urgent need to mine information pertaining to pathogenesis-related proteins especially host pathogen protein-protein interactions (HP-PPIs) from literature. METHODS: In this paper, we report our exploration of developing an automated system to identify MEDLINE abstracts referring to HP-PPIs. An annotated corpus consisting of 1360 MEDLINE abstracts was generated. With this corpus, we developed and evaluated document classification systems using support vector machines (SVMs). We also investigated the effects of three feature selection methods:information gain (IG), chi(2) test, and specific mutual information (SI). The performance was measured using normalized discounted cumulative gain (NDCG) and positive predictive value (PPV) and all measures were obtained through 10-fold cross validation. RESULTS: NDCG measures for classification systems using all features or a subset of features selected using IG and chi(2) test range from 0.83 to 0.89 while classification systems built based on features selected using SI had relatively lower NDCG measures. The classification system achieved a PPV of 50.7% for the top 10% ranked documents comparing to a baseline PPV of 10.0%. CONCLUSIONS: Our results indicate that document classification systems can be constructed to efficiently retrieve HP-PPI related documents. Feature selection was effective in reducing the dimensionality of features to build a compact system.

A meta-analysis of functional neuroimaging studies of dyslexia.

Reading and phonological processing deficits have been the primary focus of neuroimaging studies addressing the neurologic basis of developmental dyslexia, but to date there has been no objective assessment of the consistency of these findings. To address this issue, spatial coordinates reported in the literature were submitted to two parallel activation likelihood estimate (ALE) meta-analyses. First, a meta-analysis including 96 foci from nine publications identified regions where typical readers are likely to show greater activation than dyslexics: two left extrastriate areas within BA 37, precuneus, inferior parietal cortex, superior temporal gyrus, thalamus, and left inferior frontal gyrus. Right hemisphere ALE foci representing hypoactivity in dyslexia were found in the fusiform, postcentral, and superior temporal gyri. To identify regions in which dyslexic subjects reliably show greater activation than controls, 75 foci from six papers were entered into a second meta-analysis. Here ALE results revealed hyperactivity associated with dyslexia in right thalamus and anterior insula. These findings suggest that during the performance of a variety of reading tasks, normal readers activate left-sided brain areas more than dyslexic readers do, whereas dyslexia is associated with greater right-sided brain activity. The most robust result was in left extrastriate cortex, where hypoactivity associated with dyslexia was found. However, the ALE maps provided no support for cerebellar dysfunction, nor for hyperactivity in left frontal cortex in dyslexia, suggesting that these findings, unlike those described above, are likely to be more varied in terms of their reproducibility or spatial location.