Analysis of Longitudinal Random Length Data

In some clinical trials, data are gathered longitudinally on both the frequency of an event and its severity. Oftentimes, it is not feasible to obtain the exact time of the events, and the events are collected over fixed follow-up intervals. We refer to this type of data as longitudinal random length data, since the subjects are observed repeatedly and, at each assessment time, the data can be viewed as vectors of severities with lengths determined by the number of events experienced during the assessment. Suppose the interest is in comparing two treatments, and the treatments are evaluated at multiple points in time. Treatment effect is reflected in simultaneous changes in both the number of events and the severity of each event. Consequently, one needs to jointly model the two outcomes to better evaluate treatment effects. The main objective of this dissertation is to introduce a framework for longitudinal random length data. We propose two multiple population models for such data. We parameterize the models such that, at each measurement time, both the distribution of the random lengths and the distributional mean of each component of the severity vectors depend on the underlying parameter reflecting the treatment effect at that time. Given the random lengths, we assume the distribution of the severities to be multivariate normal. Conditional on the number of events, the dependence in the vector of severities recorded at a single measurement time is modeled using compound symmetry.The first model assumes the numbers of events for a subject at different time points to be independent Poisson random variables and dependence over time is built into the severity measures. The second model generalizes the first one, by adding another layer of dependence over time. We further assume the numbers of the events experienced by a subject across time to be dependent and use a multivariate Poisson distribution to model them. For each model we describe the maximum likelihood estimation procedure and provide the asymptotic properties for the estimators. We apply both models to analyze a data set containing stressful life events in adolescents with major depressive disorder

Correction to: Brief Report: Use of the Infant-Toddler Checklist in Infant Siblings of Children with Autism Spectrum Disorder.

The original version of the article unfortunately contained a mistake in the Results and Discussion section. The corrected sentences are given below: 1. In the Results section (paragraph 2): “The psychometric values were moderate, with strongest indices at 24 months: SE = 78% (95% CI 64–91%), SP = 83% (95% CI 78–89%), PPV = 52% (95% CI 40–65%), and NPV = 94% (95% CI 90–98%)." Instead should say, “SE = 77% (95% CI 64–90%), SP = 85% (95% CI 80-91%), PPV = 55% (95% CI 42–68%), and NPV = 94% (95% CI 90–98%)”. 2. In the Discussion section (paragraph 2), “Longitudinally, SE ranged from 52 to 63% and SP from 42 to 83% in our study.” Instead should say, “Longitudinally, SE ranged from 51 to 62% and SP from 42 to 85% in our study”

Clinically Significant Anxiety in Children with Autism Spectrum Disorder and Varied Intellectual Functioning.

Objective: To evaluate how distinct presentations of anxiety symptoms and intellectual impairment influence the measurement and estimated rate of clinically significant anxiety in autism spectrum disorder (ASD).Method: The sample included 75 children (ages 9-13 years) with ASD and varied IQ and 52 typically developing (TD) controls and parents. Parents completed anxiety symptom scales and a diagnostic interview, designed to (1) differentiate anxiety and ASD and (2) examine DSM-specified and unspecified ("distinct") anxiety presentations in each child, including fears of change, special interests, idiosyncratic stimuli and social confusion rather than evaluation. Children completed standard intellectual and ASD diagnostic assessments.Results: 69% of those with ASD had clinically-significant anxiety, including 21% DSM-specified anxiety disorders, 17% distinct anxiety, and 31% both. Only 8% of TD children had clinically-significant anxiety, all DSM-specified. DSM-specified anxiety disorders in children with ASD and intellectual impairment (IQ<70) were predominantly specific phobias. DSM-specified anxiety other than specific phobia was significantly less common in children with, versus without, intellectual impairment; this was not the case for distinct anxiety. The sensitivities of anxiety scales were moderate to poor, particularly in cases with intellectual impairment.Conclusions: ASD is associated with more frequent and varied presentations of clinical anxiety, which may align with and differ from the specified anxiety disorders of the DSM. Standard parent report anxiety scales have reduced sensitivity to detect clinical anxiety in ASD, particularly in children with intellectual impairment

