Development and validation of the patient-reported "Facial Function Scale" for facioscapulohumeral muscular dystrophy.

PURPOSE: Facial weakness and its functional consequences are an often underappreciated clinical feature of facioscapulohumeral muscular dystrophy (FSHD) by healthcare professionals and researchers. This is at least in part due to the fact that there are few adequate clinical outcome measures available. METHODS: We developed the Facial Function Scale, a Rasch-built questionnaire on the functional disabilities relating to facial weakness in FSHD. A preliminary 33-item questionnaire was created based on semi-structured interviews with 16 FSHD patients and completed by 119 patients. For reliability studies, 73 patients completed it again after a two-week interval. Data were subjected to semi-automated Rasch analysis to select the most appropriate item set to fit model expectations. RESULTS: This resulted in a 25-item unidimensional, linear-weighted questionnaire with high internal consistency (person separation index = 0.92) and test-retest reliability (patients' locations ICC = 0.98 and items' locations ICC = 0.99). Good external construct validity scores were obtained through correlation with the Communicative Participation Item Bank questionnaire, examiner-reported Facial Weakness Score and facial weakness subscale of the FSHD evaluation score (respectively r = 0.733, r = -0.566, and r = 0.441, all p < 0.001). CONCLUSIONS: This study provides a linear-weighted, clinimetrically sound, patient-reported outcome measure on the functional disabilities relating to facial weakness in FSHD, to enable further research on this relevant topic.Implications for rehabilitationFacial weakness and its functional consequences are an often underappreciated clinical feature of facioscapulohumeral muscular dystrophy (FSHD), both in symptomatic treatment and in research.To enable the development and testing of therapeutic symptomatic interventions for facial weakness, clinical outcome measures are required.This study provides a linear-weighted, clinimetrically sound, patient-reported outcome measure on the functional disabilities relating to facial weakness in FSHD patients.

Semi-automated Rasch analysis with differential item functioning.

Rasch analysis is a procedure to develop and validate instruments that aim to measure a person's traits. However, manual Rasch analysis is a complex and time-consuming task, even more so when the possibility of differential item functioning (DIF) is taken into consideration. Furthermore, manual Rasch analysis by construction relies on a modeler's subjective choices. As an alternative approach, we introduce a semi-automated procedure that is based on the optimization of a new criterion, called in-plus-out-of-questionnaire log likelihood with differential item functioning (IPOQ-LL-DIF), which extends our previous criterion. We illustrate our procedure on artificially generated data as well as on several real-world datasets containing potential DIF items. On these real-world datasets, our procedure found instruments with similar clinimetric properties as those suggested by experts through manual analyses.

autoRasch: An R Package to Do Semi-Automated Rasch Analysis.

The R package autoRasch has been developed to perform a Rasch analysis in a (semi-)automated way. The automated part of the analysis is achieved by optimizing the so-called in-plus-out-of-questionnaire log-likelihood (IPOQ-LL) or IPOQ-LL-DIF when differential item functioning (DIF) is included. These criteria measure the quality of fit on a pre-collected survey, depending on which items are included in the final instrument. To compute these criteria, autoRasch fits the generalized partial credit model (GPCM) or the generalized partial credit model with differential item functioning (GPCM-DIF) using penalized joint maximum likelihood estimation (PJMLE). The package further allows the user to reevaluate the output of the automated method and use it as a basis for performing a manual Rasch analysis and provides standard statistics of Rasch analyses (e.g., outfit, infit, person separation reliability, and residual correlation) to support the model reevaluation.

Potential mechanisms of the fatigue-reducing effect of cognitive-behavioral therapy in cancer survivors: Three randomized controlled trials.

