Individual differences in processing speed and curiosity explain infant habituation and dishabituation performance.

Habituation and dishabituation are the most prevalent measures of infant cognitive functioning, and they have reliably been shown to predict later cognitive outcomes. Yet, the exact mechanisms underlying infant habituation and dishabituation are still unclear. To investigate them, we tested 106 8-month-old infants on a classic habituation task and a novel visual learning task. We used a hierarchical Bayesian model to identify individual differences in sustained attention, learning performance, processing speed and curiosity from the visual learning task. These factors were then related to habituation and dishabituation. We found that habituation time was related to individual differences in processing speed, while dishabituation was related to curiosity, but only for infants who did not habituate. These results offer novel insights in the mechanisms underlying habituation and serve as proof of concept for hierarchical models as an effective tool to measure individual differences in infant cognitive functioning. RESEARCH HIGHLIGHTS: We used a hierarchical Bayesian model to measure individual differences in infants' processing speed, learning performance, sustained attention, and curiosity. Faster processing speed was related to shorter habituation time. High curiosity was related to stronger dishabituation responses, but only for infants who did not habituate.

PhenoScore quantifies phenotypic variation for rare genetic diseases by combining facial analysis with other clinical features using a machine-learning framework.

Several molecular and phenotypic algorithms exist that establish genotype-phenotype correlations, including facial recognition tools. However, no unified framework that investigates both facial data and other phenotypic data directly from individuals exists. We developed PhenoScore: an open-source, artificial intelligence-based phenomics framework, combining facial recognition technology with Human Phenotype Ontology data analysis to quantify phenotypic similarity. Here we show PhenoScore's ability to recognize distinct phenotypic entities by establishing recognizable phenotypes for 37 of 40 investigated syndromes against clinical features observed in individuals with other neurodevelopmental disorders and show it is an improvement on existing approaches. PhenoScore provides predictions for individuals with variants of unknown significance and enables sophisticated genotype-phenotype studies by testing hypotheses on possible phenotypic (sub)groups. PhenoScore confirmed previously known phenotypic subgroups caused by variants in the same gene for SATB1, SETBP1 and DEAF1 and provides objective clinical evidence for two distinct ADNP-related phenotypes, already established functionally.

Eight-Month-Old Infants Meta-Learn by Downweighting Irrelevant Evidence.

Infants learn to navigate the complexity of the physical and social world at an outstanding pace, but how they accomplish this learning is still largely unknown. Recent advances in human and artificial intelligence research propose that a key feature to achieving quick and efficient learning is meta-learning, the ability to make use of prior experiences to learn how to learn better in the future. Here we show that 8-month-old infants successfully engage in meta-learning within very short timespans after being exposed to a new learning environment. We developed a Bayesian model that captures how infants attribute informativity to incoming events, and how this process is optimized by the meta-parameters of their hierarchical models over the task structure. We fitted the model with infants' gaze behavior during a learning task. Our results reveal how infants actively use past experiences to generate new inductive biases that allow future learning to proceed faster.

Bayesian model averaging for nonparametric discontinuity design.

Quasi-experimental research designs, such as regression discontinuity and interrupted time series, allow for causal inference in the absence of a randomized controlled trial, at the cost of additional assumptions. In this paper, we provide a framework for discontinuity-based designs using Bayesian model averaging and Gaussian process regression, which we refer to as 'Bayesian nonparametric discontinuity design', or BNDD for short. BNDD addresses the two major shortcomings in most implementations of such designs: overconfidence due to implicit conditioning on the alleged effect, and model misspecification due to reliance on overly simplistic regression models. With the appropriate Gaussian process covariance function, our approach can detect discontinuities of any order, and in spectral features. We demonstrate the usage of BNDD in simulations, and apply the framework to determine the effect of running for political positions on longevity, of the effect of an alleged historical phantom border in the Netherlands on Dutch voting behaviour, and of Kundalini Yoga meditation on heart rate.

DeNovoCNN: a deep learning approach to de novo variant calling in next generation sequencing data.

De novo mutations (DNMs) are an important cause of genetic disorders. The accurate identification of DNMs from sequencing data is therefore fundamental to rare disease research and diagnostics. Unfortunately, identifying reliable DNMs remains a major challenge due to sequence errors, uneven coverage, and mapping artifacts. Here, we developed a deep convolutional neural network (CNN) DNM caller (DeNovoCNN), that encodes the alignment of sequence reads for a trio as 160$ \times$164 resolution images. DeNovoCNN was trained on DNMs of 5616 whole exome sequencing (WES) trios achieving total 96.74% recall and 96.55% precision on the test dataset. We find that DeNovoCNN has increased recall/sensitivity and precision compared to existing DNM calling approaches (GATK, DeNovoGear, DeepTrio, Samtools) based on the Genome in a Bottle reference dataset and independent WES and WGS trios. Validations of DNMs based on Sanger and PacBio HiFi sequencing confirm that DeNovoCNN outperforms existing methods. Most importantly, our results suggest that DeNovoCNN is likely robust against different exome sequencing and analyses approaches, thereby allowing the application on other datasets. DeNovoCNN is freely available as a Docker container and can be run on existing alignment (BAM/CRAM) and variant calling (VCF) files from WES and WGS without a need for variant recalling.