Owner reports of attention, activity, and impulsivity in dogs: a replication study

<p>Abstract</p> <p>Background</p> <p>When developing behaviour measurement tools that use third party assessments, such as parent report, it is important to demonstrate reliability of resulting scales through replication using novel cohorts. The domestic dog has been suggested as a model to investigate normal variation in attention, hyperactivity, and impulsive behaviours impaired in Attention Deficit Hyperactive Disorder (ADHD). The human ADHD Rating Scale, modified for dogs and using owner-directed surveys, was applied in a European sample. We asked whether findings would be replicated utilizing an Internet survey in a novel sample, where unassisted survey completion, participant attitudes and breeds might affect previous findings.</p> <p>Methods</p> <p>Using a slightly modified version of the prior survey, we collected responses (<it>n </it>= 1030, 118 breeds representing 7 breed groups) primarily in the United States and Canada. This study was conducted using an Internet survey mechanism.</p> <p>Results</p> <p>Reliability analyses confirmed two scales previously identified for dogs (inattention [IA], hyperactivity-impulsivity [HA-IM]). Models including age, training status, and breed group accounted for very little variance in subscales, with no effect of gender.</p> <p>Conclusions</p> <p>The factor invariance demonstrated in these findings confirms that owner report, using this modified human questionnaire, provides dog scores according to "inattention" and "hyperactivity-impulsivity" axes. Further characterization of naturally occurring variability of attention, activity, and impulsivity in domestic dogs may provide insight into genetic backgrounds underlying behaviours impaired in attention and associated disorders.</p

Activation of the Maternal Immune System During Pregnancy Alters Behavioral Development of Rhesus Monkey Offspring

Background: Maternal infection during pregnancy is associated with an increased risk of schizophrenia and autism in the offspring. Supporting this correlation, experimentally activating the maternal immune system during pregnancy in rodents produces offspring with abnormal brain and behavioral development. We have developed a nonhuman primate model to bridge the gap between clinical populations and rodent models of maternal immune activation (MIA). Methods: A modified form of the viral mimic, synthetic double-stranded RNA (polyinosinic:polycytidylic acid stabilized with poly-L-lysine) was delivered to two separate groups of pregnant rhesus monkeys to induce MIA: 1) late first trimester MIA (n = 6), and 2) late second trimester MIA (n = 7). Control animals (n = 11) received saline injections at the same first or second trimester time points or were untreated. Sickness behavior, temperature, and cytokine profiles of the pregnant monkeys confirmed a strong inflammatory response to MIA. Results: Behavioral development of the offspring was studied for 24 months. Following weaning at 6 months of age, MIA offspring exhibited abnormal responses to separation from their mothers. As the animals matured, MIA offspring displayed increased repetitive behaviors and decreased affiliative vocalizations. When evaluated with unfamiliar conspecifics, first trimester MIA offspring deviated from species-typical macaque social behavior by inappropriately approaching and remaining in immediate proximity of an unfamiliar animal. Conclusions: In this rhesus monkey model, MIA yields offspring with abnormal repetitive behaviors, communication, and social interactions. These results extended the findings in rodent MIA models to more human-like behaviors resembling those in both autism and schizophrenia

Relational memory weakness in autism despite the use of a controlled encoding task

