This article extends the scope of empirical likelihood methodology in three directions: to allow for plug-in estimates of nuisance parameters in estimating equations, slower than $\sqrt{n}$-rates of convergence, and settings in which there are a relatively large number of estimating equations compared to the sample size. Calibrating empirical likelihood confidence regions with plug-in is sometimes intractable due to the complexity of the asymptotics, so we introduce a bootstrap approximation that can be used in such situations. We provide a range of examples from survival analysis and nonparametric statistics to illustrate the main results.Comment: Published in at http://dx.doi.org/10.1214/07-AOS555 the Annals of Statistics (http://www.imstat.org/aos/) by the Institute of Mathematical Statistics (http://www.imstat.org

BACKGROUND AND OBJECTIVE: In adults, leukocyte telomere length (LTL) is variable, familial, and longer in women and in offspring conceived by older fathers. Although short LTL is associated with atherosclerotic cardiovascular disease, long LTL is associated with major cancers. The prevailing notion is that LTL is a "telomeric clock, " whose movement (expressed in LTL attrition) reflects the pace of aging. Accordingly, individuals with short LTL are considered to be biologically older than their peers. Recent studies suggest that LTL is largely determined before adulthood. We examined whether factors that largely characterize LTL in adults also influence LTL in newborns.

Autism is a complex neuropsychiatric syndrome with a largely unknown etiology. Inflammation during pregnancy may represent a common pathway by which infections and other insults increase risk for the disorder. Hence, we investigated the association between early gestational C-reactive protein (CRP), an established inflammatory biomarker, prospectively assayed in maternal sera, and childhood autism in a large national birth cohort with an extensive serum biobank. Other strengths of the cohort included nearly complete ascertainment of pregnancies in Finland (N=1.2 million) over the study period and national psychiatric registries consisting of virtually all treated autism cases in the population. Increasing maternal CRP levels, classified as a continuous variable, were significantly associated with autism in offspring. For maternal CRP levels in the highest quintile, compared to the lowest quintile, there was a significant, 43% elevated risk. This finding suggests that maternal inflammation may play a significant role in autism, with possible implications for identifying preventive strategies and pathogenic mechanisms in autism and other neurodevelopmental disorders.

Objective To investigate the impact of gestational exposure to selective serotonin reuptake inhibitors (SSRIs) on offspring neurodevelopment. Method This is a cohort study using national register data in Finland between the years 1996-2010. Pregnant women and their offspring were categorized into four groups: SSRI exposed (n=15,729); exposed to psychiatric disorder, no antidepressants (n=9,651); exposed to SSRIs only before pregnancy (n=7,980); and unexposed to antidepressants and psychiatric disorders (n=31,394). We investigated the cumulative incidence of offspring diagnoses of depression, anxiety, autism spectrum disorders (ASDs), and attention-deficit/hyperactivity disorders (ADHD) for the four groups from birth to 14 years, adjusting for confounders. Results The cumulative incidence of depression among offspring exposed prenatally to SSRIs was 8.2% (95% CI, 3.1-13.3%) by age 14.9, compared to 1.9% (95% CI, 0.9-2.9%) in the psychiatric disorder, no medication group (adjusted hazard ratio [HR], 1.78; 95% CI, 1.12-2.82; p=.02) and to 2.8% (95% CI, 1.4-4.3%) in the SSRI discontinued group (HR 1.84; 95% CI, 1.14-2.97; p=.01). Rates of anxiety, ASD, and ADHD diagnoses were comparable to rates in offspring of mothers with a psychiatric disorder but no medication during pregnancy. Comparing SSRI exposed to unexposed, the HRs were significantly elevated for each outcome. Conclusion Prenatal SSRI exposure was associated with increased rates of depression diagnoses in early adolescence but not with ASD or ADHD. Until confirmed, these findings must be balanced against the substantial adverse consequences of untreated maternal depression.

Context Prenatal folic acid supplements reduce the risk of neural tube defects and may have beneficial effects on other aspects of neurodevelopment. Objective To examine associations between mothers' use of prenatal folic acid supplements and risk of severe language delay in their children at age 3 years. Design, Setting, and Patients The prospective observational Norwegian Mother and Child Cohort Study recruited pregnant women between 1999 and December 2008. Data on children born before 2008 whose mothers returned the 3-year follow-up questionnaire by June 16, 2010, were used. Maternal use of folic acid supplements within the interval from 4 weeks before to 8 weeks after conception was the exposure. Relative risks were approximated by estimating odds ratios (ORs) with 95% CIs in a logistic regression analysis. Main Outcome Measure Children's language competency at age 3 years measured by maternal report on a 6-point ordinal language grammar scale. Children with minimal expressive language (only 1-word or unintelligible utterances) were rated as having severe language delay. Results Among 38 954 children, 204 (0.5%) had severe language delay. Children whose mothers took no dietary supplements in the specified exposure interval were the reference group (n=9052 [24.0%], with severe language delay in 81 children [0.9%]). Adjusted ORs for 3 patterns of exposure to maternal dietary supplements were (1) other supplements, but no folic acid (n=2480 [6.6%], with severe language delay in 22 children [0.9%]; OR, 1.04; 95% CI, 0.62-1.74); (2) folic acid only (n=7127 [18.9%], with severe language delay in 28 children [0.4%]; OR, 0.55; 95% CI, 0.35-0.86); and (3) folic acid in combination with other supplements (n=19005 [50.5%], with severe language delay in 73 children [0.4%]; OR, 0.55; 95% CI, 0.39-0.78). Conclusion Among this Norwegian cohort of mothers and children, maternal use of folic acid supplements in early pregnancy was associated with a reduced risk of severe language delay in children at age 3 years.