OBJECTIVE: Fatigue is a common symptom among cancer survivors that can be successfully treated with cognitive-behavioral therapy (CBT). Insights into the working mechanisms of CBT are currently limited. The aim of this study was to investigate whether improvements in targeted cognitive-behavioral variables and reduced depressive symptoms mediate the fatigue-reducing effect of CBT. METHODS: We pooled data from three randomized controlled trials that tested the efficacy of CBT to reduce severe fatigue. In all three trials, fatigue severity (checklist individual strength) decreased significantly following CBT. Assessments were conducted pre-treatment and 6 months later. Classical mediation analysis testing a pre-specified model was conducted and its results compared to those of causal discovery, an explorative data-driven approach testing all possible causal associations and retaining the most likely model. RESULTS: Data from 250 cancer survivors (n = 129 CBT, n = 121 waitlist) were analyzed. Classical mediation analysis suggests that increased self-efficacy and decreased fatigue catastrophizing, focusing on symptoms, perceived problems with activity and depressive symptoms mediate the reduction of fatigue brought by CBT. Conversely, causal discovery and post-hoc analyses indicate that fatigue acts as mediator, not outcome, of changes in cognitions, sleep disturbance and depressive symptoms. CONCLUSIONS: Cognitions, sleep disturbance and depressive symptoms improve during CBT. When assessed pre- and post-treatment, fatigue acts as a mediator, not outcome, of these improvements. It seems likely that the working mechanism of CBT is not a one-way causal effect but a dynamic reciprocal process. Trials integrating intermittent assessments are needed to shed light on these mechanisms and inform optimization of CBT.

Semi-automated Rasch analysis using in-plus-out-of-questionnaire log likelihood.

Rasch analysis is a popular statistical tool for developing and validating instruments that aim to measure human performance, attitudes and perceptions. Despite the availability of various software packages, constructing a good instrument based on Rasch analysis is still considered to be a complex, labour-intensive task, requiring human expertise and rather subjective judgements along the way. In this paper we propose a semi-automated method for Rasch analysis based on first principles that reduces the need for human input. To this end, we introduce a novel criterion, called in-plus-out-of-questionnaire log likelihood (IPOQ-LL). On artificial data sets, we confirm that optimization of IPOQ-LL leads to the desired behaviour in the case of multi-dimensional and inhomogeneous surveys. On three publicly available real-world data sets, our method leads to instruments that are, for all practical purposes, indistinguishable from those obtained by Rasch analysis experts through a manual procedure.

Generalized Convolution Spectral Mixture for Multitask Gaussian Processes.

Multitask Gaussian processes (MTGPs) are a powerful approach for modeling dependencies between multiple related tasks or functions for joint regression. Current kernels for MTGPs cannot fully model nonlinear task correlations and other types of dependencies. In this article, we address this limitation. We focus on spectral mixture (SM) kernels and propose an enhancement of this type of kernels, called multitask generalized convolution SM (MT-GCSM) kernel. The MT-GCSM kernel can model nonlinear task correlations and dependence between components, including time and phase delay dependence. Each task in MT-GCSM has its GCSM kernel with its number of convolution structures, and dependencies between all components from different tasks are considered. Another constraint of current kernels for MTGPs is that components from different tasks are aligned. Here, we lift this constraint by using inner and outer full cross convolution between a base component and the reversed complex conjugate of another base component. Extensive experiments on two synthetic and three real-life data sets illustrate the difference between MT-GCSM and previous SM kernels as well as the practical effectiveness of MT-GCSM.

Multioutput Convolution Spectral Mixture for Gaussian Processes.

Multioutput Gaussian processes (MOGPs) are an extension of Gaussian processes (GPs) for predicting multiple output variables (also called channels/tasks) simultaneously. In this article, we use the convolution theorem to design a new kernel for MOGPs by modeling cross-channel dependencies through cross convolution of time-and phase-delayed components in the spectral domain. The resulting kernel is called multioutput convolution spectral mixture (MOCSM) kernel. The results of extensive experiments on synthetic and real-life data sets demonstrate the advantages of the proposed kernel and its state-of-the-art performance. MOCSM enjoys the desirable property to reduce to the well-known spectral mixture (SM) kernel when a single channel is considered. A comparison with the recently introduced multioutput SM kernel reveals that this is not the case for the latter kernel, which contains quadratic terms that generate undesirable scale effects when the spectral densities of different channels are either very close or very far from each other in the frequency domain.

Causality on longitudinal data: Stable specification search in constrained structural equation modeling.

