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Medical research is often designed to investigate changes in a collection of response variables that are measured repeatedly on the same subjects. The multivariate generalized linear mixed model (MGLMM) can be used to evaluate random coefficient associations (e.g. simple correlations, partial regression coefficients) among outcomes that may be non-normal and differently distributed by specifying a multivariate normal distribution for their random effects and then evaluating the latent relationship between them. Empirical Bayes predictors are readily available for each subject from any mixed model and are observable and hence, plotable. Here, we evaluate whether second-stage association analyses of empirical Bayes predictors from a MGLMM, provide a good approximation and visual representation of these latent association analyses using medical examples and simulations. Additionally, we compare these results with association analyses of empirical Bayes predictors generated from separate mixed models for each outcome, a procedure that could circumvent computational problems that arise when the dimension of the joint covariance matrix of random effects is large and prohibits estimation of latent associations. As has been shown in other analytic contexts, the p-values for all second-stage coefficients that were determined by naively assuming normality of empirical Bayes predictors provide a good approximation to p-values determined via permutation analysis. Analyzing outcomes that are interrelated with separate models in the first stage and then associating the resulting empirical Bayes predictors in a second stage results in different mean and covariance parameter estimates from the maximum likelihood estimates generated by a MGLMM. The potential for erroneous inference from using results from these separate models increases as the magnitude of the association among the outcomes increases. Thus if computable, scatterplots of the conditionally independent empirical Bayes predictors from a MGLMM are always preferable to scatterplots of empirical Bayes predictors generated by separate models, unless the true association between outcomes is zero.

Mediation analysis evaluates the significance of an intermediate variable on the causal pathway between an exposure and an outcome. One commonly utilized test for mediation involves evaluation of counterfactual effects, estimated from separate regression models, corresponding to a composite null hypothesis. However, the “compositeness” of this null hypothesis is not commonly acknowledged and accounted for in mediation analyses. We describe a generalized multivariate approach in which these separate regression models are fit simultaneously in a single parsimonious model. This multivariate modeling approach can reproduce standard mediation analysis and has notable advantages over separate regression models, including the ability to combine distributions in the exponential family with any link functions and perform likelihood-based tests of some relevant hypotheses using existing software. We propose the use of a novel visual representation of confidence intervals of the two estimates for the indirect path with the use of a confidence ellipse. The calculation of the confidence ellipse is facilitated by the multivariate approach, can test the components of the composite null hypothesis under a single experiment-wise type I error rate, and does not require estimation of the standard error of the product of coefficients from two separate regressions. This method is illustrated using three examples. The first compares results between the multivariate method and separate regression models. The second example illustrates the proposed methods in the presence of an exposure–mediator interaction, missing data and confounding, and the third example utilizes these proposed methods for an outcome and mediator with negative binomial distributions.

ObjectivesPreviously, we found that omega-3 fatty acids (n-3 FAs) were inversely associated with anti-cyclic citrullinated peptide (anti-CCP) positivity in participants at risk for future rheumatoid arthritis (RA). We investigated whether n-3 FAs were also associated with rheumatoid factor (RF) positivity and whether these associations were modified by shared epitope (SE) positivity.MethodsThe Studies of the Etiology of RA (SERA) cohort includes RA-free participants who are at increased risk for RA. We conducted a nested case–control study (n=136) to determine the association between RF and anti-CCP2 positivity and n-3 FA percentage in erythrocyte membranes (n-3 FA% in red blood cells (RBCs)). Additionally, in the baseline visit of the SERA cohort (n=2166), we evaluated the association between reported n-3 FA supplement use and prevalence of RF and anti-CCP2. We assessed SE positivity as an effect modifier.ResultsIn the case–control study, increasing n-3 FA% in RBCs was inversely associated with RF positivity in SE-positive participants (OR 0.27, 95% CI 0.10 to 0.79), but not SE-negative participants. Similar associations were seen with anti-CCP positivity in SE-positive participants (OR 0.42, 95% CI 0.20 to 0.89), but not SE-negative participants. In the SERA cohort at baseline, n-3 FA supplement use was associated with a lower prevalence of RF positivity in SE-positive participants (OR 0.32, 95% CI 0.12 to 0.82), but not SE-negative participants; similar but non-significant trends were observed with anti-CCP2.ConclusionsThe potential protective effect of n-3 FAs on RA-related autoimmunity may be most pronounced in those who exhibit HLA class II genetic susceptibility to RA.

Objective:α7-Nicotinic receptors are involved in the final maturation of GABA inhibitory synapses before birth. Choline at levels found in the amniotic fluid is an agonist at α7-nicotinic receptors. The authors conducted a double-blind placebo-controlled trial to assess whether high-dose oral phosphatidylcholine supplementation during pregnancy to increase maternal amniotic fluid choline levels would enhance fetal development of cerebral inhibition and, as a result, decrease childhood behavior problems associated with later mental illness.Method:The authors previously reported that newborns in the phosphatidylcholine treatment group have increased suppression of the cerebral evoked response to repeated auditory stimuli. In this follow-up, they report parental assessments of the children’s behavior at 40 months of age, using the Child Behavior Checklist.Results:At 40 months, parent ratings of children in the phosphatidylcholine group (N=23) indicated fewer attention problems and less social withdrawal comp...

Objective. The aim of this study was to investigate omega-3 fatty acid (FA) supplement use and omega-3 FAs in erythrocyte membranes [omega-3 FA % in erythrocyte membranes (RBC)] and their association with anti-CCP autoantibodies in a population without RA, but who are at genetic risk for RA. Methods. The multicentre Studies of the Etiology of RA (SERA) cohort includes RA-free subjects who are first-degree relatives of RA probands or are enriched with the HLA-DR4 allele. In a nested case-control study, 30 SERA cases were identified who were anti-CCP2 antibody positive. We further identified 47 autoantibody negative controls, frequency matched to cases on age at study visit, sex, race and study site. Anti-CCP2 status, self-reported omega-3 FA supplement use and omega-3 FA % in RBCs were obtained from a single visit. Results. Anti-CCP2 positive cases were less likely than controls to report omega-3 FA supplement use (odds ratio: 0.14; 95% CI 0.03, 0.68). In addition, the likelihood of anti-CCP2 positivity was inversely associated with total omega-3 FA % in RBCs (odds ratio: 0.47; 95% CI 0.24, 0.92, for a s.d. increase). Conclusion. The inverse association between anti-CCP2 positivity and self-reported omega-3 FA supplement use and omega-3 FA % in RBCs suggests that omega-3 FAs may protect against the development of RA-related autoimmunity in pre-clinical RA.