Phenotype based prediction of exome sequencing outcome using machine learning for neurodevelopmental disorders.

PURPOSE: Although the introduction of exome sequencing (ES) has led to the diagnosis of a significant portion of patients with neurodevelopmental disorders (NDDs), the diagnostic yield in actual clinical practice has remained stable at approximately 30%. We hypothesized that improving the selection of patients to test on the basis of their phenotypic presentation will increase diagnostic yield and therefore reduce unnecessary genetic testing. METHODS: We tested 4 machine learning methods and developed PredWES from these: a statistical model predicting the probability of a positive ES result solely on the basis of the phenotype of the patient. RESULTS: We first trained the tool on 1663 patients with NDDs and subsequently showed that diagnostic ES on the top 10% of patients with the highest probability of a positive ES result would provide a diagnostic yield of 56%, leading to a notable 114% increase. Inspection of our model revealed that for patients with NDDs, comorbid abnormal (lower) muscle tone and microcephaly positively correlated with a conclusive ES diagnosis, whereas autism was negatively associated with a molecular diagnosis. CONCLUSION: In conclusion, PredWES allows prioritizing patients with NDDs eligible for diagnostic ES on the basis of their phenotypic presentation to increase the diagnostic yield, making a more efficient use of health care resources.

The JASP guidelines for conducting and reporting a Bayesian analysis.

Despite the increasing popularity of Bayesian inference in empirical research, few practical guidelines provide detailed recommendations for how to apply Bayesian procedures and interpret the results. Here we offer specific guidelines for four different stages of Bayesian statistical reasoning in a research setting: planning the analysis, executing the analysis, interpreting the results, and reporting the results. The guidelines for each stage are illustrated with a running example. Although the guidelines are geared towards analyses performed with the open-source statistical software JASP, most guidelines extend to Bayesian inference in general.

Highways to happiness for autistic adults? Perceived causal relations among clinicians.

The network approach to psychological phenomena advances our understanding of the interrelations between autism and well-being. We use the Perceived Causal Relations methodology in order to (i) identify perceived causal pathways in the well-being system, (ii) validate networks based on self-report data, and (iii) quantify and integrate clinical expertise in autism research. Trained clinicians served as raters (N = 29) completing 374 cause-effects ratings of 34 variables on well-being and symptomatology. A subgroup (N = 16) of raters chose intervention targets in the resulting network which we found to match the respective centrality of nodes. Clinicians' perception of causal relations was similar to the interrelatedness found in self-reported client data (N = 323). We present a useful tool for translating clinical expertise into quantitative information enabling future research to integrate this in scientific studies.

Validation of structural brain connectivity networks: The impact of scanning parameters.

Evaluation of the structural connectivity (SC) of the brain based on tractography has mainly focused on the choice of diffusion model, tractography algorithm, and their respective parameter settings. Here, we systematically validate SC derived from a post mortem monkey brain, while varying key acquisition parameters such as the b-value, gradient angular resolution and image resolution. As gold standard we use the connectivity matrix obtained invasively with histological tracers by Markov et al. (2014). As performance metric, we use cross entropy as a measure that enables comparison of the relative tracer labeled neuron counts to the streamline counts from tractography. We find that high angular resolution and high signal-to-noise ratio are important to estimate SC, and that SC derived from low image resolution (1.03 mm3) are in better agreement with the tracer network, than those derived from high image resolution (0.53 mm3) or at an even lower image resolution (2.03 mm3). In contradiction, sensitivity and specificity analyses suggest that if the angular resolution is sufficient, the balanced compromise in which sensitivity and specificity are identical remains 60-64% regardless of the other scanning parameters. Interestingly, the tracer graph is assumed to be the gold standard but by thresholding, the balanced compromise increases to 70-75%. Hence, by using performance metrics based on binarized tracer graphs, one risks losing important information, changing the performance of SC graphs derived by tractography and their dependence of different scanning parameters.

Node centrality measures are a poor substitute for causal inference.

