Quantitative bias analysis in an asthma study of rescue-recovery workers and volunteers from the 9/11 World Trade Center attacks.

PURPOSE: When learning bias analysis, epidemiologists are taught to quantitatively adjust for multiple biases by correcting study results in the reverse order of the error sequence. To understand the error sequence for a particular study, one must carefully examine the health study's epidemiologic data-generating process. In this article, we describe the unique data-generating process of a man-made disaster epidemiologic study. METHODS: We described the data-generating process and conducted a bias analysis for a study associating September 11, 2001 dust cloud exposure and self-reported newly physician-diagnosed asthma among rescue-recovery workers and volunteers. We adjusted an odds ratio (OR) estimate for the combined effect of missing data, outcome misclassification, and nonparticipation. RESULTS: Under our assumptions about systematic error, the ORs adjusted for all three biases ranged from 1.33 to 3.84. Most of the adjusted estimates were greater than the observed OR of 1.77 and were outside the 95% confidence limits (1.55, 2.01). CONCLUSIONS: Man-made disasters present some situations that are not observed in other areas of epidemiology. Future epidemiologic studies of disasters could benefit from a proactive approach that focuses on the technical aspect of data collection and gathers information on bias parameters to provide more meaningful interpretations of results.

Adjusting for multiple-misclassified variables in a study using birth certificates.

PURPOSE: Birth certificates are a convenient source of population data for epidemiologic studies. It is well documented, however, that birth certificate data can be highly inaccurate. Nonetheless, studies based on birth certificates are routinely analyzed without accounting for sources of data errors. We focused on the association between maternal cigarette smoking and cleft lip and palate based on birth certificate data. METHODS: We adjusted odds ratio estimates simultaneously for exposure and outcome misclassification. We also calculated odds ratios adjusted for exposure misclassification only and outcome misclassification only. RESULTS: Adjustment for both maternal smoking during pregnancy and clefting resulted in adjusted odds ratios that ranged from less than 1.0 to much greater than the unadjusted estimate of 1.16, with most adjusted estimates outside of the 95% confidence limits (1.01, 1.33). CONCLUSIONS: Because of the potentially large impact of birth certificate classification errors, we suggest that inferences from these or similar records employ quantitative methods for incorporating uncertainties caused by data errors.

Pesticide exposure and neurodevelopmental outcomes: review of the epidemiologic and animal studies.

Assessment of whether pesticide exposure is associated with neurodevelopmental outcomes in children can best be addressed with a systematic review of both the human and animal peer-reviewed literature. This review analyzed epidemiologic studies testing the hypothesis that exposure to pesticides during pregnancy and/or early childhood is associated with neurodevelopmental outcomes in children. Studies that directly queried pesticide exposure (e.g., via questionnaire or interview) or measured pesticide or metabolite levels in biological specimens from study participants (e.g., blood, urine, etc.) or their immediate environment (e.g., personal air monitoring, home dust samples, etc.) were eligible for inclusion. Consistency, strength of association, and dose response were key elements of the framework utilized for evaluating epidemiologic studies. As a whole, the epidemiologic studies did not strongly implicate any particular pesticide as being causally related to adverse neurodevelopmental outcomes in infants and children. A few associations were unique for a health outcome and specific pesticide, and alternative hypotheses could not be ruled out. Our survey of the in vivo peer-reviewed published mammalian literature focused on effects of the specific active ingredient of pesticides on functional neurodevelopmental endpoints (i.e., behavior, neuropharmacology and neuropathology). In most cases, effects were noted at dose levels within the same order of magnitude or higher compared to the point of departure used for chronic risk assessments in the United States. Thus, although the published animal studies may have characterized potential neurodevelopmental outcomes using endpoints not required by guideline studies, the effects were generally observed at or above effect levels measured in repeated-dose toxicology studies submitted to the U.S. Environmental Protection Agency (EPA). Suggestions for improved exposure assessment in epidemiology studies and more effective and tiered approaches in animal testing are discussed.