ObjectiveWe investigated whether rheumatoid arthritis (RA)-related autoantibodies were associated with systemic inflammation in a prospective cohort of first-degree relatives (FDRs) of RA probands, a population without RA but at increased risk for its future development.MethodsWe studied 44 autoantibody positive FDRs, of whom 29 were rheumatoid factor (RF) positive, 25 were positive for the high risk autoantibody profile (HRP), that is, positive for anti-cyclic citrullinated peptide and/or for at least two RF IgM, IgG or IgA isotypes, and nine FDRs who were positive for both; and 62 FDRs who were never autoantibody positive. Twenty-five cytokines/chemokines were measured using a bead-based assay in serum. As a comprehensive measure of inflammation, we calculated a Cytokine Score by summing all cytokine/chemokine levels, weighted by their regression coefficients for RA-autoantibody association. We compared C-reactive protein, individual cytokines/chemokines and Cytokine Score to the outcomes: positivity for RF and for the HRP using logistic regression.ResultsAdjusting for age, sex, ethnicity and ever smoking, the Cytokine Score and levels of IL-6 and IL-9 were associated with both RF and HRP. IL-2, granulocyte macrophage-colony stimulating factor (GM-CSF), and interferon (IFN)-γ were associated with HRP only. Associations between the Cytokine Score and RF and HRP positivity were replicated in an independent military personnel cohort.ConclusionsIn first-degree relatives of patients with RA, RA-related autoimmunity is associated with inflammation, as evidenced by associations with multiple cytokines and chemokines.

It is unclear whether information obtained from a one parent can be used to infer the other parent's history of psychopathology. Two hundred and one parental dyads were asked to complete psychiatric interviews. Based on maternal report, non-participating husbands/ fathers had higher rates than participating fathers of psychiatric illness. For fathers who did participate, maternal report did not match direct interview of paternal psychopathology with sensitivities less than 0.40 and positive predictive values of 0.33 to 0.74. Psychopa -thology may be over-represented among fathers who do not participate in research. Mother report of paternal symptoms is not an effective proxy. Alternative methods need to be developed to: i) improve father participation or ii) identify psychiatric status in fathers who do not participate in research projects.

Prenatal maternal anxiety has detrimental effects on the offspring's neurocognitive development, including impaired attentional function. Antidepressants are commonly used during pregnancy, yet their impact on offspring attention and their interaction with maternal anxiety has not been assessed. The authors used P50 auditory sensory gating, a putative marker of early attentional processes measurable in young infants, to assess the impact of maternal anxiety and antidepressant use.A total of 242 mother-infant dyads were classified relative to maternal history of anxiety and maternal prenatal antidepressant use. Infant P50 auditory sensory gating was recorded during active sleep at a mean age of 76 days (SD=38).In the absence of prenatal antidepressant exposure, infants whose mothers had a history of anxiety diagnoses had diminished P50 sensory gating. Prenatal antidepressant exposure mitigated the effect of anxiety. The effect of maternal anxiety was limited to amplitude of response to the second stimulus, while antidepressant exposure had an impact on the amplitude of response to both the first and second stimulus.Maternal anxiety disorders are associated with less inhibition during infant sensory gating, a performance deficit mitigated by prenatal antidepressant exposure. This effect may be important in considering the risks and benefits of antidepressant use during pregnancy. Cholinergic mechanisms are hypothesized for both anxiety and antidepressant effects, although the cholinergic receptors involved are likely different for anxiety and antidepressant effects.

Researchers often compare the relationship between an outcome and covariate for two or more groups by evaluating whether the fitted regression curves differ significantly. When they do, researchers need to determine the “significance region,” or the values of the covariate where the curves significantly differ. In analysis of covariance (ANCOVA), the Johnson-Neyman procedure can be used to determine the significance region; for the hierarchical linear model (HLM), the Miyazaki and Maier (M-M) procedure has been suggested. However, neither procedure can assume nonnormally distributed data. Furthermore, the M-M procedure produces biased (downward) results because it uses the Wald test, does not control the inflated Type I error rate due to multiple testing, and requires implementing multiple software packages to determine the significance region. In this article, we address these limitations by proposing solutions for determining the significance region suitable for generalized linear (mixed) model (GLM or GLMM). These proposed solutions incorporate test statistics that resolve the biased results, control the Type I error rate using Scheffé’s method, and uses a single statistical software package to determine the significance region.

Carriers of fragile X mental retardation 1 repeat expansions in the premutation range (55–200 CGG repeats), especially males, often develop tremor, ataxia, and parkinsonism. These neurological signs are believed to be a result of elevated levels of expanded CGG-repeat fragile X mental retardation 1 mRNA. The purpose of this study was to determine the prevalence of fragile X mental retardation 1 repeat expansions in a movement disorder population comprising subjects with all types of tremor, ataxia, and parkinsonism. We screened 335 consecutive patients with tremor, ataxia, or parkinsonism and 273 controls confirmed to have no movement disorders. There was no difference in fragile X mental retardation 1 premutation size expansions in the cases compared with controls. Eleven percent of the women with Parkinson's disease had fragile X mental retardation 1 gray-zone expansions compared with 4.4% of female controls (odds ratio of 3.2; 95% confidence interval, 1.2–8.7). Gray-zone expansions in patients with other phenotypes were not overrepresented in comparison with controls. Fragile X mental retardation 1 premutation range expansions are not more common in a mixed movement disorder population compared with controls. Our results, however, suggest that fragile X mental retardation 1 gray-zone alleles may be associated with Parkinson's disease in women. © 2011 Movement Disorder Society

We present a permutation approach to testing the linear hypothesis in multivariate general linear models, and apply it to the classical knee stiffness dataset of Ghosh, Grizzle, and Sen. We compare the permutation tests to commonly used approximations to the normal theory tests and conclude that among commonly available software, the SAS procedure GLM with the ‘exact’ option provides the best, albeit conservative, approximation. This article has supplemental material online.

Author(s): Hughes-Austin, Jan M; Deane, Kevin D; Giles, Jon T; Derber, Lezlie A; Zerbe, Gary O; Dabelea, Dana M; Sokolove, Jeremy; Robinson, William H; Holers, V Michael; Norris, Jill M | Abstract: BACKGROUND:Extra-articular manifestations of rheumatoid arthritis (RA), potentially due to systemic inflammation, include cardiovascular disease and sarcopenic obesity. Adiponectin, an adipose-derived cytokine, has been implicated in inflammatory processes in RA, but little is known regarding its association with inflammation in a pre-clinical period. Therefore, we investigated whether adiponectin was associated with inflammatory markers in individuals at risk for RA, and whether RA-related autoimmunity modifies these associations. METHODS:We analyzed samples from 144 first-degree relatives (FDRs) of RA probands, of whom 23 were positive for anti-cyclic citrullinated peptide antibody and/or ≥ 2 rheumatoid factor isotypes (IgM, IgG or IgA). We called this phenotype the 'high risk autoantibody profile (HRP)' as it has been shown in prior work to be g96% specific for future RA. We measured adiponectin, cytokines, and high-sensitivity C-reactive protein (hsCRP). Using linear mixed effects models, we evaluated interaction between HRP positivity and adiponectin on inflammatory markers, adjusting for age, sex, ethnicity, body mass index, pack-years smoking, and use of cholesterol-lowering medications. RESULTS:In everyone, adiponectin concentration was inversely associated with hsCRP and IL-1β in adjusted models, where a 1% higher adiponectin was associated with a 26% lower hsCRP (p = 0.04) and a 26% lower IL-1β (p = 0.04). Significant interactions between HRP and adiponectin for associations with GM-CSF, IL-6, and IL-9 were detected in fully adjusted models (p = 0.0006, p = 0.006, p = 0.01, respectively). In HRP positive FDRs but not HRP negative FDRs, a 1% higher adiponectin was associated with 97% higher GM-CSF, 73% higher IL-6, and 54% higher IL-9 concentrations. CONCLUSIONS:Adiponectin associates with inflammatory markers, and these associations differ in individuals with a high-risk autoantibody profile compared with those without. The interaction between adiponectin and autoimmunity warrants further investigation into the potential systemic effects of RA-related autoantibodies and adiponectin on inflammation in the absence of clinically apparent RA.

