Ian W. McKeague

Wavelet Methods for Curve Estimation

Abstract The theory of wavelets is a developing branch of mathematics with a wide range of potential applications. Compactly supported wavelets are particularly interesting because of their natural ability to represent data with intrinsically local properties. They are useful for the detection of edges and singularities in image and sound analysis and for data compression. But most of the wavelet-based procedures currently available do not explicitly account for the presence of noise in the data. A discussion of how this can be done in the setting of some simple nonparametric curve estimation problems is given. Wavelet analogies of some familiar kernel and orthogonal series estimators are introduced, and their finite sample and asymptotic properties are studied. We discover that there is a fundamental instability in the asymptotic variance of wavelet estimators caused by the lack of translation invariance of the wavelet transform. This is related to the properties of certain lacunary sequences. The practi...

Extending the scope of empirical likelihood

This article extends the scope of empirical likelihood methodology ill three directions: to allow for plug-in estimates Of nuisance parameters in estimating equations, slower than root 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 call be used in such situations. We provide a range of examples from survival analysis and nonparametric statistics to illustrate the main results.

Prenatal exposure to maternal infection and executive dysfunction in adult schizophrenia.

OBJECTIVE Executive dysfunction is one of the most prominent and functionally important cognitive deficits in schizophrenia. Although strong associations have been identified between executive impairments and structural and functional prefrontal cortical deficits, the etiological factors that contribute to disruption of this important cognitive domain remain unclear. Increasing evidence suggests that schizophrenia has a neurodevelopmental etiology, and several prenatal infections have been associated with risk of this disorder. The authors examined whether prenatal infection is associated with executive dysfunction in patients with schizophrenia. METHOD The authors assessed the relationship between serologically documented prenatal exposure to influenza and toxoplasmosis and performance on the Wisconsin Card Sorting Test and the Trail Making Test, part B (Trails B), as well as other measures of executive function, in 26 patients with schizophrenia from a large and well-characterized birth cohort. RESULTS Patients who were exposed to infection in utero committed significantly more total errors on the Wisconsin Card Sorting Test and took significantly more time to complete the Trails B than unexposed patients. Exposed patients also exhibited deficits on figural fluency, letter-number sequencing, and backward digit span. CONCLUSIONS Prenatal infections previously associated with schizophrenia are related to impaired performance on the Wisconsin Card Sorting Test and Trails B. The pattern of results suggests that cognitive set-shifting ability may be particularly vulnerable to this gestational exposure. Further work is needed to elucidate the specificity of prenatal infection to these executive function measures and to examine correlates with neuroanatomic and neurophysiologic anomalies.

Maternal Iron Deficiency and the Risk of Schizophrenia in Offspring

CONTEXT Iron is essential for brain development and functioning. Emerging evidence suggests that iron deficiency in early life leads to long-lasting neural and behavioral deficits in infants and children. Adopting a life course perspective, we examined the effects of early iron deficiency on the risk of schizophrenia in adulthood. OBJECTIVE To determine whether maternal iron deficiency, assessed by maternal hemoglobin concentration during pregnancy, increases the susceptibility to schizophrenia spectrum disorders (SSDs) among offspring. DESIGN Data were drawn from a population-based cohort born from 1959 through 1967 and followed up for development of SSD from 1981 through 1997. PARTICIPANTS Of 6872 offspring for whom maternal hemoglobin concentration was available, 57 had SSDs (0.8%) and 6815 did not (99.2%). MAIN OUTCOME MEASURE Prospectively assayed, the mean value of maternal hemoglobin concentration was the primary exposure. Hemoglobin concentration was analyzed as a continuous and a categorical variable. RESULTS A mean maternal hemoglobin concentration of 10.0 g/dL or less was associated with a nearly 4-fold statistically significant increased rate of SSDs (adjusted rate ratio, 3.73; 95% confidence interval, 1.41-9.81; P = .008) compared with a mean maternal hemoglobin concentration of 12.0 g/dL or higher, adjusting for maternal education and ethnicity. For every 1-g/dL increase in mean maternal hemoglobin concentration, a 27% decrease in the rate of SSDs was observed (95% confidence interval, 0.55-0.96; P = .02). CONCLUSIONS The findings suggest that maternal iron deficiency may be a risk factor for SSDs among offspring. Given that this hypothesis offers the potential for reducing the risk for SSDs, further investigation in independent samples is warranted.

Some tests for comparing cumulative incidence functions and cause-specific hazard rates

Abstract We consider the competing risks problem with the available data in the form of times and causes of failure. In many practical situations (e.g., in reliability testing) it is important to know whether two risks are equal or whether one is “more serious” than the other. We propose some distribution-free tests for comparing cumulative incidence functions and cause-specific hazard rates against ordered alternatives without making any assumptions on the nature of dependence between the risks. Both the censored and the uncensored cases are studied. The performance of the proposed tests is assessed in a simulation study. As an illustration, we compare the risks of two types of cancer mortality (thymic lymphoma and reticulum cell carcinoma) in a strain of laboratory mice.