Network models have become a valuable tool in making sense of a diverse range of social, biological, and information systems. These models marry graph and probability theory to visualize, understand, and interpret variables and their relations as nodes and edges in a graph. Many applications of network models rely on undirected graphs in which the absence of an edge between two nodes encodes conditional independence between the corresponding variables. To gauge the importance of nodes in such a network, various node centrality measures have become widely used, especially in psychology and neuroscience. It is intuitive to interpret nodes with high centrality measures as being important in a causal sense. Using the causal framework based on directed acyclic graphs (DAGs), we show that the relation between causal influence and node centrality measures is not straightforward. In particular, the correlation between causal influence and several node centrality measures is weak, except for eigenvector centrality. Our results provide a cautionary tale: if the underlying real-world system can be modeled as a DAG, but researchers interpret nodes with high centrality as causally important, then this may result in sub-optimal interventions.

Correction: The missing link: Predicting connectomes from noisy and partially observed tract tracing data.

[This corrects the article DOI: 10.1371/journal.pcbi.1005374.].

The missing link: Predicting connectomes from noisy and partially observed tract tracing data.

Our understanding of the wiring map of the brain, known as the connectome, has increased greatly in the last decade, mostly due to technological advancements in neuroimaging techniques and improvements in computational tools to interpret the vast amount of available data. Despite this, with the exception of the C. elegans roundworm, no definitive connectome has been established for any species. In order to obtain this, tracer studies are particularly appealing, as these have proven highly reliable. The downside of tract tracing is that it is costly to perform, and can only be applied ex vivo. In this paper, we suggest that instead of probing all possible connections, hitherto unknown connections may be predicted from the data that is already available. Our approach uses a 'latent space model' that embeds the connectivity in an abstract physical space. Regions that are close in the latent space have a high chance of being connected, while regions far apart are most likely disconnected in the connectome. After learning the latent embedding from the connections that we did observe, the latent space allows us to predict connections that have not been probed previously. We apply the methodology to two connectivity data sets of the macaque, where we demonstrate that the latent space model is successful in predicting unobserved connectivity, outperforming two baselines and an alternative model in nearly all cases. Furthermore, we show how the latent spatial embedding may be used to integrate multimodal observations (i.e. anterograde and retrograde tracers) for the mouse neocortex. Finally, our probabilistic approach enables us to make explicit which connections are easy to predict and which prove difficult, allowing for informed follow-up studies.

Resting-state subcortical functional connectivity in HIV-infected patients on long-term cART.

Despite long-term successful treatment with cART, impairments in cognitive functioning are still being reported in HIV-infected patients. Since changes in cognitive function may be preceded by subtle changes in brain function, neuroimaging techniques, such as resting-state functional magnetic resonance imaging (rs-fMRI) have become useful tools in assessing HIV-associated abnormalities in the brain. The purpose of the current study was to examine the extent to which HIV infection in virologically suppressed patients is associated with disruptions in subcortical regions of the brain in comparison to a matched HIV-negative control group. The sample consisted of 72 patients and 39 controls included between January 2012 and January 2014. Resting state functional connectivity was determined between fourteen regions-of-interest (ROI): the left and right nucleus accumbens, amygdala, caudate nucleus, hippocampus, putamen, pallidum and thalamus. A Bayesian method was used to estimate resting-state functional connectivity, quantified in terms of partial correlations. Both groups showed the strongest partial correlations between the left and right caudate nucleus and the left and right thalamus. However, no differences between the HIV patients and controls were found between the posterior expected network densities (control network density = 0.26, SD = 0.05, patient network density = 0.26, SD = 0.04, p = 0.58). The results of the current study show that HIV does not affect subcortical connectivity in virologically controlled patients who are otherwise healthy.

Bayesian Estimation of Conditional Independence Graphs Improves Functional Connectivity Estimates.

Functional connectivity concerns the correlated activity between neuronal populations in spatially segregated regions of the brain, which may be studied using functional magnetic resonance imaging (fMRI). This coupled activity is conveniently expressed using covariance, but this measure fails to distinguish between direct and indirect effects. A popular alternative that addresses this issue is partial correlation, which regresses out the signal of potentially confounding variables, resulting in a measure that reveals only direct connections. Importantly, provided the data are normally distributed, if two variables are conditionally independent given all other variables, their respective partial correlation is zero. In this paper, we propose a probabilistic generative model that allows us to estimate functional connectivity in terms of both partial correlations and a graph representing conditional independencies. Simulation results show that this methodology is able to outperform the graphical LASSO, which is the de facto standard for estimating partial correlations. Furthermore, we apply the model to estimate functional connectivity for twenty subjects using resting-state fMRI data. Results show that our model provides a richer representation of functional connectivity as compared to considering partial correlations alone. Finally, we demonstrate how our approach can be extended in several ways, for instance to achieve data fusion by informing the conditional independence graph with data from probabilistic tractography. As our Bayesian formulation of functional connectivity provides access to the posterior distribution instead of only to point estimates, we are able to quantify the uncertainty associated with our results. This reveals that while we are able to infer a clear backbone of connectivity in our empirical results, the data are not accurately described by simply looking at the mode of the distribution over connectivity. The implication of this is that deterministic alternatives may misjudge connectivity results by drawing conclusions from noisy and limited data.