Varicella-zoster virus (VZV)–specific cell-mediated immunity responses are essential for recovery from primary (varicella) or reactivation (herpes zoster) infection with VZV [1-4]. Patients who lack adequate VZV-specific cell-mediated immunity often have severe and prolonged infections with VZV, some of which are fatal [3-5]. Thus, VZV-specific cell-mediated immunity is a marker for protection against primary VZV infection, and the presence and magnitude of this response correlates with recovery from varicella and with the incidence and severity of reactivation as manifested by herpes zoster. VZV-specific cell-mediated immunity is also a component of primary responses to varicella vaccine administered to susceptible children and adults and has been used to evaluate candidate vaccines to prevent herpes zoster in immunocompromised and elderly individuals [6-9]. In this report, we present a regression model of VZV-specific memory CD4 responses as a function of age, from early childhood to advanced adulthood among healthy individuals with prior VZV wild-type infectionas a reference against which responses of other select groups of individuals are compared. Comparisons are made to elderly recipients of a zoster vaccine and to human immunodeficiency virus (HIV)–infected children and adults. We demonstrate that VZV-specific cell-mediated immunity is determined by the nature of primary immunization (natural infection vs VZV vaccination) and the age and immune status of the subject tested.

Endophenotypes have been proposed to identify the genetic and biological substrates of complex disorders. Three physiological inhibitory endophenotypes of large effect size in schizophrenia include suppression of P50 auditory evoked responses, inhibition of leading (small anticipatory) saccades during smooth pursuit eye movements, and cancellation of reflexive saccades in the antisaccade eye movement task. The aim of this study was to determine if the pattern of endophenotype abnormalities within individuals with schizophrenia differed from that within individuals with bipolar disorder. A second aim was to determine whether subjects with schizoaffective disorder, bipolar type, were neurophysiologically more similar to subjects with schizophrenia or subjects with bipolar disorder.Endophenotypes were recorded for subjects diagnosed with schizophrenia (N=29), bipolar disorder (DSM-IV-TR) (N=40), and schizoaffective disorder, bipolar type (N=18). Data from normal comparison subjects were used to establish normal performance.Logistic regression determined that P50 ratio and frequency of leading saccades identified subjects with schizophrenia and bipolar disorder with a sensitivity of 95% and a specificity of 83%. The schizoaffective disorder group was split, with six subjects physiologically classified as schizophrenia-like and 12 subjects as bipolar-like. Those classified as schizophrenia-like were significantly younger at illness onset and had higher symptom ratings.A composite endophenotype of P50 ratio and frequency of leading saccades is consistent with the current clinical nosology of schizophrenia and bipolar disorder and parses patients with schizoaffective disorder, bipolar type, into two subgroups.

Cognitive deficits are a central feature of schizophrenia and occur in first-degree relatives of schizophrenic probands, even in the absence of psychotic symptoms. A number of cognitive domains have been implicated including measures of response inhibition and working memory. While the stability of cognitive deficits has been demonstrated in individuals with schizophrenia, stability of deficits has not been explored in first-degree relatives. This report focuses on 25 children (ages 6–15 years), all with at least one schizophrenic parent. The children were assessed twice, utilizing inhibitory and working memory tasks, with a mean 2.6 years between visits. Stop reaction time (a measure of motor inhibition) and performance on a counting span task (a measure of verbal working memory) were borderline to mildly impaired (compared with a typically developing comparison group) at both visits with similar effect sizes (stopping task time 1, effect size = 0.46, time 2 effect size = 0.50; counting span time 1 effect size = 0.53, time 2 effect size = 0.42). For these 2 tasks, individual age-adjusted scores also correlated across both time points (r = 0.41–0.76) suggesting that individual children maintained deficits across time. As etiologically driven strategies are developed for the cognitive deficits of schizophrenia, expansion of these treatments to relatives who share the cognitive but not the psychotic symptoms may be worth exploring.

We measured the impact of chronic late gestation hypoglycemia on pancreatic islet structure and function to determine the cause of decreased insulin secretion in this sheep model of fetal nutrient deprivation. Late gestation hypoglycemia did not decrease pancreas weight, insulin content, β-cell area, β-cell mass, or islet size. The pancreatic islet isolation procedure selected a group of islets that were larger and had an increased proportion of β-cells compared with islets measured in pancreatic sections, but there were no morphologic differences between islets isolated from control and hypoglycemic fetuses. The rates of glucose-stimulated pancreatic islet glucose utilization (126.2 ± 25.3 pmol glucose·islet−1·h−1, hypoglycemic, vs. 93.5 ± 5.5 pmol glucose·islet−1·h−1, control, P = 0.47) and oxidation (10.5 ± 1.7 pmol glucose·islet−1·h−1, hypoglycemic, vs. 10.6 ± 1.6 pmol glucose·islet−1·h−1, control) were not different in hypoglycemic fetuses compared with control fetuses. Chronic late gestation hypoglycemia decreased insulin secretion in isolated pancreatic islets by almost 70% in response to direct nonnutrient membrane depolarization and in response to increased extracellular calcium entry. β-Cell ultrastructure was abnormal with markedly distended rough endoplasmic reticulum in three of the seven hypoglycemic fetuses studied, but in vitro analysis of hypoglycemic control islets showed no evidence that these changes represented endoplasmic reticulum stress, as measured by transcription of glucose regulatory protein-78 and processing of X-box binding protein-1. In conclusion, these studies show that chronic hypoglycemia in late gestation decreases insulin secretion by inhibiting the later steps of stimulus-secretion coupling after glucose metabolism, membrane depolarization, and calcium entry.

Neural mechanisms underlying the reinforcing effects of nicotine and other drugs have been widely studied and are known to involve the ventral striatum, which is part of the mesocorticolimbic dopamine system. In contrast, mechanisms of nicotine withdrawal have received less attention although subjective withdrawal likely contributes to the difficulty of quitting. The goal of this study was to determine if nicotine withdrawal was associated with alterations of cerebral blood flow (CBF) in ventral striatum. Twelve smokers, moderately dependent on nicotine, underwent MR dynamic susceptibility contrast (DSC) imaging at baseline, after overnight withdrawal from nicotine, and after nicotine replacement. DSC images were used to calculate CBF in three regions of interest: ventral striatum, thalamus, and medial frontal cortex. Subjective withdrawal symptoms were measured at each time point. In spite of significant subjective withdrawal symptoms, there was no main effect of withdrawal on CBF in the three regions. However, there was a significant correlation between the increase in withdrawal symptoms and a reduction in thalamic CBF. In contrast to withdrawal, nicotine replacement significantly increased CBF in ventral striatum. Our findings are consistent with the known role of ventral striatum in drug reward. The lack of a main effect on withdrawal, but correlation of thalamic blood flow with withdrawal symptoms suggests that more complex mechanisms mediate the subjective features of the withdrawal state.

