Abba M. Krieger

Dosage-dependent phenotypes in models of 16p11.2 lesions found in autism

Recurrent copy number variations (CNVs) of human 16p11.2 have been associated with a variety of developmental/neurocognitive syndromes. In particular, deletion of 16p11.2 is found in patients with autism, developmental delay, and obesity. Patients with deletions or duplications have a wide range of clinical features, and siblings carrying the same deletion often have diverse symptoms. To study the consequence of 16p11.2 CNVs in a systematic manner, we used chromosome engineering to generate mice harboring deletion of the chromosomal region corresponding to 16p11.2, as well as mice harboring the reciprocal duplication. These 16p11.2 CNV models have dosage-dependent changes in gene expression, viability, brain architecture, and behavior. For each phenotype, the consequence of the deletion is more severe than that of the duplication. Of particular note is that half of the 16p11.2 deletion mice die postnatally; those that survive to adulthood are healthy and fertile, but have alterations in the hypothalamus and exhibit a “behavior trap” phenotype—a specific behavior characteristic of rodents with lateral hypothalamic and nigrostriatal lesions. These findings indicate that 16p11.2 CNVs cause brain and behavioral anomalies, providing insight into human neurodevelopmental disorders.

Recent contributions to optimal product positioning and buyer segmentation

Abstract This paper discusses the advances that have been made in optimal product design and market segmentation models. We emphasize developments since 1981. Measurement methodologies include multidimensional scaling and conjoint analysis approaches. Both the single product and product line problems are discussed, along with brief descriptions of related topics, such as product bundle design and pricing.

Data mining neocortical high-frequency oscillations in epilepsy and controls.

Transient high-frequency (100-500 Hz) oscillations of the local field potential have been studied extensively in human mesial temporal lobe. Previous studies report that both ripple (100-250 Hz) and fast ripple (250-500 Hz) oscillations are increased in the seizure-onset zone of patients with mesial temporal lobe epilepsy. Comparatively little is known, however, about their spatial distribution with respect to seizure-onset zone in neocortical epilepsy, or their prevalence in normal brain. We present a quantitative analysis of high-frequency oscillations and their rates of occurrence in a group of nine patients with neocortical epilepsy and two control patients with no history of seizures. Oscillations were automatically detected and classified using an unsupervised approach in a data set of unprecedented volume in epilepsy research, over 12 terabytes of continuous long-term micro- and macro-electrode intracranial recordings, without human preprocessing, enabling selection-bias-free estimates of oscillation rates. There are three main results: (i) a cluster of ripple frequency oscillations with median spectral centroid = 137 Hz is increased in the seizure-onset zone more frequently than a cluster of fast ripple frequency oscillations (median spectral centroid = 305 Hz); (ii) we found no difference in the rates of high frequency oscillations in control neocortex and the non-seizure-onset zone neocortex of patients with epilepsy, despite the possibility of different underlying mechanisms of generation; and (iii) while previous studies have demonstrated that oscillations recorded by parenchyma-penetrating micro-electrodes have higher peak 100-500 Hz frequencies than penetrating macro-electrodes, this was not found for the epipial electrodes used here to record from the neocortical surface. We conclude that the relative rate of ripple frequency oscillations is a potential biomarker for epileptic neocortex, but that larger prospective studies correlating high-frequency oscillations rates with seizure-onset zone, resected tissue and surgical outcome are required to determine the true predictive value.

Comparison of receiver operating characteristic curves on the basis of optimal operating points

RATIONALE AND OBJECTIVES We developed a method of comparing receiver operating characteristic (ROC) curves on the basis of the utilities associated with their optimal operating points (OOPs). METHODS OOPs were computed for paired ROC curves on the basis of isocost lines in ROC space with slopes ranging from 0.1 to 3.0. For each pair of OOPs corresponding to a single isocost slope, the difference in costs and the variance of this difference was computed. A sensitivity analysis was thus obtained for the difference between the two curves over a range of isocost slopes. Three published data sets were evaluated using this technique, as well as by comparisons of areas under the curves and of true-positive fractions at fixed false-positive fractions. RESULTS The OOPs of paired ROC curves often occur at different false-positive fractions. Comparisons of ROC curves on the basis of OOPs may provide results that differ from comparisons of curves at a fixed false-positive fraction. CONCLUSION ROC curves may be compared on the basis of utilities associated with their OOPs. This comparison of the optimal performance of two diagnostic tests may differ from conventional statistical comparisons.

Choice rules and sensitivity analysis in conjoint simulators

Despite the widespread use of choice simulators in commercial conjoint applications, relatively little has been written about the applicability of various types of buyer choice rules and sensitivity analyses. This paper first discusses issues related to the selection of different buyer choice rules. We then propose six types of sensitivity analyses that can be implemented in buyer choice simulators, given the usual input data of respondents’ part worths, status quo product utilities, and background data.Each sensitivity analysis is illustrated in the context of a common business application. The paper concludes with a brief discussion of possible extensions of sensitivity analysis and areas for further research.

