Development and Validation of the PREMM5 Model for Comprehensive Risk Assessment of Lynch Syndrome.

Purpose Current Lynch syndrome (LS) prediction models quantify the risk to an individual of carrying a pathogenic germline mutation in three mismatch repair (MMR) genes: MLH1, MSH2, and MSH6. We developed a new prediction model, PREMM5, that incorporates the genes PMS2 and EPCAM to provide comprehensive LS risk assessment. Patients and Methods PREMM5 was developed to predict the likelihood of a mutation in any of the LS genes by using polytomous logistic regression analysis of clinical and germline data from 18,734 individuals who were tested for all five genes. Predictors of mutation status included sex, age at genetic testing, and proband and family cancer histories. Discrimination was evaluated by the area under the receiver operating characteristic curve (AUC), and clinical impact was determined by decision curve analysis; comparisons were made to the existing PREMM1,2,6 model. External validation of PREMM5 was performed in a clinic-based cohort of 1,058 patients with colorectal cancer. Results Pathogenic mutations were detected in 1,000 (5%) of 18,734 patients in the development cohort; mutations included MLH1 (n = 306), MSH2 (n = 354), MSH6 (n = 177), PMS2 (n = 141), and EPCAM (n = 22). PREMM5 distinguished carriers from noncarriers with an AUC of 0.81 (95% CI, 0.79 to 0.82), and performance was similar in the validation cohort (AUC, 0.83; 95% CI, 0.75 to 0.92). Prediction was more difficult for PMS2 mutations (AUC, 0.64; 95% CI, 0.60 to 0.68) than for other genes. Performance characteristics of PREMM5 exceeded those of PREMM1,2,6. Decision curve analysis supported germline LS testing for PREMM5 scores ≥ 2.5%. Conclusion PREMM5 provides comprehensive risk estimation of all five LS genes and supports LS genetic testing for individuals with scores ≥ 2.5%. At this threshold, PREMM5 provides performance that is superior to the existing PREMM1,2,6 model in the identification of carriers of LS, including those with weaker phenotypes and individuals unaffected by cancer.

Racial variation in frequency and phenotypes of APC and MUTYH mutations in 6,169 individuals undergoing genetic testing.

PURPOSE: The aim of this study was to assess whether differences in frequency and phenotype of APC and MUTYH mutations exist among racially/ethnically diverse populations. METHODS: We studied 6,169 individuals with a personal and/or family history of colorectal cancer (CRC) and polyps. APC testing involved full sequencing/large rearrangement analysis (FS/LRA); MUTYH involved "panel testing" (for Y165C, G382D mutations) or FS/LRA performed by Myriad Genetics, a commercial laboratory. Subjects were identified as Caucasian, Asian, African American (AA), or other. Statistical tests included χ(2), Fisher's exact test, analysis of variance, and z approximation. RESULTS: Among participants, 17.5% had pathogenic APC mutations and 4.8% were biallelic MUTYH carriers. With regard to race/ethnicity, 18% were non-Caucasian, with >100 adenomas and younger ages at adenoma or CRC diagnosis (P < 0.0001) than Caucasians. The overall APC mutation rate was higher in Asians, AAs, and others as compared with Caucasians (25.2, 30.9, 24, and 15.5%, respectively; P < 0.0001) but was similar in all groups when adjusted for polyp burden. More MUTYH biallelic carriers were Caucasian or other than Asian or AA (5, 7, 2.7, and 0.3%, respectively; P < 0.0001). Among Caucasians, 5% were biallelic carriers identified by panel testing versus 2% identified by sequencing/large rearrangement analysis (LRA) (P = 0.002). Among non-Caucasians, 3% undergoing panel testing were biallelic carriers versus 10% identified by sequencing/LRA (P < 0.0002). CONCLUSION: Non-Caucasians undergo genetic testing at more advanced stages of polyposis and/or are younger at CRC/polyp diagnosis. Restricted MUTYH analysis may miss significant numbers of biallelic carriers, particularly in non-Caucasians.

Looking under the hood of the dot-probe task: an fMRI study in anxious youth.

