Case-control study of association of maternal recall of diarrhea or use of antimicrobials in the periconceptional period and neural tube defects

In June 1995 a case-control study was initiated by the Texas Department of Health among Mexican American women residing in the fourteen counties of the Texas-Mexico border. Case-women had carried infants with neural tube defect. Control-women had given birth to infants without neural tube defects. The case-control protocol included a general questionnaire which elicited information regarding illnesses experienced and antibiotics taken from three months prior to conception to three months after conception. An assessment of the associations between periconceptional diarrhea and the risk of neural tube defects indicated that the unadjusted association of diarrhea and risk of neural tube defect was significant (OR = 3.3, CI = 1.4–7.6). The unadjusted association of use of oral antimicrobials and risk of neural tube defect was also significant (OR = 3.4, CI = 1.6–7.3). These associations persisted among women who had no fever during the periconceptional period and were present irrespective of folate intake. Diarrhea was associated with an increased risk of NTD independent of use of antimicrobials. The converse was also true; antimicrobials were associated with an increased risk of NTD independent of diarrhea. Further research regarding these potentially modifiable risk factors is warranted. Replication of these findings could result in interventions in addition to folate supplementation. ^

Requirement of GCN5 histone acetyltransferase in mouse neural tube closure and skeletal patterning

Histone acetylation plays an essential role in many DNA-related processes such as transcriptional regulation via modulation of chromatin structure. Many histone acetytransferases have been discovered and studied in the past few years, but the roles of different histone acetyltransferases (HAT) during mammalian development are not well defined at present. Gcn5 histone acetyltransferase is highly expressed until E16.5 during development. Previous studies in our lab using a constitutive null allele demonstrated that Gcn5 knock out mice are embryonic lethal, precluding the study of Gcn5 functions at later developmental stages. The creation of a conditional Gcn5 null allele, Gcn5flox allele, bypasses the early lethality. Mice homozygous for this allele are viable and appear healthy. In contrast, mice homozygous for a Gcn5 Δex3-18 allele created by Cre-loxP mediated deletion display a phenotype identical to our original Gcn5 null mice. Strikingly, a Gcn5flox(neo) allele, which contain a neomycin cassette in the second intron of Gcn5 is only partially functional and gives rise to a hypomorphic phenotype. Initiation of cranial neural tube closure at forebrain/midbrain boundary fails, resulting in an exencephaly in some Gcn5flox(neo)/flox(neo) embryos. These defects were found at an even greater penetrance in Gcn5flox(neo)/Δ embryos and become completely penetrant in the 129Sv genetic background, suggesting that Gcn5 controls mouse neural tube closure in a dose dependent manner. Furthermore, both Gcn5flox(neo)/flox(neo) and Gcn5 flox(neo)/Δ embryos exhibit anterior homeotic transformations in lower thoracic and lumbar vertebrae. These defects are accompanied by decreased expression levels and a shift in anterior expression boundary of Hoxc8 and Hoxc9. This study provides the first evidence that Gcn5 regulates Hox gene expression and is required for normal axial skeletal patterning in mice. ^

Response to chemotherapy, recurrence and survival in advanced-stage ovarian, fallopian tube and primary peritoneal cancer patients with non-Ashkenazi Jewish BRCA mutations, compared to those without

Objectives. Previous studies have shown a survival advantage in ovarian cancer patients with Ashkenazi-Jewish (AJ) BRCA founder mutations, compared to sporadic ovarian cancer patients. The purpose of this study was to determine if this association exists in ovarian cancer patients with non-Ashkenazi Jewish BRCA mutations. In addition, we sought to account for possible "survival bias" by minimizing any lead time that may exist between diagnosis and genetic testing. ^ Methods. Patients with stage III/IV ovarian, fallopian tube, or primary peritoneal cancer and a non-Ashkenazi Jewish BRCA1 or 2 mutation, seen for genetic testing January 1996-July 2007, were identified from genetics and institutional databases. Medical records were reviewed for clinical factors, including response to initial chemotherapy. Patients with sporadic (non-hereditary) ovarian, fallopian tube, or primary peritoneal cancer, without family history of breast or ovarian cancer, were compared to similar cases, matched by age, stage, year of diagnosis, and vital status at time interval to BRCA testing. When possible, 2 sporadic patients were matched to each BRCA patient. An additional group of unmatched, sporadic ovarian, fallopian tube and primary peritoneal cancer patients was included for a separate analysis. Progression-free (PFS) & overall survival (OS) were calculated by the Kaplan-Meier method. Multivariate Cox proportional hazards models were calculated for variables of interest. Matched pairs were treated as clusters. Stratified log rank test was used to calculate survival data for matched pairs using paired event times. Fisher's exact test, chi-square, and univariate logistic regression were also used for analysis. ^ Results. Forty five advanced-stage ovarian, fallopian tube and primary peritoneal cancer patients with non-Ashkenazi Jewish (non-AJ) BRCA mutations, 86 sporadic-matched and 414 sporadic-unmatched patients were analyzed. Compared to the sporadic-matched and sporadic-unmatched ovarian cancer patients, non-AJ BRCA mutation carriers had longer PFS (17.9 & 13.8 mos. vs. 32.0 mos., HR 1.76 [95% CI 1.13–2.75] & 2.61 [95% CI 1.70–4.00]). In relation to the sporadic- unmatched patients, non-AJ BRCA patients had greater odds of complete response to initial chemotherapy (OR 2.25 [95% CI 1.17–5.41]) and improved OS (37.6 mos. vs. 101.4 mos., HR 2.64 [95% CI 1.49–4.67]). ^ Conclusions. This study demonstrates a significant survival advantage in advanced-stage ovarian cancer patients with non-AJ BRCA mutations, confirming the previous studies in the Jewish population. Our efforts to account for "survival bias," by matching, will continue with collaborative studies. ^