A typical problem in causal modeling is the instability of model structure learning, i.e., small changes in finite data can result in completely different optimal models. The present work introduces a novel causal modeling algorithm for longitudinal data, that is robust for finite samples based on recent advances in stability selection using subsampling and selection algorithms. Our approach uses exploratory search but allows incorporation of prior knowledge, e.g., the absence of a particular causal relationship between two specific variables. We represent causal relationships using structural equation models. Models are scored along two objectives: the model fit and the model complexity. Since both objectives are often conflicting, we apply a multi-objective evolutionary algorithm to search for Pareto optimal models. To handle the instability of small finite data samples, we repeatedly subsample the data and select those substructures (from the optimal models) that are both stable and parsimonious. These substructures can be visualized through a causal graph. Our more exploratory approach achieves at least comparable performance as, but often a significant improvement over state-of-the-art alternative approaches on a simulated data set with a known ground truth. We also present the results of our method on three real-world longitudinal data sets on chronic fatigue syndrome, Alzheimer disease, and chronic kidney disease. The findings obtained with our approach are generally in line with results from more hypothesis-driven analyses in earlier studies and suggest some novel relationships that deserve further research.

Handling hybrid and missing data in constraint-based causal discovery to study the etiology of ADHD.

Causal discovery is an increasingly important method for data analysis in the field of medical research. In this paper, we consider two challenges in causal discovery that occur very often when working with medical data: a mixture of discrete and continuous variables and a substantial amount of missing values. To the best of our knowledge, there are no methods that can handle both challenges at the same time. In this paper, we develop a new method that can handle these challenges based on the assumption that data are missing at random and that continuous variables obey a non-paranormal distribution. We demonstrate the validity of our approach for causal discovery on simulated data as well as on two real-world data sets from a monetary incentive delay task and a reversal learning task. Our results help in the understanding of the etiology of attention-deficit/hyperactivity disorder (ADHD).

A Causal and Mediation Analysis of the Comorbidity Between Attention Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD).

Autism spectrum disorder (ASD) and Attention-deficit/hyperactivity disorder (ADHD) are often comorbid. The purpose of this study is to explore the relationships between ASD and ADHD symptoms by applying causal modeling. We used a large phenotypic data set of 417 children with ASD and/or ADHD, 562 affected and unaffected siblings, and 414 controls, to infer a structural equation model using a causal discovery algorithm. Three distinct pathways between ASD and ADHD were identified: (1) from impulsivity to difficulties with understanding social information, (2) from hyperactivity to stereotypic, repetitive behavior, (3) a pairwise pathway between inattention, difficulties with understanding social information, and verbal IQ. These findings may inform future studies on understanding the pathophysiological mechanisms behind the overlap between ASD and ADHD.

Statistical Evidence Suggests that Inattention Drives Hyperactivity/Impulsivity in Attention Deficit-Hyperactivity Disorder.

BACKGROUND: Numerous factor analytic studies consistently support a distinction between two symptom domains of attention-deficit/hyperactivity disorder (ADHD), inattention and hyperactivity/impulsivity. Both dimensions show high internal consistency and moderate to strong correlations with each other. However, it is not clear what drives this strong correlation. The aim of this paper is to address this issue. METHOD: We applied a sophisticated approach for causal discovery on three independent data sets of scores of the two ADHD dimensions in NeuroIMAGE (total N = 675), ADHD-200 (N = 245), and IMpACT (N = 164), assessed by different raters and instruments, and further used information on gender or a genetic risk haplotype. RESULTS: In all data sets we found strong statistical evidence for the same pattern: the clear dependence between hyperactivity/impulsivity symptom level and an established genetic factor (either gender or risk haplotype) vanishes when one conditions upon inattention symptom level. Under reasonable assumptions, e.g., that phenotypes do not cause genotypes, a causal model that is consistent with this pattern contains a causal path from inattention to hyperactivity/impulsivity. CONCLUSIONS: The robust dependency cancellation observed in three different data sets suggests that inattention is a driving factor for hyperactivity/impulsivity. This causal hypothesis can be further validated in intervention studies. Our model suggests that interventions that affect inattention will also have an effect on the level of hyperactivity/impulsivity. On the other hand, interventions that affect hyperactivity/impulsivity would not change the level of inattention. This causal model may explain earlier findings on heritable factors causing ADHD reported in the study of twins with learning difficulties.