Adjusting for outcome misclassification: the importance of accounting for case-control sampling and other forms of outcome-related selection.

PURPOSE: Special care must be taken when adjusting for outcome misclassification in case-control data. Basic adjustment formulas using either sensitivity and specificity or predictive values (as with external validation data) do not account for the fact that controls are sampled from a much larger pool of potential controls. A parallel problem arises in surveys and cohort studies in which participation or loss is outcome related. METHODS: We review this problem and provide simple methods to adjust for outcome misclassification in case-control studies, and illustrate the methods in a case-control birth certificate study of cleft lip/palate and maternal cigarette smoking during pregnancy. RESULTS: Adjustment formulas for outcome misclassification that ignore case-control sampling can yield severely biased results. In the data we examined, the magnitude of error caused by not accounting for sampling is small when population sensitivity and specificity are high, but increases as (1) population sensitivity decreases, (2) population specificity decreases, and (3) the magnitude of the differentiality increases. Failing to account for case-control sampling can result in an odds ratio adjusted for outcome misclassification that is either too high or too low. CONCLUSIONS: One needs to account for outcome-related selection (such as case-control sampling) when adjusting for outcome misclassification using external information.

Self-report versus medical record - perinatal factors in a study of infant leukaemia: a study from the Children's Oncology Group.

In a case-control study of infant leukaemia, we assessed agreement between medical records and mother's self-reported pregnancy-related conditions and procedures and infant treatments. Interview and medical record data were available for 234 case and 215 control mothers. Sensitivity, specificity and predictive values for maternal report were estimated for case and control mothers separately, taking the medical record as correct. For most perinatal conditions, sensitivity and specificity were over 75%. Low sensitivity was observed for maternal protein or albumin in the urine (cases: 12% [95% exact confidence interval (CI) 8%, 18%]; controls: 11% [95% CI 7%, 17%]) and infant supplemental oxygen use (cases: 25% [95% CI 11%, 43%]; controls: 24% [95% CI 13%, 37%]). Low specificity was found for peripheral oedema (cases: 47% [95% CI 37%, 58%]; controls: 54% [95% CI 43%, 64%]). Sensitivity for maternal hypertension appeared much lower for cases (cases: 46% [95% CI 28%, 66%]; controls: 90% [95% CI 70%, 99%]; P = 0.003). We did not detect other case-control differences in recall (differentiality), even though the average time between childbirth and interview was 2.7 years for case and 3.7 years for control mothers. Many conditions exhibited notable differences between interview and records. We recommend use of multiple measurement sources to allow both cross-checking and synthesis of results into more accurate measures.

Evaluation of newborn screening bloodspot-based genetic testing as second tier screen for bedside newborn hearing screening.

PURPOSE: : Bedside newborn hearing screening is highly successful in identifying deaf or hard-of-hearing infants. However, newborn hearing screening protocols have high loss to follow-up rates. We propose that bloodspot-based genetic testing for GJB2 alleles can provide a means for rapid confirmation in a subset of infants who fail bedside newborn hearing screening. METHODS: : We performed a case-control study comparing the prevalence of common GJB2 mutations from deidentified bloodspots designated as "refer" by newborn hearing screening and contemporaneously selected randomly chosen controls designated as "pass." Between March 2006 and December 2007, 2354 spots were analyzed for common alleles, c.35delG, c.167delT, c.235delC, and p.V37I in GJB2 with a subset reanalyzed by conventional Sanger sequencing to search for additional alleles. RESULTS: : The prevalence of biallelic GJB2 mutations in bloodspots from infants who referred by newborn hearing screening is approximately 1 in 50 (23/1177). In contrast, one bloodspot from an infant who passed newborn hearing screening was identified to harbor biallelic GJB2 mutations. CONCLUSIONS: : These findings show that when a newborn refers by newborn hearing screening, there is a significant chance that GJB2-related hearing loss is present. Bloodspot-based genetic testing for common GJB2 alleles should be considered as second tier testing for bedside newborn hearing screening.