Determining associations and assessing methodological issues in a case-control study of hazardous air pollutants and neural tube defects

Recent studies have reported positive associations between maternal exposures to air pollutants and several adverse birth outcomes. However, there have been no assessments of the association between environmental hazardous air pollutants (HAPs) such as benzene, toluene, ethylbenzene, and xylene (BTEX) and neural tube defects (NTDs) a common and serious group of congenital malformations. Before examining this association, two important methodological questions must be addressed: (1) is maternal residential movement likely to result in exposure misclassification and (2) is it appropriate to lump defects of the neural tube, such as anencephaly and spina bifida, into a composite disease endpoint (i.e., NTDs). ^ Data from the National Birth Defects Prevention Study and Texas Birth Defects Registry were used to: (1) assess the extent to which change of residence may result in exposure misclassification when exposure is based on the address at delivery; (2) formally assess heterogeneity of the associations between known risk factors for NTDs, using polytomous logistic regression; and (3) conduct a case-control study assessing the association between ambient air levels of BTEX and the risk of NTDs among offspring. ^ Regarding maternal residential mobility, this study suggests address at delivery was not significantly different from using address at conception when assigning quartile of benzene exposure (OR 1.0, 95% CI 0.9, 1.3). On the question of effect heterogeneity among NTDs, the effect estimates for infant sex P = 0.017), maternal body mass index P = 0.016), and folate supplementation P = 0.050) were significantly different for anencephaly and spina bifida, suggesting it is often more appropriate to assess potential risk factors among subgroups of NTDs. For the main study question on the association between environmental HAPs and NTDs, mothers who have offspring with isolated spina bifida are 2.4 times likely to live in areas with the highest benzene levels (95% CI 1.1, 5.0). However, no other significant associations were observed.^ This project is the first to include not only an assessment of the relationship between environmental levels of BTEX and NTDs, but also two separate studies addressing important methodological issues associated with this question. Our results contribute to the growing body of evidence regarding air pollutant exposure and adverse birth outcomes. ^

The use of the computerized and revised vital record in conducting etiologic studies on neural tube defects

The purpose of this study was to evaluate the adequacy of computerized vital records in Texas for conducting etiologic studies on neural tube defects (NTDs), using the revised and expanded National Centers for Health Statistics vital record forms introduced in Texas in 1989.^ Cases of NTDs (anencephaly and spina bifida) among Harris County (Houston) residents were identified from the computerized birth and death records for 1989-1991. The validity of the system was then measured against cases ascertained independently through medical records and death certificates. The computerized system performed poorly in its identification of NTDs, particularly for anencephaly, where the false positive rate was 80% with little or no improvement over the 3-year period. For both NTDs the sensitivity and predictive value positive of the tapes were somewhat higher for Hispanic than non-Hispanic mothers.^ Case control studies were conducted utilizing the tape set and the independently verified data set, using controls selected from the live birth tapes. Findings varied widely between the data sets. For example, the anencephaly odds ratio for Hispanic mothers (vs. non-Hispanic) was 1.91 (CI = 1.38-2.65) for the tape file, but 3.18 (CI = 1.81-5.58) for verified records. The odds ratio for diabetes was elevated for the tape set (OR = 3.33, CI = 1.67-6.66) but not for verified cases (OR = 1.09, CI = 0.24-4.96), among whom few mothers were diabetic. It was concluded that computerized tapes should not be solely relied on for NTD studies.^ Using the verified cases, Hispanic mother was associated with spina bifida, and Hispanic mother, teen mother, and previous pregnancy terminations were associated with anencephaly. Mother's birthplace, education, parity, and diabetes were not significant for either NTD.^ Stratified analyses revealed several notable examples of statistical interaction. For anencephaly, strong interaction was observed between Hispanic origin and trimester of first prenatal care.^ The prevalence was 3.8 per 10,000 live births for anencephaly and 2.0 for spina bifida (5.8 per 10,000 births for the combined categories). ^