Background Herpes zoster vaccine (ZV) was administered as a second dose to 200 participants ≥ 70 years old who had received a dose of ZV ≥ 10 years previously (NCT01245751). Methods Varicella zoster virus (VZV) antibody titers (measured by a VZV glycoprotein-based enzyme-linked immunosorbent assay [gpELISA]) and levels of interferon γ (IFN-γ) and interleukin 2 (IL-2; markers of VZV-specific cell-mediated immunity [CMI], measured by means of ELISPOT analysis) in individuals aged ≥ 70 years who received a booster dose of ZV were compared to responses of 100 participants aged 50-59 years, 100 aged 60-69 years, and 200 aged ≥ 70 years who received their first dose of ZV. The study was powered to demonstrate noninferiority of the VZV antibody response at 6 weeks in the booster-dose group, compared with the age-matched first-dose group. Results Antibody responses were similar at baseline and after vaccination across all age and treatment groups. Both baseline and postvaccination VZV-specific CMI were lower in the older age groups. Peak gpELISA titers and their fold rise from baseline generally correlated with higher baseline and postvaccination VZV-specific CMI. IFN-γ and IL-2 results for subjects ≥ 70 years old were significantly higher at baseline and after vaccination in the booster-dose group, compared with the first-dose group, indicating that a residual effect of ZV on VZV-specific CMI persisted for ≥ 10 years and was enhanced by the booster dose. Conclusions These findings support further investigation of ZV administration in early versus later age and of booster doses for elderly individuals at an appropriate interval after initial immunization against HZ. Clinical trials registration NCT01245751.

Objective: To examine perinatal and childhood risk factors for the presence of rheumatoid factor in healthy children. Methods: The Diabetes Autoimmunity Study in the Young (DAISY) is a longitudinal study of children at increased risk of type 1 diabetes, based on possession of human leucocyte antigen (HLA)-DR4 and DR3 alleles or a family history of diabetes. 651 children who participated in DAISY, with an average age of 6.4 (range 1–15) years, were tested for the presence of rheumatoid factor in their most recent serum sample. 23 children were positive for rheumatoid factor. Exposure data were collected prospectively by interview. HLA-DR4 alleles were identified using polymerase chain reaction-based Class II genotyping. Results: While exploring risk factors for rheumatoid factor positivity in a multivariate model, several important interaction terms involving HLA-DR4 status suggested the need to evaluate risk factors in HLA-DR4-positive and HLA-DR4-negative children separately. In HLA-DR4-negative children, rheumatoid factor-positive infants were less likely to have been breast fed for >3 months (odds ratio (OR) 0.18; 95% confidence interval (CI) 0.04 to 0.99), more likely to have been exposed to non-parental tobacco smoke (OR 5.38; 95% CI 0.93 to 31.27) and more likely to be a race/ethnicity other than non-Hispanic white (OR 6.94; 95% CI 1.10 to 43.88) compared with rheumatoid factor-negative children, after adjusting for age, sex and maternal education. In HLA-DR4-positive children, there were no significantly associated risk factors for rheumatoid factor positivity. Conclusions: Risk factors for rheumatoid factor positivity in children vary by HLA-DR4 genotype. In HLA-DR4-negative children, breast feeding may decrease the risk, and environmental tobacco smoke may increase the risk, of autoimmunity.

The aim of the study was to evaluate the impact of clinical severity and placental weight upon fetal lactacidemia in intrauterine growth restricted (IUGR) pregnancies. Seventy pregnancies complicated by IUGR were compared with 70 normal (appropriate for gestational age, AGA) pregnancies at the time of elective cesarean section. IUGR pregnancies were divided according to clinical severity in three groups: Group 1 had normal fetal heart rate (FHR) and normal pulsatility index of the umbilical artery (PI); Group 2 had normal FHR and abnormal PI; and Group 3 had abnormal FHR and PI. No cases with severe lactacidemia had placental weightsor=250 g. Forty-four fetuses had placental weight250 g: Twenty-four had severe lactacidemia and all were Group 2 and 3, whereas 20 had normal umbilical artery lac (lactate) (and small placentas) regardless of the clinical severity. Gestational age, fetal and placental weights, F/P ratios, uv (umbilical vein) and ua lac and ua oxygen content and pH were significantly decreased in fetuses with small placentas and high lactate. There was a significant relationship between fetal and placental weight in AGA and IUGR. However, IUGR fetuses with placental weightor=250 g exhibited an F/P ratio significantly lower than that in AGA fetuses suggesting that IUGR may be due to a reduction of placental function per gram of tissue.

We determined in vivo and in vitro pancreatic islet insulin secretion and glucose metabolism in fetuses with intrauterine growth restriction (IUGR) caused by chronic placental insufficiency to identify functional deficits in the fetal pancreas that might be caused by nutrient restriction. Plasma insulin concentrations in the IUGR fetuses were 69% lower at baseline and 76% lower after glucose-stimulated insulin secretion (GSIS). Similar deficits were observed with arginine-stimulated insulin secretion. Fetal islets, immunopositive for insulin and glucagon, secreted insulin in response to increasing glucose and KCl concentrations. Insulin release as a fraction of total insulin content was greater in glucose-stimulated IUGR islets, but the mass of insulin released per IUGR islet was lower because of their 82% lower insulin content. A deficiency in islet glucose metabolism was found in the rate of islet glucose oxidation at maximal stimulatory glucose concentrations (11 mmol/liter). Thus, pancreatic islets from nutritionally deprived IUGR fetuses caused by chronic placental insufficiency have impaired insulin secretion caused by reduced glucose-stimulated glucose oxidation rates, insulin biosynthesis, and insulin content. This impaired GSIS occurs despite an increased fractional rate of insulin release that results from a greater proportion of releasable insulin as a result of lower insulin stores. Because this animal model recapitulates the human pathology of chronic placental insufficiency and IUGR, the β-cell GSIS dysfunction in this model might indicate mechanisms that are developmentally adaptive for fetal survival but in later life might predispose offspring to adult-onset diabetes that has been previously associated with IUGR.

Background: The delayed oculomotor response (DOR) task requires response inhibition followed by movement of gaze towards a known spatial location without a current stimulus. Abnormalities in response inhibition and in the spatial accuracy of the eye movement are found in individuals with schizophrenia and in many of their relatives, supporting the use of these saccadic abnormalities as endophenotypes in genetic studies. It is unknown whether school-age children, either with psychosis or as relatives of a schizophrenic proband, can be included. Method: One hundred eighty-seven children, ages 5.8–16.0 years – 45 children with childhood-onset schizophrenia, 64 children with a first-degree relative with schizophrenia, and 84 typically developing children – completed DOR tasks with 1 and 3 second delays. Results: Children with childhood-onset schizophrenia demonstrated impaired response inhibition and impaired spatial accuracy compared to both relatives and typicals; however, relatives and typicals did not differ from each other. Conclusions: Children with childhood-onset schizophrenia have saccadic abnormalities similar to those found in adults with schizophrenia, supporting the continuity of executive function deficits in childhood-onset with adolescent and adult-onset schizophrenia. However, saccadic tasks are not sensitive to genetic risk in non-psychotic children and 6–15-year-old children should not be included in genetic studies utilizing this endophenotype.