Maternal dietary patterns during early pregnancy and the odds of childhood germ cell tumors: A Children's Oncology Group study.

Maternal diet during pregnancy may be associated with cancer in offspring. Intake of individual foods, as well as dietary patterns, can be used when examining these relations. Here, the authors examined associations between maternal dietary intake patterns and pediatric germ cell tumors (GCTs) using principal components analysis and logistic regression. Mothers of 222 GCT cases aged less than 15 years who were diagnosed at a Children's Oncology Group institution between 1993 and 2001 and those of 336 frequency-matched controls completed a self-administered food frequency questionnaire of diet during early pregnancy. Four dietary patterns were identified: "Western," "fruits and vegetables," "protein," and "healthful." With adjustment for birth weight, parity, and vitamin use, the fruits and vegetables pattern was significantly associated with a lower odds for GCTs (odds ratio (OR) = 0.83, 95% confidence interval (CI): 0.69, 0.99; 2 sided). Upon stratification, the fruits and vegetables pattern was significantly associated with a lower odds in males (OR = 0.66, 95% CI: 0.47, 0.92) but not females (OR = 0.91, 95% CI: 0.72, 1.14). A quantitative assessment of assumed nondifferential reporting error indicated no notable deviations from unadjusted odds ratio estimates. Results of this exploratory analysis suggest that maternal prenatal dietary patterns could be considered in future studies of GCTs in offspring.

The inborn errors of metabolism information system: A project of the Region 4 Genetics Collaborative Priority 2 Workgroup.

The Region 4 Genetics Collaborative has brought together metabolic clinicians and follow-up specialists from state departments of health in the region (Illinois, Indiana, Kentucky, Michigan, Minnesota, Ohio, and Wisconsin) in a workgroup to create a dynamic registry, the Inborn Errors of Metabolism Information System, to facilitate gathering information about long-term follow-up for individuals identified by newborn blood spot screening. With the concept that by developing a core series of agreed-on data elements and general treatment strategies, differences in treatment plans could yield evidence about optimal treatment choices, data elements for initial intake, and interval follow-up were selected based on a paradigm condition, medium-chain acyl-CoA dehydrogenase deficiency. Demographic elements that will be used as a common data set for all conditions were identified along with condition-specific elements and general information to be obtained at intervals. Subjects were enrolled after obtaining prospective informed consent; data entry began in January 2007. Additional conditions have had data sets defined and data entry initiated; 21 disorders as of July 2009. Web-based data entry has been employed using DocSite® as the platform for data entry. With continued collaboration among members of the workgroup, we hope to extend the intellectual questions that can be explored using this data, expand the spectrum of the registry and number of patients engaged, and integrate the registry into additional domains.

The association between atopy and childhood/adolescent leukemia: a meta-analysis.

Atopic disease is hypothesized to be protective against several malignancies, including childhood/adolescent leukemia. To summarize the available epidemiologic evidence, the authors performed a meta-analysis of associations between atopy/allergies, asthma, eczema, hay fever, and hives and childhood/adolescent leukemia, acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML). They searched MEDLINE literature (1952-March 2009) and queried international experts to identify eligible studies. Ten case-control studies were included. Summary odds ratios and 95% confidence intervals were computed via random-effects models. Odds ratios for atopy/allergies were 1.42 (95% confidence interval (CI): 0.60, 3.35) for 3 studies of leukemia overall, 0.69 (95% CI: 0.54, 0.89) for 6 studies of ALL, and 0.87 (95% CI: 0.62, 1.22) for 2 studies of AML, with high levels of heterogeneity detected for leukemia overall and ALL. Inverse associations were observed for ALL and asthma (odds ratio (OR) = 0.79, 95% CI: 0.61, 1.02), eczema (OR = 0.74, 95% CI: 0.58, 0.96), and hay fever (OR = 0.55, 95% CI: 0.46, 0.66) examined separately. Odds ratios for ALL differed by study design, exposure data source, and latency period, indicating that these factors affect study results. These results should be interpreted cautiously given the modest number of studies, substantial heterogeneity, and potential exposure misclassification but are useful in designing future research.

