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ImportanceHeterogeneous mental health outcomes during the COVID-19 pandemic are recognized in the general population, but it has not been systematically assessed in youth with neurodevelopmental disorders (NDD), including autism spectrum (ASD).ObjectiveIdentify subgroups of youth with ASD/NDD based on the pandemic impact on symptoms and service changes, as well as predictors of outcomes.Design, Setting, and ParticipantsThis is a naturalistic observational study conducted across 14 North American and European clinical and/or research sites. Parent responses on the Coronavirus Health and Impact Survey Initiative (CRISIS) adapted for Autism and Related Neurodevelopmental Conditions (AFAR) were cross-sectionally collected from April to October 2020. The sample included 1275, 5-21 year-old youth with ASD and/or NDD who were clinically well-characterized prior to the pandemic.Main Outcomes and MeasuresTo identify impact subgroups, hierarchical clustering analyzed eleven AFAR factors measuring pre- to pandemic changes in clinically relevant symptoms and service access. Random forest classification assessed the relative contribution in predicting subgroup membership of 20 features including socio-demographics, pre-pandemic service, and clinical severity along with indices of COVID-19 related experiences and environments empirically-derived from AFAR parent responses and global open sources.ResultsClustering analyses revealed four ASD/NDD impact subgroups. One subgroup - broad symptom worsening only (20% of the aggregate sample) - included youth with worsening symptoms that were above and beyond that of their ASD/NDD peers and with similar service disruptions as those in the aggregate average. The three other subgroups showed symptom changes similar to the aggregate average but differed in service access: primarily modified services (23%), primarily lost services (6%), and average services/symptom changes (53%). Pre-pandemic factors (e.g., number of services), pandemic environments and experiences (e.g., COVID-19 cases, related restrictions, COVID-19 Worries), and age emerged in unique combinations as distinct protective or risk factors for each subgroup. Together they highlighted the role of universal risk factors, such as risk perception, and the protective role of services before and during the pandemic, in middle childhood.Conclusions and RelevanceConcomitant assessment of changes in both symptoms and services access is critical to understand heterogeneous impact of the pandemic on ASD/NDD youth. It enabled the delineation of pathways to risk and resilience that include universal and ASD/NDD specific contributors.

Multiple myeloma (MM) prognosis incorporates a variety of metrics including treatment received, clinical factors, and genomic characteristics, with several specific genomic features predicting for shorter progression free survival (PFS). No study to date has integrated genomic data from a systems view, incorporating interactions between biomarkers in a network. We use a geometric network analysis that integrates complex interactions to characterize patterns of biological behavior not captured by individual genomic events. The methodology is mathematically well-defined and has no fitting parameters. We hypothesized that such a systems mathematical approach applied to gene interaction networks may delineate biologically relevant MM subtypes and potential new therapeutic targets. We overlaid RNA-Seq and copy number alteration data from the MMRF CoMMpass study (IA19) on a gene interactome derived from the Human Protein Reference Database using a novel graph metric of network robustness — Ollivier-Ricci curvature (ORC). Results were clustered, with the optimal number determined via silhouette score. Survival analysis for PFS was performed employing Kaplan-Meier and log-rank tests. A differential gene expression analysis between high and low risk groups was conducted. Differences in scalar ORC between the low-risk and high-risk groups were examined and contextualized using a pathway analysis. Pathway analysis was performed using the Broad Institute’s Gene Set Enrichment Analysis tool and the pathways used are from the hallmark gene set from the Human MSigDB collection. The dataset included 659 patients and the incorporated protein-protein interactions resulted in a network with 8,468 nodes and 33,695 edges. The ORC analysis discovered 6 clusters, with specific genomic features being associated with clusters predicting for long [hyperdiploidy, t(11:14)], and short [t(4;14), MAF/MAFB translocations] PFS. A differential gene expression analysis comparing the high risk and low risk groups identified 118 key genes. These genes were associated with various pathways both known and unknown to be associated with multiple myeloma, including mitotic spindle, DNA repair, inflammatory response, and the P53 pathways. Further scalar curvature analysis showed differences in the apoptosis, TGF beta signaling, and other signaling pathways. In summary, we applied the geometric network analysis tool ORC to multi-omics data in MM represented as biological networks to identify individuals at high risk of short PFS and relevant biological correlates. Decreased robustness of signaling near immune-related genes was associated with shorter survival, highlighting the plausible utility of using these methods to uncover new biological insights. Citation Format: Anish K. Simhal, Kylee H. Maclachlan, Rena Elkin, Jiening Zhu, Saad Z. Usmani, Jonathan J. Keats, Larry Norton, Joseph O. Deasy, Jung Hun Oh, Allen Tannenbaum. Protein network analysis uncovers a poor-survival subtype in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2061.

