Psychiatric disorders are increasingly being recognised as having a biological basis, but their diagnosis is made exclusively behaviourally. A promising approach for 'biomarker' discovery has been ...based on pattern recognition methods applied to neuroimaging data, which could yield clinical utility in future. In this review we survey the literature on pattern recognition for making diagnostic predictions in psychiatric disorders, and evaluate progress made in translating such findings towards clinical application. We evaluate studies on many criteria, including data modalities used, the types of features extracted and algorithm applied. We identify problems common to many studies, such as a relatively small sample size and a primary focus on estimating generalisability within a single study. Furthermore, we highlight challenges that are not widely acknowledged in the field including the importance of accommodating disease prevalence, the necessity of more extensive validation using large carefully acquired samples, the need for methodological innovations to improve accuracy and to discriminate between multiple disorders simultaneously. Finally, we identify specific clinical contexts in which pattern recognition can add value in the short to medium term.
Abstract Background Despite many successes, the case-control approach is problematic in biomedical science: It introduces an artificial symmetry whereby all clinical groups (e.g. patients and ...controls) are assumed to be well-defined, when biologically they are often highly heterogeneous. By definition, it also precludes inference over the validity of the diagnostic labels. In response, the NIMH Research Domain Criteria (RDoC) proposes to map relationships between symptom dimensions and broad behavioural and biological domains, cutting across diagnostic categories. To date, however, RDoC has prompted few methods to meaningfully stratify clinical cohorts. Methods We introduce normative modelling for parsing heterogeneity in clinical cohorts while allowing predictions at an individual subject level. This aims to map variation within the cohort and is distinct from, and complementary to, existing approaches that tackle heterogeneity by employing clustering techniques to fractionate cohorts. To demonstrate this approach, we map the relationship between trait impulsivity and reward-related brain activity in a large healthy cohort (N=491). Results We identify participants that are outliers within this distribution and show that the degree of deviation (outlier magnitude) relates to specific attention deficit hyperactivity disorder symptoms (hyperactivity, but not inattention) on the basis of individualized patterns of abnormality. Conclusions Normative modelling provides a natural framework to study disorders at the individual participant level without dichotomizing the cohort. Instead, disease can be considered as an extreme of the normal range or as – possibly idiosyncratic – deviation from normal functioning. It also enables inferences over the degree to which behavioural variables – including diagnostic labels – map onto biology.
Brain regions are often topographically connected: nearby locations within one brain area connect with nearby locations in another area. Mapping these connection topographies, or ‘connectopies’ in ...short, is crucial for understanding how information is processed in the brain. Here, we propose principled, fully data-driven methods for mapping connectopies using functional magnetic resonance imaging (fMRI) data acquired at rest by combining spectral embedding of voxel-wise connectivity ‘fingerprints’ with a novel approach to spatial statistical inference. We apply the approach in human primary motor and visual cortex, and show that it can trace biologically plausible, overlapping connectopies in individual subjects that follow these regions' somatotopic and retinotopic maps. As a generic mechanism to perform inference over connectopies, the new spatial statistics approach enables rigorous statistical testing of hypotheses regarding the fine-grained spatial profile of functional connectivity and whether that profile is different between subjects or between experimental conditions. The combined framework offers a fundamental alternative to existing approaches to investigating functional connectivity in the brain, from voxel- or seed-pair wise characterizations of functional association, towards a full, multivariate characterization of spatial topography.
•We propose methods for mapping individualised connectopies using resting-state fMRI.•These methods include a spatial statistics approach for inference over connectopies.•The approach can tease apart overlapping connectopies that coexist within an area.•We demonstrate the methods in somatotopic and retinotopic cortex.
The present paper presents a fundamentally novel approach to model individual differences of persons with the same biologically heterogeneous mental disorder. Unlike prevalent case-control analyses, ...that assume a clear distinction between patient and control groups and thereby introducing the concept of an 'average patient', we describe each patient's biology individually, gaining insights into the different facets that characterize persistent attention-deficit/hyperactivity disorder (ADHD).
Using a normative modeling approach, we mapped inter-individual differences in reference to normative structural brain changes across the lifespan to examine the degree to which case-control analyses disguise differences between individuals.
At the level of the individual, deviations from the normative model were frequent in persistent ADHD. However, the overlap of more than 2% between participants with ADHD was only observed in few brain loci. On average, participants with ADHD showed significantly reduced gray matter in the cerebellum and hippocampus compared to healthy individuals. While the case-control differences were in line with the literature on ADHD, individuals with ADHD only marginally reflected these group differences.
Case-control comparisons, disguise inter-individual differences in brain biology in individuals with persistent ADHD. The present results show that the 'average ADHD patient' has limited informative value, providing the first evidence for the necessity to explore different biological facets of ADHD at the level of the individual and practical means to achieve this end.
Standard univariate analysis of neuroimaging data has revealed a host of neuroanatomical and functional differences between healthy individuals and patients suffering a wide range of neurological and ...psychiatric disorders. Significant only at group level however these findings have had limited clinical translation, and recent attention has turned toward alternative forms of analysis, including Support-Vector-Machine (SVM). A type of machine learning, SVM allows categorisation of an individual's previously unseen data into a predefined group using a classification algorithm, developed on a training data set. In recent years, SVM has been successfully applied in the context of disease diagnosis, transition prediction and treatment prognosis, using both structural and functional neuroimaging data. Here we provide a brief overview of the method and review those studies that applied it to the investigation of Alzheimer's disease, schizophrenia, major depression, bipolar disorder, presymptomatic Huntington's disease, Parkinson's disease and autistic spectrum disorder. We conclude by discussing the main theoretical and practical challenges associated with the implementation of this method into the clinic and possible future directions.