Socioeconomic predictors of cognition in Ugandan children: implications for community interventions.

BACKGROUND: Several interventions to improve cognition in at risk children have been suggested. Identification of key variables predicting cognition is necessary to guide these interventions. This study was conducted to identify these variables in Ugandan children and guide such interventions. METHODS: A cohort of 89 healthy children (45 females) aged 5 to 12 years old were followed over 24 months and had cognitive tests measuring visual spatial processing, memory, attention and spatial learning administered at baseline, 6 months and 24 months. Nutritional status, child's educational level, maternal education, socioeconomic status and quality of the home environment were also measured at baseline. A multivariate, longitudinal model was then used to identify predictors of cognition over the 24 months. RESULTS: A higher child's education level was associated with better memory (p = 0.03), attention (p = 0.005) and spatial learning scores over the 24 months (p = 0.05); higher nutrition scores predicted better visual spatial processing (p = 0.002) and spatial learning scores (p = 0.008); and a higher home environment score predicted a better memory score (p = 0.03). CONCLUSION: Cognition in Ugandan children is predicted by child's education, nutritional status and the home environment. Community interventions to improve cognition may be effective if they target multiple socioeconomic variables.

Detection of cytomegalovirus DNA in dried blood spots of Minnesota infants who do not pass newborn hearing screening.

BACKGROUND: Up to 15% of infants with asymptomatic congenital cytomegalovirus (CMV) infection will experience some degree of sensorineural hearing loss. Many infants who fail newborn hearing screening (NHS) are likely to have congenital CMV infection, but may escape definitive virologic identification because diagnostic evaluation may not commence until several weeks or months of age, making differentiation between congenital and postnatal CMV infection difficult. Early diagnosis linking virologic identification of congenital CMV infection to infants failing NHS may improve diagnostic precision and enhance opportunities for therapeutic intervention. METHODS: The goal of this study was to compare newborn dried blood spots from Minnesota infants who had failed NHS, and were designated for referral, with control infants who passed NHS, for the presence of CMV DNA by real-time PCR, using hybridization probes for the CMV gene UL54. RESULTS: Of 479 infants with a failed NHS (bilateral failure), 13 had CMV DNA present in the blood spot (2.7%). This compared with only 2/479 positive results from a control group of infants who passed the NHS (0.4%; P = 0.007, Fisher exact test). Comparisons of the glycoprotein B (gB) genotype as well as direct DNA sequencing of selected positives revealed that PCR positive samples represented unique clinical isolates. The mean viral load among the 15 positive samples was 1.6 x 10(3) genomes/microgram of total DNA. CONCLUSIONS: Newborn bloodspot CMV screening by real-time PCR may be a useful and rapid adjunct to functional NHS and may enable more rapid etiologic diagnosis of sensorineural hearing loss in newborns.

Specifying exposure classification parameters for sensitivity analysis: family breast cancer history.

One of the challenges to implementing sensitivity analysis for exposure misclassification is the process of specifying the classification proportions (eg, sensitivity and specificity). The specification of these assignments is guided by three sources of information: estimates from validation studies, expert judgment, and numerical constraints given the data. The purpose of this teaching paper is to describe the process of using validation data and expert judgment to adjust a breast cancer odds ratio for misclassification of family breast cancer history. The parameterization of various point estimates and prior distributions for sensitivity and specificity were guided by external validation data and expert judgment. We used both nonprobabilistic and probabilistic sensitivity analyses to investigate the dependence of the odds ratio estimate on the classification error. With our assumptions, a wider range of odds ratios adjusted for family breast cancer history misclassification resulted than portrayed in the conventional frequentist confidence interval.

Sexual identity and tobacco use in a venue-based sample of adolescents and young adults.