Responder cell frequencies (RCF), which describe vaccine-boosted immune responses in herpes zoster (HZ) prevention studies, have been estimated by using limiting dilution assays (LDA). The theoretical linearity assumption between the logarithm of the proportion of nonresponding wells (s) and the cell concentration (N) (or dilution level) in LDA, based on the single-hit Poisson model, is often violated with observed data resulting in biased estimates of RCF. In this article, the Poisson assumption is modified by applying a mixture of Poisson and gamma distributions, resulting in a negative binomial assumption, which presents a better fit between s and N. In LDA for HZ prevention studies, binary responses (responder or non-responder wells) are measured repeatedly at different cell concentrations and over time. To account for the correlation between responses to varying dilution levels from individuals, and the correlation between repeated assays of individuals over time simultaneously, a binomial three-level nonlinear mixed-effects model is proposed. For parameter estimation, a maximum likelihood method is applied via adaptive Gaussian quadrature. There is a lack of non-Gaussian multilevel nonlinear mixed-effects software, which can execute such a complicated fit. In this article, an algorithm for the three-level nonlinear mixed-effects model, which can be inserted into the code in the SAS procedure NLMIXED, is suggested.

Varicella zoster virus (VZV) becomes latent in human ganglia after primary infection. VZV reactivation occurs primarily in elderly individuals, organ transplant recipients, and patients with cancer and AIDS, correlating with a specific decline in cell-mediated immunity to the virus. VZV can also reactivate after surgical stress. The unexpected occurrence of thoracic zoster 2 days before space flight in a 47-year-old healthy astronaut from a pool of 81 physically fit astronauts prompted our search for VZV reactivation during times of stress to determine whether VZV can also reactivate after non-surgical stress. We examined total DNA extracted from 312 saliva samples of eight astronauts before, during, and after space flight for VZV DNA by polymerase chain reaction: 112 samples were obtained 234-265 days before flight, 84 samples on days 2 through 13 of space flight, and 116 samples on days 1 through 15 after flight. Before space flight, only one of the 112 saliva samples from a single astronaut was positive for VZV DNA. In contrast, during and after space flight, 61 of 200 (30%) saliva samples were positive in all eight astronauts. No VZV DNA was detected in any of 88 saliva samples from 10 healthy control subjects. These results indicate that VZV can reactivate subclinically in healthy individuals after non-surgical stress.

The cosinor model, used for variables governed by circadian and other biological rhythms, is a nonlinear model in the amplitude and acrophase parameters that has a linear representation upon transformation. With linear cosinor analysis, amplitude and acrophase for each harmonic can be computed as nonlinear functions of the estimated linear regression coefficients. Here a flexible mixed model approach to cosinor analysis is considered, where the fixed effect parameters may enter nonlinearly as acrophase and amplitude for each harmonic or linearly after transformation to regression coefficients. In addition, the random effects may enter nonlinearly as subject-specific deviations from the acrophases and amplitudes or linearly as subject-specific deviations from the regression coefficients. It is also possible for the fixed effects to enter nonlinearly while the random effects enter linearly. Additionally, we evaluate whether including higher order linear harmonic terms as random effects, that is, Rao-Khatri 'covariance adjustment', improves precision. Applying the delta method to nonlinear functions of the parameters from linear mixed cosinor models to obtain approximate variances produces results that are often identical to results from nonlinear mixed models. Consequently, traditional linear cosinor analysis can often be used to estimate and compare the nonlinear parameters of interest, that is, amplitudes and acrophases, via the delta method. This is advantageous since the nonlinear mixed model may have convergence difficulties for more complex models. However, for some multiple-group analyses, the linear cosinor transformation should not be used and we clarify when the two methods are equivalent and when they differ.

Different types of outcomes (e.g. binary, count, continuous) can be simultaneously modeled with multivariate generalized linear mixed models by assuming: (1) same or different link functions, (2) same or different conditional distributions, and (3) conditional independence given random subject effects. Others have used this approach for determining simple associations between subject-specific parameters (e.g. correlations between slopes). We demonstrate how more complex associations (e.g. partial regression coefficients between slopes adjusting for intercepts, time lags of maximum correlation) can be estimated. Reparameterizing the model to directly estimate coefficients allows us to compare standard errors based on the inverse of the Hessian matrix with more usual standard errors approximated by the delta method; a mathematical proof demonstrates their equivalence when the gradient vector approaches zero. Reparameterization also allows us to evaluate significance of coefficients with likelihood ratio tests and to compare this approach with more usual Wald-type t-tests and Fisher’s z transformations. Simulations indicate that the delta method and inverse Hessian standard errors are nearly equivalent and consistently overestimate the true standard error. Only the likelihood ratio test based on the reparameterized model has an acceptable type I error rate and is therefore recommended for testing associations between stochastic parameters. Online supplementary materials include our medical data example, annotated code, and simulation details.

Abnormalities during a smooth pursuit eye movement task (SPEM) are common in schizophrenic patients and their relatives. This study assessed various components of SPEM performance in first-degree unaffected relatives of schizophrenic patients. One hundred individuals with schizophrenia, 137 unaffected first-degree relatives, and 69 normal controls completed a 16.7 degrees/s SPEM task. Smooth pursuit gain, catch-up saccades (CUS), large anticipatory saccades, and leading saccades (LS) were identified. Groups were compared with parametric and admixture analyses. Schizophrenic patients performed more poorly than unaffected relatives and normals on gain, CUS, and LS. Unaffected relatives were more frequently impaired than normals only on gain and LS. Relatives of childhood-onset and adult-onset probands had similar impairments. Gain and frequency of leading saccades may be genetic endophenotypes in childhood-onset and adult-onset schizophrenia.

Objective.Anti-carbamylated protein (anti-CarP) antibodies could further elucidate early rheumatoid arthritis (RA) pathogenesis and predict clinical disease. We compared the diagnostic accuracy of anti-CarP antibodies for future RA to other RA-related antibodies in military personnel.Methods.Stored pre-RA diagnosis serum samples from 76 RA cases were tested for anti-CarP fetal calf serum (FCS), anti-CarP fibrinogen (Fib), anticyclic citrullinated peptide antibodies version 2 (anti-CCP2), rheumatoid factor-nephelometry (RF-Neph), and RF isotypes [immunoglobulin M (IgM), IgG, and IgA]. Positivity for all antibodies was determined as ≥ 2 SD of log-transformed means from controls. Relationships between autoantibodies and future RA were assessed in prediagnosis serum for all RA cases compared to controls using sensitivity, specificity, and logistic regression. Differences in diagnostic accuracy between antibody combinations were assessed using comparisons of area under the curves (AUC).Results.Anti-CarP-FCS was 26% sensitive and 95% specific for future RA, whereas anti-CarP-Fib was 16% sensitive and 95% specific for future RA. Anti-CarP-FCS positivity was associated with future RA, while anti-CarP-Fib trended toward association. The antibody combination of anti-CCP2 and/or ≥ 2 RF (RF-Neph and/or RF-isotypes) resulted in an AUC of 0.72 for future RA, where the AUC was 0.71 with the addition of anti-CarP-FCS to this prior combination.Conclusion.Adding anti-CarP-FCS to antibody combinations did not improve AUC. However, anti-CarP-FCS was associated with future onset of RA, and was present in prediagnosis serum in ∼10% of RA cases negative for anti-CCP2 but positive for RF.