BACKGROUND: Anxious youth have shown altered behavioral performance on the dot-probe task, but neural activation patterns provoked by the task remain poorly understood. In particular, neural mechanisms of threat disengagement, a clinically relevant construct, have been inadequately explored. METHOD: During fMRI acquisition, 121 youth (ages 9-13; 90 with Generalized Anxiety Disorder, Separation Anxiety Disorder, and/or Social Phobia; 31 nonanxious controls) completed a dot-probe task, which required participants to identify the location of a dot replacing either a neutral or fearful face in a pair containing both faces. We assessed neural substrates of threat disengagement by comparing congruent trials (in which the dot replaces the fearful face) to incongruent trials (in which the dot replaces the neutral face). RESULTS: Across subjects, decreased rostrodorsal anterior cingulate cortex (rdACC) activity was observed specifically during incongruent trials. Nonanxious youth showed a convergent pattern in bilateral parahippocampal and hippocampal regions, whereas anxious youth showed an opposing pattern in these limbic areas, suggesting less integration of response across cortical and limbic areas relevant to threat appraisal. Reduced functional connectivity between rdACC and left parahippocampus/hippocampus was associated with greater anxiety. CONCLUSIONS: In the largest dot-probe fMRI sample to date, both anxious and nonanxious youth showed a neural pattern consistent with successful disengagement of threat reactivity in the rdACC. However, anxious youth showed evidence of abnormal disengagement in bilateral parahippocampal/hippocampal clusters when attention was directed away from threat. Early interventions targeting neural mechanisms of threat disengagement may be beneficial, for example, by increasing integration across rdACC and limbic regions.

Dual origins of functionally distinct O-LM interneurons revealed by differential 5-HT(3A)R expression.

Forebrain circuits rely upon a relatively small but remarkably diverse population of GABAergic interneurons to bind and entrain large principal cell assemblies for network synchronization and rhythmogenesis. Despite the high degree of heterogeneity across cortical interneurons, members of a given subtype typically exhibit homogeneous developmental origins, neuromodulatory response profiles, morphological characteristics, neurochemical signatures and electrical features. Here we report a surprising divergence among hippocampal oriens-lacunosum moleculare (O-LM) projecting interneurons that have hitherto been considered a homogeneous cell population. Combined immunocytochemical, anatomical and electrophysiological interrogation of Htr3a-GFP and Nkx2-1-cre:RCE mice revealed that O-LM cells parse into a caudal ganglionic eminence-derived subpopulation expressing 5-HT(3A) receptors (5-HT(3A)Rs) and a medial ganglionic eminence-derived subpopulation lacking 5-HT(3A)Rs. These two cohorts differentially participate in network oscillations, with 5-HT(3A)R-containing O-LM cell recruitment dictated by serotonergic tone. Thus, members of a seemingly uniform interneuron population can exhibit unique circuit functions and neuromodulatory properties dictated by disparate developmental origins.

Sustained neural alterations in anxious youth performing an attentional bias task: a pupilometry study.

BACKGROUND: Biased attention patterns have been observed at early (16-500 ms poststimulus onset) and intermediate (1,500-4,000 ms post-onset) time points in anxious youth, but it is unclear whether a more sustained form of neural attentional bias, persisting well beyond the time frame of stimulus presentation and behavioral response, is also apparent. We investigated early, intermediate, and sustained forms of bias using behavioral measures and pupillary reactivity, an index of cognitive and affective load, to gain insight into potential neurocognitive targets for early intervention. METHOD: Twenty nonanxious youth and 74 youth with generalized anxiety disorder (GAD), separation anxiety disorder (SAD), and/or social phobia (SP) completed a dot-probe task, which requires participants to respond to a dot replacing either a neutral or fearful face. Emotional faces were presented for short/early (200 ms) or intermediate (2 s) intervals and followed by a sustained (up to 10.5 s) poststimulus interval. Pupil dilation, gaze direction, and reaction times (RTs) were measured during task completion. RESULTS: Early and intermediate vigilance patterns in RTs and an avoidant pattern in gaze direction were observed in all participants irrespective of anxiety. Sustained pupil dilation in anxious youth was observed on trials in which the dot replaced fearful faces, along with an inflexible pattern of pupillary responding in comparison to controls. CONCLUSION: Sustained cognitive-affective load following emotional face viewing is altered and inflexible in anxious youth. These prolonged alterations extend well beyond the time frame of behavioral attentional bias and may indicate inflexible and insufficient sustained cognitive control. Early interventions targeting these alterations could improve long-term mental health trajectories.

Mom-it helps when you're right here! Attenuation of neural stress markers in anxious youths whose caregivers are present during fMRI.

Close proximity to an attachment figure, such as a caregiver, has been shown to attenuate threat-related activity in limbic regions such as the hypothalamus in healthy individuals. We hypothesized that such features might be similarly attenuated by proximity during a potentially stressful situation in a clinically anxious population of youths. Confirmation of this hypothesis could support the role of attachment figures in the management of anxiety among children and adolescents. Three groups were analyzed: anxious children and adolescents who requested that their caregiver accompany them in the scanner room, anxious children and adolescents without their caregiver in the scanner room and healthy controls (each of N = 10). The groups were matched for age and, among the two anxious groups, for diagnosis (mean age 9.5). The children and adolescents were exposed to physical threat words during an fMRI assessment. Results indicate that activity in the hypothalamus, ventromedial, and ventrolateral prefrontal cortex were significantly reduced in anxious children and adolescents who requested that their caregiver accompany them in the scanner room compared to those without their caregiver in the scanner room. Mean activity in these regions in anxious children and adolescents with their caregiver in the scanner room was comparable to that of healthy controls. These data suggest links between social contact and neural mechanisms of emotional reactivity; specifically, presence of caregivers moderates the increase in anxiety seen with stressful stimuli. Capitalizing on the ability of anxious youths to manifest low levels of anxiety-like information processing in the presence of a caregiver could help in modeling adaptive function in behavioral treatments.