IntroductionRecent work challenged past findings that documented relational memory impairments in autism. Previous studies often relied solely on explicit behavioral responses to assess relational memory integrity, but successful performance on behavioral tasks may rely on other cognitive abilities (e.g., executive functioning) that are impacted in some autistic individuals. Eye-tracking tasks do not require explicit behavioral responses, and, further, eye movements provide an indirect measure of memory. The current study examined whether memory-specific viewing patterns toward scenes differ between autistic and non-autistic individuals.MethodsUsing a long-term memory paradigm that equated for complexity between item and relational memory tasks, participants studied a series of scenes. Following the initial study phase, scenes were re-presented, accompanied by an orienting question that directed participants to attend to either features of an item (i.e., in the item condition) or spatial relationships between items (i.e., in the relational condition) that might be subsequently modified during test. At test, participants viewed scenes that were unchanged (i.e., repeated from study), scenes that underwent an “item” modification (an exemplar switch) or a “relational” modification (a location switch), and scenes that had not been presented before. Eye movements were recorded throughout.ResultsDuring study, there were no significant group differences in viewing directed to regions of scenes that might be manipulated at test, suggesting comparable processing of scene details during encoding. However, there was a group difference in explicit recognition accuracy for scenes that underwent a relational change. Marginal group differences in the expression of memory-based viewing effects during test for relational scenes were consistent with this behavioral outcome, particularly when analyses were limited to scenes recognized correctly with high confidence. Group differences were also evident in correlational analyses that examined the association between study phase viewing and recognition accuracy and between performance on the Picture Sequence Memory Test and recognition accuracy.DiscussionTogether, our findings suggest differences in the integrity of relational memory representations and/or in the relationships between subcomponents of memory in autism

Diagnostic stability in young children at risk for autism spectrum disorder:A baby siblings research consortium study

BACKGROUND: The diagnosis of autism spectrum disorder (ASD) made before age 3 has been found to be remarkably stable in clinic- and community-ascertained samples. The stability of an ASD diagnosis in prospectively ascertained samples of infants at risk for ASD due to familial factors has not yet been studied, however. The American Academy of Pediatrics recommends intensive surveillance and screening for this high-risk group, which may afford earlier identification. Therefore, it is critical to understand the stability of an ASD diagnosis made before age 3 in young children at familial risk. METHODS: Data were pooled across 7 sites of the Baby Siblings Research Consortium. Evaluations of 418 later-born siblings of children with ASD were conducted at 18, 24, and 36 months of age and a clinical diagnosis of ASD or Not ASD was made at each age. RESULTS: The stability of an ASD diagnosis at 18 months was 93% and at 24 months was 82%. There were relatively few children diagnosed with ASD at 18 or 24 months whose diagnosis was not confirmed at 36 months. There were, however, many children with ASD outcomes at 36 months who had not yet been diagnosed at 18 months (63%) or 24 months (41%). CONCLUSIONS: The stability of an ASD diagnosis in this familial-risk sample was high at both 18 and 24 months of age and comparable with previous data from clinic- and community-ascertained samples. However, almost half of children with ASD outcomes were not identified as being on the spectrum at 24 months and did not receive an ASD diagnosis until 36 months. Thus, longitudinal follow-up is critical for children with early signs of social-communication difficulties, even if they do not meet diagnostic criteria at initial assessment. A public health implication of these data is that screening for ASD may need to be repeated multiple times in the first years of life. These data also suggest that there is a period of early development in which ASD features unfold and emerge but have not yet reached levels supportive of a diagnosis

Nitric oxide from inflammatory origin impairs neural stem cell proliferation by inhibiting epidermal growth factor receptor signaling