Pediatric brain imaging holds significant promise for understanding neurodevelopment. However, the requirement to remain still inside a noisy, enclosed scanner remains a challenge. Verbal or visual descriptions of the process, and/or practice in MRI simulators are the norm in preparing children. Yet, the factors predictive of successfully obtaining neuroimaging data remain unclear. We examined data from 250 children (6–12 years, 197 males) with autism and/or attention-deficit/hyperactivity disorder. Children completed systematic MRI simulator training aimed to habituate to the scanner environment and minimize head motion. An MRI session comprised multiple structural, resting-state, task and diffusion scans. Of the 201 children passing simulator training and attempting scanning, nearly all (94%) successfully completed the first structural scan in the sequence, and 88% also completed the following functional scan. The number of successful scans decreased as the sequence progressed. Multivariate analyses revealed that age was the strongest predictor of successful scans in the session, with younger children having lower success rates. After age, sensorimotor atypicalities contributed most to prediction. Results provide insights on factors to consider in designing pediatric brain imaging protocols.

Pediatric brain imaging holds significant promise for understanding neurodevelopment. However, the requirement to remain still inside a noisy, enclosed scanner remains a challenge. Verbal or visual descriptions of the process, and/or practice in MRI simulators are the norm in preparing children. Yet, the factors predictive of successfully obtaining neuroimaging data remain unclear. We examined data from 250 children (6-12 years, 197 males) with autism and/or attention-deficit/hyperactivity disorder. Children completed systematic MRI simulator training aimed to habituate to the scanner environment and minimize head motion. An MRI session comprised multiple structural, resting-state, task and diffusion scans. Of the 201 children passing simulator training and attempting scanning, nearly all (94%) successfully completed the first structural scan in the sequence, and 88% also completed the following resting state fMRI scan. The number of successful scans decreased as the sequence progressed. Multivariate analyses revealed that age was the strongest predictor of successful scans in the session, with younger children having lower success rates. After age, sensorimotor atypicalities contributed most to prediction. Results provide insights on factors to consider in designing pediatric brain imaging protocols.

Ollivier–Ricci curvature is a method for measuring the robustness of connections in a network. In this work, we use curvature to measure changes in robustness of brain networks in children with autism spectrum disorder (ASD). In an open label clinical trials, participants with ASD were administered a single infusion of autologous umbilical cord blood and, as part of their clinical outcome measures, were imaged with diffusion MRI before and after the infusion. By using Ricci curvature to measure changes in robustness, we quantified both local and global changes in the brain networks and their potential relationship with the infusion. Our results find changes in the curvature of the connections between regions associated with ASD that were not detected via traditional brain network analysis.

Fragile X Syndrome (FXS), a common inheritable form of intellectual disability, is known to alter neocortical circuits. However, its impact on the diverse synapse types comprising these circuits, or on the involvement of astrocytes, is not well known. We used immunofluorescent array tomography to quantify different synaptic populations and their association with astrocytes in layers 1 through 4 of the adult somatosensory cortex of a FXS mouse model, the FMR1 knockout mouse. The collected multi-channel data contained approximately 1.6 million synapses which were analyzed using a probabilistic synapse detector. Our study reveals complex, synapse-type and layer specific changes in the neocortical circuitry of FMR1 knockout mice. In layers 1 and 2/3, there is a significant decrease in the density of excitatory glutamatergic synapses, both VGluT1 and VGluT2 type, and their association with astrocytes, while the changes in inhibitory GABAergic synapses are less pronounced. Meanwhile in layer 4, there is a significant increase in the density of small VGluT1 synapses, with no changes in the astrocytic association of synapses. The ability to dissect the circuit deficits by synapse type and astrocytic involvement, will be crucial for understanding how these changes affect circuit function, and ultimately define targets for therapeutic intervention.

GoalIn this work, we propose methods for (1) automatic feature extraction and classification for acetic acid and Lugol’s iodine cervigrams and (2) methods for combining features/diagnosis of different contrasts in cervigrams for improved performance.MethodsWe developed algorithms to pre-process pathology-labeled cervigrams and to extract simple but powerful color and textural-based features. The features were used to train a support vector machine model to classify cervigrams based on corresponding pathology for visual inspection with acetic acid, visual inspection with Lugol’s iodine, and a combination of the two contrasts.ResultsThe proposed framework achieved a sensitivity, specificity, and accuracy of 81.3%, 78.6%, and 80.0%, respectively when used to distinguish cervical intraepithelial neoplasia (CIN+) relative to normal and benign tissues. This is superior to the average values achieved by three expert physicians on the same data set for discriminating normal/benign cases from CIN+ (77% sensitivity, 51% specificity, 63% accuracy).ConclusionThe results suggest that utilizing simple color- and textural-based features from visual inspection with acetic acid and visual inspection with Lugol’s iodine images may provide unbiased automation of cervigrams.SignificanceThis would enable automated, expert-level diagnosis of cervical pre-cancer at the point-of-care.