BACKGROUND: Tobacco use has been found to be more prevalent among lesbian, gay, bisexual, and transgender (LGBT) adults than among the general population, but there is little information about LGBT youth. This study examined tobacco use in relation to sexual identity in a community venue-based sample of youth. METHODS: Time-space sampling was used to select individuals aged 13-24 years visiting venues frequented by both LGBT and non-LGBT youth, including drop-in and recreational centers, cafes, bars, and a park. ORs for the association between LGBT identity and tobacco use were estimated using logistic regression models with adjustment for demographic covariates and venue selection. The two main outcomes were lifetime and last-30-day cigarette smoking. Sixteen secondary outcomes pertained to the type, initiation, frequency, and quantity of tobacco use; symptoms of dependence; and cessation. RESULTS: Seventy-seven percent (500/653) of eligible participants completed surveys by interview in 2005-2006. Sixty-three percent smoked in the last 30 days, 22% smoked more than 30 days ago, and 17% reported no prior cigarette smoking. LGBT identity predicted any prior cigarette use (OR 2.2, 95% CI=1.7, 3.2), but not recent use. Compared to non-LGBT youth, LGBT participants were less likely to use smokeless tobacco (OR 0.6, 95% CI=0.5, 0.7) and to want to quit smoking cigarettes (OR 0.6, 95% CI=0.5, 0.8). Other tobacco-related attitudes and behaviors were similar. CONCLUSIONS: Few meaningful differences in tobacco use were related to sexual identity. The remarkably high levels of cigarette smoking in the sample highlights the need for prevention and cessation resources.

Cerebral malaria in children is associated with long-term cognitive impairment.

OBJECTIVE: Cerebral malaria affects >785000 African children every year. We previously documented an increased frequency of cognitive impairment in children with cerebral malaria 6 months after their initial malaria episode. This study was conducted to determine the long-term effects of cerebral malaria on the cognitive function of these children. METHODS: Children who were 5 to 12 years of age and presented to Mulago Hospital, Kampala, Uganda, with cerebral malaria (n = 44) or uncomplicated malaria (n = 54), along with healthy, asymptomatic community children (n = 89), were enrolled in a prospective cohort study of cognition. Cognitive testing was performed at enrollment and 2 years later. The primary outcome was presence of a deficit in >or=1 of 3 cognitive areas tested. RESULTS: At 2-year follow-up testing, 26.3% of children with cerebral malaria and 12.5% with uncomplicated malaria had cognitive deficits in >or=1 area, as compared with 7.6% of community children. Deficits in children with cerebral malaria were primarily in the area of attention (cerebral malaria, 18.4%, vs community children, 2.5%). After adjustment for age, gender, nutrition, home environment, and school level, children with cerebral malaria had a 3.67-fold increased risk for a cognitive deficit compared with community children. Cognitive impairment at 2-year follow-up was associated with hyporeflexia on admission and neurologic deficits 3 months after discharge. CONCLUSIONS: Cerebral malaria is associated with long-term cognitive impairments in 1 of 4 child survivors. Future studies should investigate the mechanisms involved so as to develop interventions aimed at prevention and rehabilitation.

Cerebrospinal fluid cytokine levels and cognitive impairment in cerebral malaria.

Cerebrospinal fluid (CSF) and serum levels of 12 cytokines or chemokines important in central nervous system (CNS) infections were measured in 76 Ugandan children with cerebral malaria (CM) and 8 control children. As compared with control children, children with cerebral malaria had higher cerebrospinal fluid levels of interleukin (IL)-6, CXCL-8/IL-8, granulocyte-colony stimulating factor (G-CSF), tumor necrosis factor-alpha (TNF-alpha), and IL-1 receptor antagonist. There was no correlation between cerebrospinal and serum cytokine levels for any cytokine except G-CSF. Elevated cerebrospinal fluid but not serum TNF-alpha levels on admission were associated with an increased risk of neurologic deficits 3 months later (odds ratio 1.55, 95% CI: 1.10, 2.18, P = 0.01) and correlated negatively with age-adjusted scores for attention (Spearman rho, -0.34, P = 0.04) and working memory (Spearman rho, -0.32, P = 0.06) 6 months later. In children with cerebral malaria, central nervous system TNF-alpha production is associated with subsequent neurologic and cognitive morbidity.