Elevated Maternal C-Reactive Protein and Increased Risk of Schizophrenia in a National Birth Cohort

OBJECTIVE The objective of the present study was to investigate an association between early gestational C-reactive protein, an established inflammatory biomarker, prospectively assayed in maternal sera, and schizophrenia in a large, national birth cohort with an extensive serum biobank. METHOD A nested case-control design from the Finnish Prenatal Study of Schizophrenia cohort was utilized. A total of 777 schizophrenia cases (schizophrenia, N=630; schizoaffective disorder, N=147) with maternal sera available for C-reactive protein testing were identified and matched to 777 control subjects in the analysis. Maternal C-reactive protein levels were assessed using a latex immunoassay from archived maternal serum specimens. RESULTS Increasing maternal C-reactive protein levels, classified as a continuous variable, were significantly associated with schizophrenia in offspring (adjusted odds ratio=1.31, 95% confidence interval=1.10-1.56). This finding remained significant after adjusting for potential confounders, including maternal and parental history of psychiatric disorders, twin/singleton birth, urbanicity, province of birth, and maternal socioeconomic status. CONCLUSIONS This finding provides the most robust evidence to date that maternal inflammation may play a significant role in schizophrenia, with possible implications for identifying preventive strategies and pathogenic mechanisms in schizophrenia and other neurodevelopmental disorders.

Prenatal Exposure to Lead, δ-Aminolevulinic Acid, and Schizophrenia : Further Evidence

Background A previously conducted study of prenatal lead exposure and schizophrenia using δ-aminolevulinic acid, a biologic marker of Pb exposure, in archived maternal serum samples collected from subjects enrolled in the Childhood Health and Development Study (1959–1966) based in Oakland, California, suggested a possible association between prenatal Pb exposure and the development of schizophrenia in later life. Objectives In the present study we extend these findings using samples collected from the New England cohort of the National Collaborative Perinatal Project (1959–1966). Using similar methods, in this study we found results that suggest a comparable association in this cohort. Methods We pooled matched sets of cases and controls from both the California and New England sites using a multilevel random-intercept logistic regression model, accounting for matching and site structure as well as adjusting for maternal age at delivery and maternal education. Results The estimated odds ratio for schizophrenia associated with exposure corresponding to 15 μg/dL of blood Pb was 1.92 (95% confidence interval, 1.05–3.87; p = 0.03). Conclusion Although several limitations constrain generalizability, these results are consistent with previous findings and provide further evidence for the role of early environmental exposures in the development of adult-onset psychiatric disorders.

Likelihood Ratio-Based Confidence Bands for Survival Functions

Abstract Thomas and Grunkemeier introduced a nonparametric likelihood ratio approach to confidence interval estimation of survival probabilities based on right-censored data. We construct simultaneous confidence bands using this approach. The boundaries of the bands are contained within [0, 1]. A procedure essentially equivalent to a bias correction is developed. The resulting increase in coverage accuracy is illustrated by an example and a simulation study. We look at various versions of log-likelihood ratio-based confidence bands and compare them to the Hall-Wellner band and Nairs equal precision band. We also construct likelihood ratio-based bands for cumulative hazard functions.

Simultaneous confidence bands for ratios of survival functions via empirical likelihood

We derive a simultaneous confidence band for the ratio of two survival functions based on independent right-censored data. Earlier authors have studied such bands for the difference of two survival functions, but the ratio provides a more appropriate comparison in some applications, e.g., in comparing two treatments in biomedical settings. Our approach is formulated in terms of empirical likelihood and allows us to avoid the use of simulation techniques that are often needed for Wald-type confidence bands. By the transformation-preserving property we also obtain confidence bands for the difference in the cumulative hazard functions. The approach is illustrated with a real data example.

Pregnancy Complications Following Prenatal Exposure to SSRIs or Maternal Psychiatric Disorders: Results From Population-Based National Register Data

OBJECTIVE Using national register data, the authors examined the relationship between prenatal selective serotonin reuptake inhibitor (SSRI) treatment and pregnancy complications, accounting for psychiatric diagnoses related to SSRI use. METHOD This was a population-based prospective birth cohort study using national register data. The sampling frame included 845,345 offspring, representing all singleton live births in Finland between 1996 and 2010. Pregnancies were classified as exposed to SSRIs (N=15,729), unexposed to SSRIs but with psychiatric diagnoses (N=9,652), and unexposed to medications and psychiatric diagnoses (N=31,394). Pregnancy outcomes in SSRI users were compared with those in the unexposed groups. RESULTS Offspring of mothers who received SSRI prescriptions during pregnancy had a lower risk for late preterm birth (odds ratio=0.84, 95% CI=0.74-0.96), for very preterm birth (odds ratio=0.52, 95% CI=0.37-0.74), and for cesarean section (odds ratio=0.70, 95% CI=0.66-0.75) compared with offspring of mothers unexposed to medications but with psychiatric disorders. In contrast, in SSRI-treated mothers, the risk was higher for offspring neonatal complications, including low Apgar score (odds ratio=1.68, 95% CI=1.34-2.12) and monitoring in a neonatal care unit (odds ratio=1.24, 95% CI=1.14-1.35). Compared with offspring of unexposed mothers, offspring of SSRI-treated mothers and mothers unexposed to medications but with psychiatric disorders were both at increased risk of many adverse pregnancy outcomes, including cesarean section and need for monitoring in a neonatal care unit. CONCLUSIONS In a large national birth cohort, treatment of maternal psychiatric disorders with SSRIs during pregnancy was related to a lower risk of preterm birth and cesarean section but a higher risk of neonatal maladaptation. The findings provide novel evidence for a protective role of SSRIs on some deleterious reproductive outcomes, possibly by reducing maternal depressive symptoms. The divergent findings suggest that clinical decisions on SSRI use during pregnancy should be individualized, taking into account the mothers psychiatric and reproductive history.