Background: Consumption of inorganic arsenic in drinking water at high levels has been associated with chronic diseases. Chronic diseases including coronary heart disease and diabetes mellitus (DM)...

Increased frequency of anticipatory saccades during smooth pursuit eye movements is a potential marker of genetic risk for schizophrenia. Postsaccadic slowing criteria are used to separate anticipatory from other types of saccades. However, the necessary duration of slowed pursuit required to identify an anticipatory saccade remains undetermined. We explored the effect of various postsaccadic slowing duration criteria on effect size in a comparison of younger and older schizophrenic and normal adults. For large anticipatory saccades, varying the duration of postsaccadic slowing criteria did not notably change effect size. For smaller leading saccades, a limited 50-ms duration postsaccadic slowing criterion produced the largest effect size (1.54), and maintained a similar effect size across a broad age range. Leading saccades with a limited duration postsaccadic slowing criteria are a possible marker of genetic risk for schizophrenia.

Healthy, varicella-zoster virus (VZV)-seropositive subjects, aged 55-89 years (mean age 66 years), received either 4000 PFU of live, attenuated VZV vaccine (n=85) or an equal volume of this vaccine that was heat-inactivated (n=82). Both vaccines significantly boosted VZV antibody (enzyme immunoassay) and gamma-interferon production by peripheral blood mononuclear cells stimulated by VZV antigen. These responses returned to baseline by 12 months. Circulating mononuclear cells that proliferated in response to VZV antigen were significantly more numerous (responder cell frequency assay) after either vaccine, and persisted with a half-life of 17. 5-21.3 months. There were no differences in immune response to either vaccine in this older age cohort.

We have studied the effects of granulocyte colony-stimulating factor (G-CSF) administration to normal individuals on a variety of functional and biochemical neutrophil characteristics that relate to host defense. G-CSF adversely affected neutrophil (polymorphonuclear leukocyte [PMN]) chemotaxis. While this could be partially explained by reduced assembly of neutrophil F-actin, we also recognized an elevated cytosolic calcium mobilization and a normal upregulation of neutrophil CD11b. G-CSF resulted in reduced PMN killing of Staphylococcus aureus with a 10:1 (bacteria:neutrophil) ratio and normal killing with a 1:1 ratio. In association with this, we demonstrated divergent effects on the respiratory burst of intact cells and divergent effects on the content of marker proteins for neutrophil granules. While G-CSF may have resulted in increased content of cytochrome b558 in the cell membrane, it did not alter the amounts of cytosolic oxidase components. After therapy, there was normal content of the azurophilic granule marker, myeloperoxidase, decreased content of the specific granule marker, lactoferrin, and normal content of lysozyme (found in both granules classes). Finally, G-CSF therapy markedly reduced the apoptotic rate of the isolated neutrophil. Therefore, considering disparate functional and biochemical activities, the real benefit of G-CSF therapy may lie in enhanced number and survival of neutrophils.

Most delinquent youths have conduct disorder (CD), often with comorbid substance use disorder (SUD), attention-deficit/hyperactivity disorder (ADHD) and depression. Some youths' conduct problems later abate, while those of others persist into adult antisocial personality disorder. Earlier CD onset and ADHD reportedly predict persisting antisocial problems, but predictors of persisting SUD are poorly understood. Males aged 13-19 years (n = 89), most referred by criminal justice and social service agencies, received residential treatment for comorbid CD and SUD. They had diagnostic assessments for SUD at intake and for CD, ADHD, and depression (as well as drug-use assessments) at intake and 6, 12 and 24 months later. At intake nearly all had DSM-III-R substance dependence (usually on alcohol and marijuana) and CD with considerable violence and criminality. The 2-year follow-ups revealed improvements in criminality, CD, depression and ADHD, but substance use remained largely unchanged. Various aspects of conduct, crime and substance outcomes at 2 years were predicted by intake measures of intensity of substance involvement, and by CD severity and onset age, but not by severity of either ADHD or depression, nor by treatment duration. Earlier CD onset, more severe CD and more drug dependence predicted worse outcomes, supporting the validity of these diagnoses in adolescents.

Objective: To determine whether there are clinical or physical factors that could be used to predict the duration of dependence on parenteral nutrition (PN) in infants who have undergone resection of small intestine in the neonatal period. Study design: Medical records of 44 patients who had small intestinal resection as neonates from 1985 to 1996 and who were dependent on PN for at least 3 months were reviewed. Statistical evaluation of patient variables and their impact on duration of dependence on PN were determined by using the Cox Proportional Hazard model. Results: Twenty-seven patients became independent of PN before the age of 36 months. Seven patients between 40 and 129 months of age are permanently dependent on PN. Outcome could not be determined in 10 patients, four of whom died of hepatic failure while still receiving PN and six of whom are still receiving PN but are younger than 36 months of age. Small bowel length after initial surgery and the percent of daily energy intake received by the enteral route at 12 weeks' adjusted age were significantly related to the duration of dependence on PN. Gestational age, presence of the ileocecal valve, and development of cholestasis were not significantly related. With the use of the Cox Proportional Hazards survival model, a formula was generated to allow estimation of the duration of dependence on PN. Conclusions: The duration of dependence on PN can be predicted at an early age in neonatal short bowel syndrome by using two patient variables: the length of residual small bowel after initial surgery and the percent of daily energy intake tolerated through the enteral route. (J Pediatr 1998;132:80-4)

This study examines the loss of peripherally induced B cell immune tolerance in Rheumatoid arthritis (RA) and establishes a novel signaling-based measure of activation in a subset of autoreactive B cells - the Induced tolerance status index (ITSI). Naturally occurring naive autoreactive B cells can escape the “classical” tolerogenic mechanisms of clonal deletion and receptor editing, but remain peripherally tolerized through B cell receptor (BCR) signaling inhibition (postdevelopmental “receptor tuning” or anergy). ITSI is a statistical index that numerically determines the level of homology between activation patterns of BCR signaling intermediaries in B cells that are either tolerized or activated by auto antigen exposure, and thus quantifies the level of peripheral immune tolerance. The index is based on the logistic regression analysis of phosphorylation levels in a panel of BCR signaling proteins. Our results demonstrate a new approach to identifying autoreactive B cells based on their BCR signaling features.