How far from non-differential does exposure or disease misclassification have to be to bias measures of association away from the null?

A well-known heuristic in epidemiology is that non-differential exposure or disease misclassification biases the expected values of an estimator toward the null value. This heuristic works correctly only when additional conditions are met, such as independence of classification errors. We present examples to show that, even when the additional conditions are met, if the misclassification is only approximately non-differential, then bias is not guaranteed to be toward the null. In light of such examples, we advise that evaluation of misclassification should not be based on the assumption of exact non-differentiality unless the latter can be deduced logically from the facts of the situation.

Uncertainty analysis: an example of its application to estimating a survey proportion.

Uncertainty analysis is a method, established in engineering and policy analysis but relatively new to epidemiology, for the quantitative assessment of biases in the results of epidemiological studies. Each uncertainty analysis is situation specific, but usually involves four main steps: (1) specify the target parameter of interest and an equation for its estimator; (2) specify the equation for random and bias effects on the estimator; (3) specify prior probability distributions for the bias parameters; and (4) use Monte-Carlo or analytic techniques to propagate the uncertainty about the bias parameters through the equation, to obtain an approximate posterior probability distribution for the parameter of interest. A basic example is presented illustrating uncertainty analyses for four proportions estimated from a survey of the epidemiological literature.

Cognitive impairment after cerebral malaria in children: a prospective study.

OBJECTIVE: This study was conducted to assess prospectively the frequency of cognitive deficits in children with cerebral malaria. METHODS: Cognitive testing in the areas of working memory, attention, and learning was performed for Ugandan children 5 to 12 years of age with cerebral malaria (n = 44), children with uncomplicated malaria (n = 54), and healthy community children (n = 89) at admission and 3 and 6 months later. RESULTS: Six months after discharge, 21.4% of children with cerebral malaria had cognitive deficits, compared with 5.8% of community children. Deficits were seen in the areas of working memory (11.9% vs 2.3%) and attention (16.7% vs 2.3%). Children with cerebral malaria had a 3.7-fold increased risk of a cognitive deficit, compared with community children, after adjustment for age, gender, nutritional status, school level, and home environment. Among children with cerebral malaria, those with a cognitive deficit had more seizures before admission (mean: 4.1 vs 2.2) and a longer duration of coma (43.6 vs 30.5 hours), compared with those without a deficit. Children with uncomplicated malaria did not have an increased frequency of cognitive deficits. CONCLUSIONS: Cerebral malaria may be a major cause of cognitive impairment in children in sub-Saharan Africa. Cognitive deficits in children with cerebral malaria are more likely for those who have multiple seizures before effective treatment for cerebral malaria.

Exposure-measurement error is frequently ignored when interpreting epidemiologic study results.

INTRODUCTION: One important source of error in study results is error in measuring exposures. When interpreting study results, one should consider the impact that exposure-measurement error (EME) might have had on study results. METHODS: To assess how often this consideration is made and the form it takes, journal articles were randomly sampled from original articles appearing in the American Journal of Epidemiology and Epidemiology in 2001, and the International Journal of Epidemiology between December 2000 and October 2001. RESULTS: Twenty-two (39%) of the 57 articles surveyed mentioned nothing about EME. Of the 35 articles that mentioned something about EME, 16 articles described qualitatively the effect EME could have had on study results. Only one study quantified the impact of EME on study results; the investigators used a sensitivity analysis. Few authors discussed the measurement error in their study in any detail. CONCLUSIONS: Overall, the potential impact of EME on error in epidemiologic study results appears to be ignored frequently in practice.