Causal discovery in an adult ADHD data set suggests indirect link between DAT1 genetic variants and striatal brain activation during reward processing.

Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable disorder affecting both children and adults. One of the candidate genes for ADHD is DAT1, encoding the dopamine transporter. In an attempt to clarify its mode of action, we assessed brain activity during the reward anticipation phase of the Monetary Incentive Delay (MID) task in a functional MRI paradigm in 87 adult participants with ADHD and 77 controls (average age 36.5 years). The MID task activates the ventral striatum, where DAT1 is most highly expressed. A previous analysis based on standard statistical techniques did not show any significant dependencies between a variant in the DAT1 gene and brain activation [Hoogman et al. (2013); Neuropsychopharm 23:469-478]. Here, we used an alternative method for analyzing the data, that is, causal modeling. The Bayesian Constraint-based Causal Discovery (BCCD) algorithm [Claassen and Heskes (2012); Proceedings of the 28th Conference on Uncertainty in Artificial Intelligence] is able to find direct and indirect dependencies between variables, determines the strength of the dependencies, and provides a graphical visualization to interpret the results. Through BCCD one gets an opportunity to consider several variables together and to infer causal relations between them. Application of the BCCD algorithm confirmed that there is no evidence of a direct link between DAT1 genetic variability and brain activation, but suggested an indirect link mediated through inattention symptoms and diagnostic status of ADHD. Our finding of an indirect link of DAT1 with striatal activity during reward anticipation might explain existing discrepancies in the current literature. Further experiments should confirm this hypothesis. © 2015 Wiley Periodicals, Inc.

Using model checking for critiquing based on clinical guidelines.

OBJECTIVE: Medical critiquing systems compare clinical actions performed by a physician with a predefined set of actions. In order to provide useful feedback, an important task is to find differences between the actual actions and a set of 'ideal' actions as described by a clinical guideline. In case differences exist, the critiquing system provides insight into the extent to which they are compatible. METHODS AND MATERIAL: We propose a computational method for such critiquing, where the ideal actions are given by a formal model of a clinical guideline, and where the actual actions are derived from real world patient data. We employ model checking to investigate whether a part of the actual treatment is consistent with the guideline. RESULTS: We show how critiquing can be cast in terms of temporal logic, and what can be achieved by using model checking. Furthermore, a method is introduced for off-line computing relevant information which can be exploited during critiquing. The method has been applied to a clinical guideline of breast cancer in conjunction with breast cancer patient data.

Formal methods for verification of clinical practice guidelines.

Formal methods play an important role in the development of software and hardware systems. In recent years, there has been a growing interest to apply these methods in the area of medical guidelines and protocols. This paper summarises these efforts, compares the approaches and discusses the role of formal methods in this area.

Adaptation of clinical practice guidelines.

A rigorous development process of clinical practice guidelines through a systematic appraisal of available evidence is costly and time consuming. One way to reduce the costs and time, and avoid unnecessary duplication of effort of guideline development is by relying on a local adaptation approach of guidelines developed at the (inter)national level by expert groups. In this chapter we survey the work on guideline adaptation, which includes methodologies, case studies, assessment of effectiveness, and related work on guideline adaptation in the Artificial Intelligence community.

A constraint-based approach to medical guidelines and protocols.

Medical guidelines and protocols are documents aimed at improving the quality of medical care by offering support in medical decision making in the form of management recommendations based on scientific evidence. Whereas medical guidelines are intended for nation-wide use, and thus omit medical management details that may differ among hospitals, medical protocols are aimed at local use, e.g., within hospitals, and, therefore, include more detailed information. Although a medical guideline and an associated protocol concerning the management of a particular disorder are related to each other, one question is to what extent they are different. Formal methods are applied to shed light on this issue. A Dutch medical guideline regarding the treatment of breast cancer, and a Dutch protocol based on it, are taken as an example.