Background: Chronic diseases, including coronary heart disease (CHD), have been associated with ingestion of drinking water with high levels of inorganic arsenic (> 1,000 μg/L). However, associations have been inconclusive in populations with lower levels (< 100 μg/L) of inorganic arsenic exposure. Objectives: We conducted a case-cohort study based on individual estimates of lifetime arsenic exposure to examine the relationship between chronic low-level arsenic exposure and risk of CHD. Methods: This study included 555 participants with 96 CHD events diagnosed between 1984 and 1998 for which individual lifetime arsenic exposure estimates were determined using data from structured interviews and secondary data sources to determine lifetime residence, which was linked to a geospatial model of arsenic concentrations in drinking water. These lifetime arsenic exposure estimates were correlated with historically collected urinary arsenic concentrations. A Cox proportional-hazards model with time-dependent CHD risk factors was used to assess the association between time-weighted average (TWA) lifetime exposure to low-level inorganic arsenic in drinking water and incident CHD. Results: We estimated a positive association between low-level inorganic arsenic exposure and CHD risk [hazard ratio (HR): = 1.38, 95% CI: 1.09, 1.78] per 15 μg/L while adjusting for age, sex, first-degree family history of CHD, and serum low-density lipoprotein levels. The risk of CHD increased monotonically with increasing TWAs for inorganic arsenic exposure in water relative to < 20 μg/L (HR = 1.2, 95% CI: 0.6, 2.2 for 20–30 μg/L; HR = 2.2; 95% CI: 1.2, 4.0 for 30–45 μg/L; and HR = 3, 95% CI: 1.1, 9.1 for 45–88 μg/L). Conclusions: Lifetime exposure to low-level inorganic arsenic in drinking water was associated with increased risk for CHD in this population. Citation: James KA, Byers T, Hokanson JE, Meliker JR, Zerbe GO, Marshall JA. 2015. Association between lifetime exposure to inorganic arsenic in drinking water and coronary heart disease in Colorado residents. Environ Health Perspect 123:128–134; http://dx.doi.org/10.1289/ehp.1307839

IntroductionStudies suggest that respiratory exposures including smoking, proximity to traffic and air pollution might be associated with development of rheumatoid arthritis (RA). RA-related autoantibodies are predictive of the development of RA.ObjectiveWe evaluated the relationship between RA-related autoantibodies and exposure to particulate matter (PM), a measure of air pollution of interest to health, in individuals without RA.MethodsThe Studies of the Etiology of Rheumatoid Arthritis (SERA) is a multicentre study following first-degree relatives (FDRs) of a proband with RA. FDRs are without the 1987 ACR (American College of Rheumatology) classifiable RA at enrolment and are followed for the development of RA-related autoimmunity. RA-related autoantibody outcomes as well as tender and swollen joint outcomes were assessed. Exposure to PM was assigned using ambient air pollution monitoring data and interpolated with inverse distance weighting spatial analyses using Geographic Information Systems. PM exposures were linked to FDR's residential zip codes.ResultsRA-related autoantibodies as well as tender or swollen joints are not associated with ambient PM concentrations.DiscussionWhile other respiratory exposures may be associated with increased risk of RA, our data suggest that ambient PM is not associated with autoantibodies and joint signs among individuals without RA, but at increased risk of developing RA.

We describe an application of recently developed generalized Michaelis-Menten response surface and non-linear mixed model methodologies to model glucose utilization in foetal sheep. More specifically, we model the response surface of glucose utilization rate in the foetal sheep as a function of glucose and insulin concentrations using a three-dimensional analogue of the Michaelis-Menten pharmacokinetic model. To account for multiple measurements per sheep, we apply the non-linear mixed effects model proposed by Lindstrom and Bates using the EM algorithm computational scheme presented by Hirst et al.

Consumption of inorganic arsenic in drinking water at high levels has been associated with chronic diseases. Research groups have estimated historic exposure using databases and models of arsenic in drinking water supplies, along with participant residential histories. Urinary arsenic species are an established biomarker of recent exposure; we compare arsenic concentrations in historically collected urine samples with predicted estimates of arsenic exposure. Using a cohort of 462 subjects with at least one urine sample collected from 1984-1992 and an arsenic exposure estimate through drinking water at the time of the urine sample, individual exposure estimates were compared with speciated urine arsenic (UAs) concentrations using correlation and multiple regression analyses. Urine inorganic arsenic (UIAs) concentrations (trivalent arsenic, pentavalent arsenic, monomethylarsonic acid, dimethylarsonic acid) were best predicted by residential water arsenic concentrations (R(2)=0.3688), compared with metrics including water consumption (R(2)=0.2038) or water concentrations at employment locations (R(2)=0.2331). UIAs concentrations showed similar correlation when stratified by whether the arsenic concentration was predicted or measured. Residential water arsenic concentrations, independent of water intake or water concentrations at places of employment, best explain the variability in UIAs concentrations, suggesting historical reconstruction of arsenic exposure that accounts for space-time variability and water concentrations may serve as a proxy for exposure.

Background: Consumption of drinking water with high levels of inorganic arsenic (over 500 mg/L) has been associated with type II diabetes mellitus (DM), but previous studies have been inconclusive about risks at lower levels (o 100 mg/L). We present a case-cohort study based on individual estimates of lifetime arsenic exposure to examine the relationship between chronic low-level arsenic exposure and risk of DM. Methods: This case-cohort study included 141 cases of DM diagnosed between 1984 and 1998 as part of the prospective San Luis Valley Diabetes Study. A comparison sub-cohort of 488 participants was randomly sampled from 936 eligible participants who were disease free at baseline. Individual lifetime arsenic exposure estimates were determined using a methodology that incorporates the use of a structured interview to determine lifetime residence and employment history, geospatial modeling of arsenic concentrations in drinking water, and urine arsenic concentrations. A Cox proportional hazards model with known DM risk factors as time-dependent covariates was used to assess the association between lifetime exposure to inorganic arsenic in drinking water and incident DM. Results: Our findings show a significant association between inorganic arsenic exposure and DM risk (hazard ratio [HR] ¼ 1.27, 95% ¼1.01, 1.59 per 15 mg/L) while adjusting for ethnicity and time varying covariates age, body mass index and physical activity level. Conclusions: Exposure to low-level inorganic arsenic in drinking water is associated with increased risk for type II DM in this population based on a comprehensive lifetime exposure assessment.

Limiting dilution cultures have been used to estimate the frequency of T cells which respond to antigen stimulation in vitro, but nothing is known of the reproducibility of this assay when applied to human blood. We developed a simplified form of limiting dilution culture in which blood mononuclear cells were diluted in round bottom 96-well plates and cultured for 10 days. The assay was used to estimate the frequency of blood mononuclear cells proliferating in response to varicella-zoster virus antigen. 250 subjects aged 25-87 years were studied: 95 of these subjects had annual measurements repeated over a 4 year period. The coefficients of variation for intra-assay replicates was 5%, and for inter-assay comparisons was 17.6% and 26% for tests at a 1 or 3 month interval respectively. For subjects studied at 1 year intervals the coefficient of variation was 42% with the total variability equally distributed between the variation between subjects and the variation within subjects. These data provide the first quantitative data to validate limiting dilution cultures for the long term in vitro measurement of human T cell responses.