Indeterminate QunatiFERON-TB Gold In-Tube assay results in association with procedural specimen collection in children

BACKGROUND. The development of interferon-gamma release assays (IGRA) has introduced powerful tools in diagnosing latent tuberculosis infection (LTBI) and may play a critical role in the future of tuberculosis diagnosis. However, there have been reports of high indeterminate results in young patient populations (0-18 years). This study investigated results of the QunatiFERON-TB Gold In-Tube (QFT-GIT) IGRA in a population of children (0-18 years) at Texas Children's Hospital in association with specimen collection procedures using surrogate variables. ^ METHODS. A retrospective case-control study design was used for this investigation. Cases were defined as having QFT-GIT indeterminate results. Controls were defined as having either positive or negative results (determinates). Patients' admission status, staff performing specimen collection, and specific nurse performing specimen collection were used as surrogates to measure specimen collection procedures. ^ To minimize potential confounding, abstraction of patients' electronic medical records was performed. Abstracted data included patients' medications and evaluation at the time of QFT-GIT specimen collection in addition to their medical history. QFT-GIT related data was also abstracted. Cases and controls were characterized using chi-squared tests or Fisher's exact tests across categorical variables. Continuous variables were analyzed using one-way ANOVA and t-tests for continuous variables. A multivariate model was constructed by backward stepwise removal of statistically significant variables from univariate analysis. ^ RESULTS. Patient data was abstracted from 182 individuals aged 0-18 years from July 2010 to August 2011 at Texas Children's Hospital. 56 cases (indeterminates) and 126 controls (determinates) were enrolled. Cancer was found to be an effect modifier with subsequent stratification resulting in a cancer patient population too small to analyze (n=13). Subsequent analyses excluded these patients. ^ The exclusion of cancer patients resulted in a population of 169 patients with 49 indeterminates (28.99%) and 120 determinates (71.01%), with mean ages of 9.73 (95% CI: 8.03, 11.43) years and 11.66 (95% CI: 10.75, 12.56) years (p = 0.033), respectively. Median age of patients who were indeterminates and determinates were 12.37 and 12.87 years, respectively. Lack of data for our specific nurse surrogate (QFTNurse) resulted in its exclusion from analysis. The final model included only our remaining surrogate variables (QFTStaff and QFTInpatientOutpatient). The staff collecting surrogate (QFTStaff) was found to be modestly associated with indeterminates when nurses collected the specimen (OR = 1.54, 95% CI: 0.51, 4.64, p = 0.439) in the final model. Inpatients were found to have a strong and statistically significant association with indeterminates (OR = 11.65, 95% CI: 3.89, 34.9, p < 0.001) in the final model. ^ CONCLUSION. Inpatient status was used as a surrogate for indication of nurse drawn blood specimens. Nurses have had little to no training regarding shaking of tubes versus phlebotomists regarding QFT-GIT testing procedures. This was also measured by two other surrogates; specifically a medical note stating whether a nurse or phlebotomist collected the specimen (QFTStaff) and the name and title of the specific nurse if collection was performed by a nurse (QFTNurse). Results indicated that inpatient status was a strong and statistically significant factor for indeterminates, however, nurse collected specimens and indeterminate results had no statistically significant association in non-cancer patients. The lack of data denoting the specific nurse performing specimen collection excluded the QFTNurse surrogate in our analysis. ^ Findings suggests training of staff personnel in specimen procedures may have little effect on the number of indeterminates while inpatient status and thus possibly illness severity may be the most important factor for indeterminate results in this population. The lack of congruence between our surrogate measures may imply that our inpatient surrogate gauged illness severity rather than collection procedures as intended. ^ Despite the lack of clear findings, our analysis indicated that more than half of indeterminates were found in specimens drawn by nurses and as such staff training may be explored. Future studies may explore methods in measuring modifiable variables during pre-analytical QFT-GIT procedures that can be discerned and controlled. Identification of such measures may provide insight into ways to lowering indeterminate QFT-GIT rates in children.^