Normative models are a class of emerging statistical techniques useful for understanding the heterogeneous biology underlying psychiatric disorders at the level of the individual participant. ...Analogous to normative growth charts used in paediatric medicine for plotting child development in terms of height or weight as a function of age, normative models chart variation in clinical cohorts in terms of mappings between quantitative biological measures and clinically relevant variables. An emerging body of literature has demonstrated that such techniques are excellent tools for parsing the heterogeneity in clinical cohorts by providing statistical inferences at the level of the individual participant with respect to the normative range. Here, we provide a unifying review of the theory and application of normative modelling for understanding the biological and clinical heterogeneity underlying mental disorders. We first provide a statistically grounded yet non-technical overview of the conceptual underpinnings of normative modelling and propose a conceptual framework to link the many different methodological approaches that have been proposed for this purpose. We survey the literature employing these techniques, focusing principally on applications of normative modelling to quantitative neuroimaging-based biomarkers in psychiatry and, finally, we provide methodological considerations and recommendations to guide future applications of these techniques. We show that normative modelling provides a means by which the importance of modelling individual differences can be brought from theory to concrete data analysis procedures for understanding heterogeneous mental disorders and ultimately a promising route towards precision medicine in psychiatry.
•We present a warped Bayesian Linear Regression (BLR) and demonstrate it on data from the UK Biobank.•The non-linearity of the model improves the fit and out of sample predictions for most ...variables.•Non-Gaussianity of the data can be included with the incorporation of the likelihood warping.•A trade-off between fit and complexity can be chosen optimally, without crossvalidation.•BLR is computationally less demanding than GPR and is therefore scalable to big datasets.
Normative modelling is becoming more popular in neuroimaging due to its ability to make predictions of deviation from a normal trajectory at the level of individual participants. It allows the user to model the distribution of several neuroimaging modalities, giving an estimation for the mean and centiles of variation. With the increase in the availability of big data in neuroimaging, there is a need to scale normative modelling to big data sets. However, the scaling of normative models has come with several challenges.
So far, most normative modelling approaches used Gaussian process regression, and although suitable for smaller datasets (up to a few thousand participants) it does not scale well to the large cohorts currently available and being acquired. Furthermore, most neuroimaging modelling methods that are available assume the predictive distribution to be Gaussian in shape. However, deviations from Gaussianity can be frequently found, which may lead to incorrect inferences, particularly in the outer centiles of the distribution. In normative modelling, we use the centiles to give an estimation of the deviation of a particular participant from the ‘normal’ trend. Therefore, especially in normative modelling, the correct estimation of the outer centiles is of utmost importance, which is also where data are sparsest.
Here, we present a novel framework based on Bayesian linear regression with likelihood warping that allows us to address these problems, that is, to correctly model non-Gaussian predictive distributions and scale normative modelling elegantly to big data cohorts. In addition, this method provides likelihood-based statistics, which are useful for model selection.
To evaluate this framework, we use a range of neuroimaging-derived measures from the UK Biobank study, including image-derived phenotypes (IDPs) and whole-brain voxel-wise measures derived from diffusion tensor imaging. We show good computational scaling and improved accuracy of the warped BLR for certain IDPs and voxels if there was a deviation from normality of these parameters in their residuals.
The present results indicate the advantage of a warped BLR in terms of; computational scalability and the flexibility to incorporate non-linearity and non-Gaussianity of the data, giving a wider range of neuroimaging datasets that can be correctly modelled.
•Extensive overview on pattern classification and stratification studies in ASD.•Compares pattern classification and stratifications approaches head-on.•Presents potential future directions for both ...approaches in ASD research.•Suggest promising avenues for clinical translation of these two approaches.
Pattern classification and stratification approaches have increasingly been used in research on Autism Spectrum Disorder (ASD) over the last ten years with the goal of translation towards clinical applicability. Here, we present an extensive scoping literature review on those two approaches. We screened a total of 635 studies, of which 57 pattern classification and 19 stratification studies were included. We observed large variance across pattern classification studies in terms of predictive performance from about 60% to 98% accuracy, which is among other factors likely linked to sampling bias, different validation procedures across studies, the heterogeneity of ASD and differences in data quality. Stratification studies were less prevalent with only two studies reporting replications and just a few showing external validation. While some identified strata based on cognition and intelligence reappear across studies, biology as a stratification marker is clearly underexplored. In summary, mapping biological differences at the level of the individual with ASD is a major challenge for the field now. Conceptualizing those mappings and individual trajectories that lead to the diagnosis of ASD, will become a major challenge in the near future.
Dementia is a highly heterogeneous condition, with pronounced individual differences in age of onset, clinical presentation, progression rates and neuropathological hallmarks, even within a specific ...diagnostic group. However, the most common statistical designs used in dementia research studies and clinical trials overlook this heterogeneity, instead relying on comparisons of group average differences (e.g. patient versus control or treatment versus placebo), implicitly assuming within-group homogeneity. This one-size-fits-all approach potentially limits our understanding of dementia aetiology, hindering the identification of effective treatments. Neuroimaging has enabled the characterization of the average neuroanatomical substrates of dementias; however, the increasing availability of large open neuroimaging datasets provides the opportunity to examine patterns of neuroanatomical variability in individual patients. In this update, we outline the causes and consequences of heterogeneity in dementia and discuss recent research that aims to tackle heterogeneity directly, rather than assuming that dementia affects everyone in the same way. We introduce spatial normative modelling as an emerging data-driven technique, which can be applied to dementia data to model neuroanatomical variation, capturing individualized neurobiological 'fingerprints'. Such methods have the potential to detect clinically relevant subtypes, track an individual's disease progression or evaluate treatment responses, with the goal of moving towards precision medicine for dementia.
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