Exploring the relationship between anxiety and insistence on sameness in autism spectrum disorders.

Elevated anxiety symptoms are one of the most common forms of psychopathology to co‐occur with autism spectrum disorders (ASDs). The purpose of this study was to explore the association between anxiety and ASD symptoms, particularly the degree to which the relationship is explained by insistence on sameness (IS) behaviors and/or cognitive ability. The sample included 1429 individuals aged 5:8–18:0 years who participated in the Simons Simplex Collection, a genetic consortium study of ASD. Child Behavior Checklist Anxiety Problems T‐scores and Autism Diagnostic Interview‐Revised “IS“ item raw totals were treated as both categorical and continuous measures of anxiety and IS, respectively. Chronological age, verbal intelligence quotient (IQ), and a variety of ASD phenotype‐related and other behavioral variables were assessed for potential association with anxiety and IS. Anxiety and IS continuous variables were minimally, although significantly, associated with each other and with chronological age and verbal IQ. Neither anxiety nor IS was associated with other core autism diagnostic scores. Anxiety was associated with a variety of other psychiatric and behavioral symptoms in ASD, including irritability, attention problems, and aggression, while IS was not. Anxiety and IS appear to function as distinct constructs, each with a wide range of expression in children with ASD across age and IQ levels. Thus, both variables could be of use in ASD behavioral research or in dimensional approaches to genetic exploration. Unlike IS, however, anxiety is related to non‐ASD‐specific behavioral symptoms. Autism Res 2012, ●●: ●●–●●.

An Analysis of Real World TV Advertising Tests: A 15-Year Update

ABSTRACT An analysis is performed on the results of 241 real world TV advertising tests conducted by Information Resources, Inc. between 1989 and 2003 to partially update the findings of Lodish et al. [Journal of Marketing Research 32, 2 (1995): 125–39]. Two types of market test results, BehaviorScan and Matched-Market, are analyzed. Overall, the improvement of TV advertising sales effectiveness because of media weight increase is significantly larger than zero for established products, which is different from Lodish et al.s finding. A further analysis indicates that such significance is mainly driven by more recent tests. A comparison between the new results and Lodish et al. reveals a significant increase in the average advertising effectiveness for tests completed after 1995. The new data still suggest (as did the original data) that it is of great managerial interest to identify advertising effectiveness before launching advertising campaigns.

Neutral mitochondrial heteroplasmy and the influence of aging

The development and maintenance of mitochondrial heteroplasmy has important consequences for both health and heredity. Previous studies using pathogenic mutations have shown considerable variability between maternally related individuals and studies of several D-loop polymorphisms have suggested a relationship between heteroplasmy and somatic aging. To broadly explore the variation of human heteroplasmy and to clarify the dynamics of somatic heteroplasmy over the course of lifespan, we analyzed mitochondrial sequence variation across a range of ages. We utilized array-generated single-nucleotide polymorphism data that were well correlated with independent measures of heteroplasmy. Significant levels of heteroplasmy were identified at 0.24% of sites evaluated. By examining mother-child pairs, we found that heteroplasmy was inherited (30%) but could occur de novo in offspring or, conversely, be present in mothers but eliminated in their children (70%). Cumulatively, mitochondrial heteroplasmy across the genome increased significantly with advanced age (r = 0.224, P =8 × 10(-30)). Surprisingly, changes in heteroplasmy were not uniform with some sites demonstrating a loss of variation (increased homoplasmy) with aging. These data suggest that both mutation and selective pressure affect blood mitochondrial DNA sequence over the course of the human lifespan and reveal the unexpectedly dynamic nature of human heteroplasmy.

Ordinal Association in Contingency Tables: Some Interpretive Aspects

Abstract Two families of models for ordered contingency tables—Goodmans association models and canonical correlation models—are investigated and compared with respect to the interpretation of their parameters. We show that the two families of models actually refer to different kinds of ordinal association: stochastic order extremity for correlation models and stochastic order entropy for association models. This difference is related to the way the two models scale interaction. The scale difference is proven to be of substantial consequence, especially under strong association.

Sexual behavior frequency and menstrual cycle length in mature premenopausal women

Abstract (1) Women who had regular weekly sexual intercourse with men had menstrual cycles, the average duration of which was 29 days (range 26–33), while women with less frequent behavioral interactions tended to have more extreme cycle lengths, as shown in 3 different studies in which prospective double blind measurements of data were used. (2) The effect was noted consistently in college women but also occurred in infertile patients. Sexual behavior and consistent menstrual cycle length were associated in all women studied. (3) The mechanism appeared to be related to the regularity with which sexual activity occurred during all the non-menstruating days of the cycle.