Pediatric functional magnetic resonance neuroimaging: tactics for encouraging task compliance.

BACKGROUND: Neuroimaging technology has afforded advances in our understanding of normal and pathological brain function and development in children and adolescents. However, noncompliance involving the inability to remain in the magnetic resonance imaging (MRI) scanner to complete tasks is one common and significant problem. Task noncompliance is an especially significant problem in pediatric functional magnetic resonance imaging (fMRI) research because increases in noncompliance produces a greater risk that a study sample will not be representative of the study population. METHOD: In this preliminary investigation, we describe the development and application of an approach for increasing the number of fMRI tasks children complete during neuroimaging. Twenty-eight healthy children ages 9-13 years participated. Generalization of the approach was examined in additional fMRI and event-related potential investigations with children at risk for depression, children with anxiety and children with depression (N=120). Essential features of the approach include a preference assessment for identifying multiple individualized rewards, increasing reinforcement rates during imaging by pairing tasks with chosen rewards and presenting a visual 'road map' listing tasks, rewards and current progress. RESULTS: Our results showing a higher percentage of fMRI task completion by healthy children provides proof of concept data for the recommended tactics. Additional support was provided by results showing our approach generalized to several additional fMRI and event-related potential investigations and clinical populations. DISCUSSION: We proposed that some forms of task noncompliance may emerge from less than optimal reward protocols. While our findings may not directly support the effectiveness of the multiple reward compliance protocol, increased attention to how rewards are selected and delivered may aid cooperation with completing fMRI tasks. CONCLUSION: The proposed approach contributes to the pediatric neuroimaging literature by providing a useful way to conceptualize and measure task noncompliance and by providing simple cost effective tactics for improving the effectiveness of common reward-based protocols.

Perinatal exposure to polychlorinated biphenyls alters social behaviors in rats.

Perinatal exposure to polychlorinated biphenyls (PCBs) leads to significant alterations of neural and hormonal systems. These alterations have been shown to impair motor and sensory development. Less is known about the influence of PCB exposure on developing emotional and motivational systems involved in social interactions and social learning. The present study examined the impact of perinatal PCB exposure (mixture of congeners 47 and 77) on social recognition in juvenile animals, conspecific-directed investigation in adults and on neural and hormonal systems involved in social functions. We used a standard habituation-dishabituation paradigm to evaluate juvenile recognition and a social port paradigm to monitor adult social investigation. Areal measures of the periventricular nucleus (PVN) of the hypothalamus were obtained to provide correlations with related hormone and brain systems. PCB exposed rats were significantly impaired in social recognition as indicated by persistent conspecific-directed exploration by juvenile animals regardless of social experience. As adults, PCB exposure led to a dampening of the isolation-induced enhancement of social investigation. There was not a concomitant alteration of social investigation in pair-housed PCB exposed animals at this stage of development. Interestingly, PVN area was significantly decreased in juvenile animals exposed to PCB during the perinatal period. Shifts in hypothalamic regulation of hormones involved in social behavior and stress could be involved in the behavioral changes observed. Overall, the results suggest that PCB exposure impairs context or experience-dependent modulation of social approach and investigation. These types of social-context deficits are similar to behavioral deficits observed in social disorders such as autism and other pervasive developmental disorders.

The effects of prenatal stress on motivation in the rat pup.

Exposure to prenatal stress (PNS) has been shown to induce a set of psychological and behavioral changes in developing offspring. We used the rodent model to investigate whether PNS produces changes in the ability of the pup to express social motivation. We used a set of behavioral tasks including monitoring ultrasonic vocalizations after isolation, a conditioned place preference, and a novel and familiar odor approach test. Pregnant Long-Evans rats were exposed to an unpredictable, variable stressor twice daily during the third week of gestation. Isolation vocalizations were assessed on postnatal day (PND) 10. Pup affinity for the dam was evaluated on PND 15. Typically, pups display a selective preference for an odor-paired environment only after the odor has been associated with the dam. This previous association produces a positive conditioned stimulus (CS). Normally, pups exposed to a neutral CS (odor paired with cotton balls) do not form this place preference. Results indicate that PNS exposed pups had significantly increased distress vocalizations and an equal preference for the positive and neutral conditioned stimuli. This type of alteration in forming early preferences could be detrimental because of decreases in the specificity of social learning and an impaired responsiveness in social relationships.