Neuroinflammation is characterized by activation of microglial cells, followed by production of nitric oxide (NO), which may have different outcomes on neurogenesis, favoring or inhibiting this process. In the present study, we investigated how the inflammatory mediator NO can affect proliferation of neural stem cells (NSCs), and explored possible mechanisms underlying this effect. We investigated which mechanisms are involved in the regulation of NSC proliferation following treatment with an inflammatory stimulus (lipopolysaccharide plus IFN-gamma), using a culture system of subventricular zone (SVZ)-derived NSCs mixed with microglia cells obtained from wild-type mice (iNOS(+/+)) or from iNOS knockout mice (iNOS(-/-)). We found an impairment of NSC cell proliferation in iNOS(+/+) mixed cultures, which was not observed in iNOS(-/-) mixed cultures. Furthermore, the increased release of NO by activated iNOS(+/+) microglial cells decreased the activation of the ERK/MAPK signaling pathway, which was concomitant with an enhanced nitration of the EGF receptor. Preventing nitrogen reactive species formation with MnTBAP, a scavenger of peroxynitrite (ONOO-), or using the ONOO- degradation catalyst FeTMPyP cell proliferation and ERK signaling were restored to basal levels in iNOS(+/+) mixed cultures. Moreover, exposure to the NO donor NOC-18 (100 mu M), for 48 h, inhibited SVZ-derived NSC proliferation. Regarding the antiproliferative effect of NO, we found that NOC-18 caused the impairment of signaling through the ERK/MAPK pathway, which may be related to increased nitration of the EGF receptor in NSC. Using MnTBAP nitration was prevented, maintaining ERK signaling, rescuing NSC proliferation. We show that NO from inflammatory origin leads to a decreased function of the EGF receptor, which compromised proliferation of NSC. We also demonstrated that NO-mediated nitration of the EGF receptor caused a decrease in its phosphorylation, thus preventing regular proliferation signaling through the ERK/MAPK pathway.Foundation for Science and Technology, (FCT, Portugal); COMPETE; FEDER [PEst-C/SAU/LA0001/2013-2014, PEst-OE/EQB/LA0023/2013-2014, PTDC/SAU-NEU/102612/2008, PTDC/NEU-OSD/0473/2012]; FCT, Portugal [SERH/BPD/78901/2011, SERH/BD/38127/2007, SFRH/BD/77903/2011, SFRH/BD/79308/2011]info:eu-repo/semantics/publishedVersio

Prenatal and Postnatal Serum PCB Concentrations and Cochlear Function in Children at 45 Months of Age

Background: Some experimental and human data suggest that exposure to polychlorinated biphenyls (PCBs) may induce ototoxicity, though results of previous epidemiologic studies are mixed and generally focus on either prenatal or postnatal PCB concentrations exclusively. Objectives: Our aim was to evaluate the association between pre- and postnatal PCB concentrations in relation to cochlear status, assessed by distortion product otoacoustic emissions (DPOAEs), and to further clarify the critical periods in development where cochlear status may be most susceptible to PCBs. Methods: A total of 351 children from a birth cohort in eastern Slovakia underwent otoacoustic testing at 45 months of age. Maternal pregnancy, cord, and child 6-, 16-, and 45-month blood samples were collected and analyzed for PCB concentrations. At 45 months of age, DPOAEs were assessed at 11 frequencies in both ears. Multivariate, generalized linear models were used to estimate the associations between PCB concentrations at different ages and DPOAEs, adjusting for potential confounders. Results: Maternal and cord PCB-153 concentrations were not associated with DPOAEs at 45 months. Higher postnatal PCB concentrations at 6-, 16-, and 45-months of age were associated with lower (poorer) DPOAE amplitudes. When all postnatal PCB exposures were considered as an area-under-the-curve metric, an increase in PCB-153 concentration from the 25th to the 75th percentile was associated with a 1.6-dB SPL (sound pressure level) decrease in DPOAE amplitude (95% CI: –2.6, –0.5; p = 0.003). Conclusions: In this study, postnatal rather than maternal or cord PCB concentrations were associated with poorer performance on otoacoustic tests at age 45 months. Citation: Jusko TA, Sisto R, Iosif AM, Moleti A, Wimmerová S, Lancz K, Tihányi J, Šovčíková E, Drobná B, Palkovičová L, Jurečková D, Thevenet-Morrison K, Verner MA, Sonneborn D, Hertz-Picciotto I, Trnovec T. 2014. Prenatal and postnatal serum PCB concentrations and cochlear function in children at 45 months of age. Environ Health Perspect 122:1246–1252; http://dx.doi.org/10.1289/ehp.130747