Analytical validation of NeXT Personal®, an ultra-sensitive personalized circulating tumor DNA assay.

We describe the analytical validation of NeXT Personal®, an ultra-sensitive, tumor-informed circulating tumor DNA (ctDNA) assay for detecting residual disease, monitoring therapy response, and detecting recurrence in patients diagnosed with solid tumor cancers. NeXT Personal uses whole genome sequencing of tumor and matched normal samples combined with advanced analytics to accurately identify up to ~1,800 somatic variants specific to the patient's tumor. A personalized panel is created, targeting these variants and then used to sequence cell-free DNA extracted from patient plasma samples for ultra-sensitive detection of ctDNA. The NeXT Personal analytical validation is based on panels designed from tumor and matched normal samples from two cell lines, and from 123 patients across nine cancer types. Analytical measurements demonstrated a detection threshold of 1.67 parts per million (PPM) with a limit of detection at 95% (LOD95) of 3.45 PPM. NeXT Personal showed linearity over a range of 0.8 to 300,000 PPM (Pearson correlation coefficient = 0.9998). Precision varied from a coefficient of variation of 12.8% to 3.6% over a range of 25 to 25,000 PPM. The assay targets 99.9% specificity, with this validation study measuring 100% specificity and in silico methods giving us a confidence interval of 99.92 to 100%. In summary, this study demonstrates NeXT Personal as an ultra-sensitive, highly quantitative and robust ctDNA assay that can be used to detect residual disease, monitor treatment response, and detect recurrence in patients.

Retinal Imaging Findings in Carriers With PSEN1-Associated Early-Onset Familial Alzheimer Disease Before Onset of Cognitive Symptoms.

Importance: Individuals with autosomal dominant mutations for Alzheimer disease are valuable in determining biomarkers present prior to the onset of cognitive decline, improving the ability to diagnose Alzheimer disease as early as possible. Optical coherence tomography (OCT) has surfaced as a potential noninvasive technique capable of analyzing central nervous system tissues for biomarkers of Alzheimer disease. Objective: To evaluate whether OCT can detect early retinal alterations in carriers of the presenilin 1 (PSEN1 [OMIM 104311]) E280A mutation who are cognitively unimpaired. Design, Setting, and Participants: A cross-sectional imaging study conducted from July 13, 2015, to September 16, 2020, included 10 carriers of the PSEN1 E280A mutation who were cognitively unimpaired and 10 healthy noncarrier family members, all leveraged from a homogenous Colombian kindred. Statistical analysis was conducted from September 9, 2017, to September 16, 2020. Main Outcomes and Measures: Mixed-effects multiple linear regression was performed to compare the thickness values of the whole retina and individual retinal layers on OCT scans between mutation carriers and noncarriers. Simple linear-effects and mixed-effects multiple linear regression models were used to assess whether age was an effect modifier for PSEN1 mutation of amyloid ß levels and retinal thickness, respectively. Fundus photographs were used to compare the number of arterial and venous branch points, arterial and venous tortuosity, and fractal dimension. Results: This study included 10 carriers of the PSEN1 E280A mutation who were cognitively unimpaired (7 women [70%]; mean [SD] age, 36.3 [8.1] years) and 10 healthy noncarrier family members (7 women [70%]; mean [SD] age, 36.4 [8.2] years). Compared with noncarrier controls, PSEN1 mutation carriers who were cognitively unimpaired had a generalized decrease in thickness of the whole retina as well as individual layers detected on OCT scans, with the inner nuclear layer (outer superior quadrant, ß = -3.06; P = .007; outer inferior quadrant, ß = -2.60; P = .02), outer plexiform layer (outer superior quadrant, ß = -3.44; P = .03), and outer nuclear layer (central quadrant, ß = -8.61; P = .03; inner nasal quadrant, ß = -8.39; P = .04; inner temporal quadrant, ß = -9.39; P = .02) showing the greatest amount of statistically significant thinning. Age was a significant effect modifier for the association between PSEN1 mutation and amyloid ß levels in cortical regions (ß = 0.03; P = .001) but not for the association between PSEN1 mutation and retinal thickness. No statistical difference was detected in any of the vascular parameters studied. Conclusions and Relevance: These findings suggest that OCT can detect functional and morphologic changes in the retina of carriers of familial Alzheimer disease who are cognitively unimpaired several years before clinical onset, suggesting that OCT findings and retinal vascular parameters may be biomarkers prior to the onset of cognitive decline.

Females excel at basic face perception.

Females are generally better than males at recognizing facial emotions. However, it is not entirely clear whether and in what way females may also excel at non-affective face recognition. Here, we tested males and females on two perceptual face recognition tasks that involved only neutral expressions: detection and identity discrimination. On face detection (Experiment 1), females were significantly more accurate than males in detecting upright faces. This gender difference was reduced during inverted face detection, and not present during tree detection, suggesting that the magnitude of the gender difference for performance co-varies with the extent to which face processing mechanisms are involved. On facial identity discrimination (Experiment 2), females again outperformed males, particularly when face images were masked by visual noise, or the delay between comparison face images was extended from 0.5 to 3s. These results reveal a female advantage in processing face-specific information and underscore the role of perceptual factors in socially relevant gender differences.

Altered 'three-flash' illusion in response to two light pulses in schizophrenia.

BACKGROUND: Disorganization is a core dysfunction in schizophrenia. Coherent thought and behavior rely on the interactive neural responses to temporally discrete external events. Previous studies have demonstrated that a single visual stimulus (event) is abnormally affected by another (as in backward masking), but the integration (or 'synthesis') of temporally discrete events remains largely unexplored in schizophrenia. We examined the perceived interaction of two elementary visual events in schizophrenia patients, using a psychophysical approach. METHODS: Two brief, spatially-coincident foveal light pulses (5 ms) were presented with different inter-stimulus intervals (ISIs). At ISIs around 100 ms, a substantial proportion of the light pulse pairs was paradoxically perceived as three flashes, a known phenomenon in normal subjects. The subjects reported the number of flashes perceived ('one', 'two' or 'three'). RESULTS: Schizophrenia patients (n=28) reported fewer 'three flashes' than normal controls (n=26) at the ISIs where 'three flash' reports were greatest in normal subjects (90 to 110 ms). On the other hand, at longer ISIs (130-310 ms) patients reported 'three flashes' in more trials than did normal subjects. The perception of three flashes in patients was correlated with certain aspects of clinical status, including the positive and general subscales of the PANSS. DISCUSSION: The alteration of the 'three-flash' illusion in schizophrenia suggests that the synthesis of discrete visual events is temporally 'dilated' or distorted, which might contribute to disorganized thought and behavior.