Inadequate zinc intake may lead to poor growth and developmental outcome in very-low-birth-weight (VLBW; < 1,500 g) infants. Fifty-two infants (mean birth weight, 1,117 +/- 287 g; mean gestational age, 29 +/- 2.9 weeks) were randomly allocated to two groups. SUPP infants received a regular term formula plus zinc supplements (4.4 mg/L; final content, 11 mg/L); PLAC infants received the same formula plus placebo (final content, 6.7 mg/L). Infants started their formula at 1,853 +/- 109 g and consumed the formula for 6 months. All subjects were evaluated at 3, 6, 9, and 12 +/- 0.75 months corrected-for-gestational-age. At each evaluation, weight, length, and head circumference were measured, a Griffiths developmental assessment was performed, and a blood sample was taken. Higher plasma zinc levels (p < 0.05) were found in the SUPP group at 1 and 3 months, and improved linear growth velocity was found in the SUPP group over the study period for the whole group as well as for girls alone. Maximum motor development scores were higher (p = 0.018) in the SUPP (98 +/- 10) than the PLAC (90 +/- 8) group, indicating that increased zinc intake in early infancy may be beneficial to VLBW infants.

The Oka strain live attenuated varicella-zoster virus (VZV) vaccine was administered subcutaneously to 202 VZV-immune individuals who were 55 to greater than 87 years old. The dose administered varied from 1100 to 12,000 pfu. One cohort received 3000 pfu with a 3000 pfu booster 3 months later. The vaccine was well tolerated. VZV-specific immunologic responses were evaluated over a 24-month period. The mean anti-VZV antibody level was significantly increased for 12 months after vaccination. Interferon-gamma production in vitro by peripheral blood mononuclear cells (PBMC) of vaccinees was also increased for 6 months after vaccination. Most significantly, VZV-specific proliferating T cells in PBMC of vaccinees were increased in frequency from 1 in 68,000 to 1 in 40,000. This vaccine-enhanced frequency of VZV-responding T cells is similar to the frequency observed in 35- to 40-year-old adults. Dose and age of the vaccinees did not significantly influence the magnitude of the mean cell-mediated immune response. The data indicate that VZV immunity in the elderly can be boosted by active immunization. If the increased incidence of herpes zoster that accompanies aging results from the natural waning of immunity, active immunization may prevent or attenuate zoster in the elderly.

Linear random effects models for longitudinal data discussed by Laird and Ware (1982), Jennrich and Schluchter (1986), Lange and Laird (1989), and others are extended in a straight forward manner to nonlinear random effects models. This results in a simple computational approach which accommodates patterned covariance matrices and data insufficient for fitting each subject separately. The technique is demonstrated with an interesting medical data set, and a short, simple SAS PROC IML program based on the EM algorithm is presented.

The survival rate of critically ill patients who develop acute renal failure is extremely low, in spite of the sophisticated support systems, including dialysis. Therefore, it would be advantageous to identify, early in the disease course, those few survivors. We reviewed the clinical course of 43 consecutive critically ill patients who developed acute renal failure and were first dialyzed in an intensive-care unit setting to define comorbid conditions, present at the time of first dialysis, that were predictive of outcome. Mortality rate was 88%. Adult respiratory distress syndrome (p less than 0.05), requirement for antibiotics (p less than 0.01) and ventilatory failure (p less than 0.01) impacted negatively on recovery of renal function. The most powerful predictor of mortality was the need for ventilatory support (p less than 0.001). The presence of ventilatory failure at the initiation of dialysis predicted a 100% mortality (89-100%; 95% confidence limits). The initiation of dialysis in intensive-care unit patients with acute renal failure requiring ventilatory support did not alter the uniformly fatal outcome.

Hind limb blood flow and O2 uptake, mean blood pressure, and heart rate were measured in six fetal sheep at 127-141 d gestation in the control state and at different levels of hypoxia that were induced by partial occlusion of the maternal terminal aorta. Blood flow was measured by an ultrasonic flow transducer. Control fetal arterial O2 content ([O2]a) in the descending aorta was 3.25 + 0.17 mM. In response to graded acute hypoxia, blood flow first increased (22.2 versus 19.9 mL.min−1.100 g−1, p = 0.003) and then decreased abruptly at approximately 1.5 mM [O2]a.O2 uptake decreased about 12% (14.74 versus 16.71, p = 0.03) as [O2]a decreased to 1.5 mM, and then fell markedly, tending toward zero for [O2]a = 0.9 mM. In the 2.7- to 1.5-mM [O2]a range, heart rate increased above control (194 versus 169 min−1, p = 0.0024), whereas mean blood pressure did not change significantly. For [O2]a < 1.5 mM, heart rate decreased to 148 min−1 (p = 0.0005) and mean blood pressure increased above baseline (55 versus 47 torr, p = 0.0001). In conjunction with previous evidence, these results define a state of acute moderate hypoxia in which the whole fetus can sustain a relatively high rate of oxidative metabolism, and a state of acute severe hypoxia ([O2]a between 1.5 and 1.0 mM) in which O2 uptake by some fetal organs is selectively and markedly decreased.

The aim of this paper is to generalize permutation methods for multiple testing adjustment of significant partial regression coefficients in a linear regression model used for microarray data. Using a permutation method outlined by Anderson and Legendre [1999] and the permutation P-value adjustment from Simon et al. [2004], the significance of disease related gene expression will be determined and adjusted after accounting for the effects of covariates, which are not restricted to be categorical. We apply these methods to a microarray dataset containing confounders and illustrate the comparisons between the permutation-based adjustments and the normal theory adjustments. The application of a linear model is emphasized for data containing confounders and the permutation-based approaches are shown to be better suited for microarray data. Genet. Epidemiol. 31, 2007. © 2007 Wiley-Liss, Inc.

Objectives To characterize the time course and physiologic significance of decline in serum immunoreactive trypsinogen (IRT) levels in infants with cystic fibrosis (CF) by mode of diagnosis and genotype, and to examine IRT heritability. Study design We studied longitudinal IRT measurements in 317 children with CF. We developed statistical models to describe IRT decline. Pancreatic disease severity (Mild or Severe) was assigned using CF genotype and was confirmed in 47 infants through fat malabsorption studies. Results Infants with severe disease exhibited IRT decline with non-detectable levels typically seen by 5 years of age. Infants with mild disease exhibited a decline in the first 2 years, asymptomatically approaching a level greater than published norms. IRT and fecal fat were inversely correlated. IRT values in infants with meconium ileus (MI) were significantly lower than newborn-screened infants at birth. The high proportion of shared variation in predicted IRT values among sibling pairs with severe disease suggests that IRT is heritable. Conclusions IRT declines characteristically in infants with CF. Lower IRT values in newborns with MI suggest increased pancreatic injury. Furthermore, IRT is heritable among patients with severe disease suggesting genetic modifiers of early CF pancreatic injury. This study demonstrates heritability of a statistically modeled quantitative phenotype.