The world health organization recommends visual inspection with acetic acid (VIA) and/or Lugol’s Iodine (VILI) for cervical cancer screening in low-resource settings. Human interpretation of diagnostic indicators for visual inspection is qualitative, subjective, and has high inter-observer discordance, which could lead both to adverse outcomes for the patient and unnecessary follow-ups. In this work, we a simple method for automatic feature extraction and classification for Lugol’s Iodine cervigrams acquired with a low-cost, miniature, digital colposcope. Algorithms to preprocess expert physician-labelled cervigrams and to extract simple but powerful color-based features are introduced. The features are used to train a support vector machine model to classify cervigrams based on expert physician labels. The selected framework achieved a sensitivity, specificity, and accuracy of 89.2%, 66.7% and 80.6% with majority diagnosis of the expert physicians in discriminating cervical intraepithelial neoplasia (CIN +) relative to normal tissues. The proposed classifier also achieved an area under the curve of 84 when trained with majority diagnosis of the expert physicians. The results suggest that utilizing simple color-based features may enable unbiased automation of VILI cervigrams, opening the door to a full system of low-cost data acquisition complemented with automatic interpretation.

Application-specific validation of antibodies is a critical prerequisite for their successful use. Here we introduce an automated framework for characterization and screening of antibodies against synaptic molecules for high-resolution immunofluorescence array tomography (AT). The proposed Synaptic Antibody Screening Tool (SACT), is designed to provide an automatic, robust, flexible, and efficient tool for antibody characterization at scale. By allowing the user to define the molecular composition and size of synapses expected to contain the antigen, the method detects and characterizes puncta and synapses, and outputs automatically computed characteristics such as synapse density and target specificity ratio, which reflect the sensitivity and specificity of immunolabeling with a given antibody. These measurements provide an objective way to characterize and compare the performance of different antibodies against the same target, and can be used to objectively select the antibodies best suited for AT and potentially for other immunolabeling applications.

Deeper exploration of the brain’s vast synaptic networks will require new tools for high-throughput structural and molecular profiling of the diverse populations of synapses that compose those networks. Fluorescence microscopy (FM) and electron microscopy (EM) offer complementary advantages and disadvantages for single-synapse analysis. FM combines exquisite molecular discrimination capacities with high speed and low cost, but rigorous discrimination between synaptic and non-synaptic fluorescence signals is challenging. In contrast, EM remains the gold standard for reliable identification of a synapse, but offers only limited molecular discrimination and is slow and costly. To develop and test single-synapse image analysis methods, we have used datasets from conjugate array tomography (cAT), which provides voxel-conjugate FM and EM (annotated) images of the same individual synapses. We report a novel unsupervised probabilistic method for detection of synapses from multiplex FM (muxFM) image data, and evaluate this method both by comparison to EM gold standard annotated data and by examining its capacity to reproduce known important features of cortical synapse distributions. The proposed probabilistic model-based synapse detector accepts molecular-morphological synapse models as user queries, and delivers a volumetric map of the probability that each voxel represents part of a synapse. Taking human annotation of cAT EM data as ground truth, we show that our algorithm detects synapses from muxFM data alone as successfully as human annotators seeing only the muxFM data, and accurately reproduces known architectural features of cortical synapse distributions. This approach opens the door to data-driven discovery of new synapse types and their density. We suggest that our probabilistic synapse detector will also be useful for analysis of standard confocal and super-resolution FM images, where EM cross-validation is not practical., Author summary Brain function results from communication between neurons connected by complex synaptic networks. Synapses are themselves highly complex and diverse signaling machines, containing protein products of hundreds of different genes, some in hundreds of copies, precisely arranged at each individual synapse. Synapses are fundamental not only to synaptic network function but also to network development, adaptation, and memory. In addition, abnormalities of synapse numbers or their molecular components have been implicated in a variety of mental and neurological disorders. Despite their obvious importance, mammalian synapse populations have so far resisted detailed quantitative study. In human brains and most animal nervous systems, synapses are very small and very densely packed: there are approximately 1 billion synapses per cubic millimeter of human cortex. This volumetric density poses very substantial challenges to proteometric analysis at the critical level of the individual synapse. The present work describes new probabilistic image analysis methods suitable for single-synapse analysis of synapse populations in both animal and human brains, in health and disorder.