Probabilistic clustering of the human connectome identifies communities and hubs.

A fundamental assumption in neuroscience is that brain function is constrained by its structural properties. This motivates the idea that the brain can be parcellated into functionally coherent regions based on anatomical connectivity patterns that capture how different areas are interconnected. Several studies have successfully implemented this idea in humans using diffusion weighted MRI, allowing parcellation to be conducted in vivo. Two distinct approaches to connectivity-based parcellation can be identified. The first uses the connection profiles of brain regions as a feature vector, and groups brain regions with similar connection profiles together. Alternatively, one may adopt a network perspective that aims to identify clusters of brain regions that show dense within-cluster and sparse between-cluster connectivity. In this paper, we introduce a probabilistic model for connectivity-based parcellation that unifies both approaches. Using the model we are able to obtain a parcellation of the human brain whose clusters may adhere to either interpretation. We find that parts of the connectome consistently cluster as densely connected components, while other parts consistently result in clusters with similar connections. Interestingly, the densely connected components consist predominantly of major cortical areas, while the clusters with similar connection profiles consist of regions that have previously been identified as the 'rich club'; regions known for their integrative role in connectivity. Furthermore, the probabilistic model allows quantification of the uncertainty in cluster assignments. We show that, while most clusters are clearly delineated, some regions are more difficult to assign. These results indicate that care should be taken when interpreting connectivity-based parcellations obtained using alternative deterministic procedures.

Quantifying uncertainty in brain network measures using Bayesian connectomics.

The wiring diagram of the human brain can be described in terms of graph measures that characterize structural regularities. These measures require an estimate of whole-brain structural connectivity for which one may resort to deterministic or thresholded probabilistic streamlining procedures. While these procedures have provided important insights about the characteristics of human brain networks, they ultimately rely on unwarranted assumptions such as those of noise-free data or the use of an arbitrary threshold. Therefore, resulting structural connectivity estimates as well as derived graph measures fail to fully take into account the inherent uncertainty in the structural estimate. In this paper, we illustrate an easy way of obtaining posterior distributions over graph metrics using Bayesian inference. It is shown that this posterior distribution can be used to quantify uncertainty about graph-theoretical measures at the single subject level, thereby providing a more nuanced view of the graph-theoretical properties of human brain connectivity. We refer to this model-based approach to connectivity analysis as Bayesian connectomics.

Structurally-informed Bayesian functional connectivity analysis.

Functional connectivity refers to covarying activity between spatially segregated brain regions and can be studied by measuring correlation between functional magnetic resonance imaging (fMRI) time series. These correlations can be caused either by direct communication via active axonal pathways or indirectly via the interaction with other regions. It is not possible to discriminate between these two kinds of functional interaction simply by considering the covariance matrix. However, the non-diagonal elements of its inverse, the precision matrix, can be naturally related to direct communication between brain areas and interpreted in terms of partial correlations. In this paper, we propose a Bayesian model for functional connectivity analysis which allows estimation of a posterior density over precision matrices, and, consequently, allows one to quantify the uncertainty about estimated partial correlations. In order to make model estimation feasible it is assumed that the sparseness structure of the precision matrices is given by an estimate of structural connectivity obtained using diffusion imaging data. The model was tested on simulated data as well as resting-state fMRI data and compared with a graphical lasso analysis. The presented approach provides a theoretically solid foundation for quantifying functional connectivity in the presence of uncertainty.

Bayesian inference of structural brain networks.

Structural brain networks are used to model white-matter connectivity between spatially segregated brain regions. The presence, location and orientation of these white matter tracts can be derived using diffusion-weighted magnetic resonance imaging in combination with probabilistic tractography. Unfortunately, as of yet, none of the existing approaches provide an undisputed way of inferring brain networks from the streamline distributions which tractography produces. State-of-the-art methods rely on an arbitrary threshold or, alternatively, yield weighted results that are difficult to interpret. In this paper, we provide a generative model that explicitly describes how structural brain networks lead to observed streamline distributions. This allows us to draw principled conclusions about brain networks, which we validate using simultaneously acquired resting-state functional MRI data. Inference may be further informed by means of a prior which combines connectivity estimates from multiple subjects. Based on this prior, we obtain networks that significantly improve on the conventional approach.