spillR: spillover compensation in mass cytometry data.

MOTIVATION: Channel interference in mass cytometry can cause spillover and may result in miscounting of protein markers. Chevrier et al. introduce an experimental and computational procedure to estimate and compensate for spillover implemented in their R package CATALYST. They assume spillover can be described by a spillover matrix that encodes the ratio between the signal in the unstained spillover receiving and stained spillover emitting channel. They estimate the spillover matrix from experiments with beads. We propose to skip the matrix estimation step and work directly with the full bead distributions. We develop a nonparametric finite mixture model and use the mixture components to estimate the probability of spillover. Spillover correction is often a pre-processing step followed by downstream analyses, and choosing a flexible model reduces the chance of introducing biases that can propagate downstream. RESULTS: We implement our method in an R package spillR using expectation-maximization to fit the mixture model. We test our method on simulated, semi-simulated, and real data from CATALYST. We find that our method compensates low counts accurately, does not introduce negative counts, avoids overcompensating high counts, and preserves correlations between markers that may be biologically meaningful. AVAILABILITY AND IMPLEMENTATION: Our new R package spillR is on bioconductor at bioconductor.org/packages/spillR. All experiments and plots can be reproduced by compiling the R markdown file spillR_paper.Rmd at github.com/ChristofSeiler/spillR_paper.

Improving 1-year mortality prediction in ACS patients using machine learning.

BACKGROUND: The Global Registry of Acute Coronary Events (GRACE) score is an established clinical risk stratification tool for patients with acute coronary syndromes (ACS). We developed and internally validated a model for 1-year all-cause mortality prediction in ACS patients. METHODS: Between 2009 and 2012, 2'168 ACS patients were enrolled into the Swiss SPUM-ACS Cohort. Biomarkers were determined in 1'892 patients and follow-up was achieved in 95.8% of patients. 1-year all-cause mortality was 4.3% (n = 80). In our analysis we consider all linear models using combinations of 8 out of 56 variables to predict 1-year all-cause mortality and to derive a variable ranking. RESULTS: 1.3% of 1'420'494'075 models outperformed the GRACE 2.0 Score. The SPUM-ACS Score includes age, plasma glucose, NT-proBNP, left ventricular ejection fraction (LVEF), Killip class, history of peripheral artery disease (PAD), malignancy, and cardio-pulmonary resuscitation. For predicting 1-year mortality after ACS, the SPUM-ACS Score outperformed the GRACE 2.0 Score which achieves a 5-fold cross-validated AUC of 0.81 (95% CI 0.78-0.84). Ranking individual features according to their importance across all multivariate models revealed age, trimethylamine N-oxide, creatinine, history of PAD or malignancy, LVEF, and haemoglobin as the most relevant variables for predicting 1-year mortality. CONCLUSIONS: The variable ranking and the selection for the SPUM-ACS Score highlight the relevance of age, markers of heart failure, and comorbidities for prediction of all-cause death. Before application, this score needs to be externally validated and refined in larger cohorts. CLINICAL TRIAL REGISTRATION: NCT01000701.

Causality in Cognitive Neuroscience: Concepts, Challenges, and Distributional Robustness.

Whereas probabilistic models describe the dependence structure between observed variables, causal models go one step further: They predict, for example, how cognitive functions are affected by external interventions that perturb neuronal activity. In this review and perspective article, we introduce the concept of causality in the context of cognitive neuroscience and review existing methods for inferring causal relationships from data. Causal inference is an ambitious task that is particularly challenging in cognitive neuroscience. We discuss two difficulties in more detail: the scarcity of interventional data and the challenge of finding the right variables. We argue for distributional robustness as a guiding principle to tackle these problems. Robustness (or invariance) is a fundamental principle underlying causal methodology. A (correctly specified) causal model of a target variable generalizes across environments or subjects as long as these environments leave the causal mechanisms of the target intact. Consequently, if a candidate model does not generalize, then either it does not consist of the target variable's causes or the underlying variables do not represent the correct granularity of the problem. In this sense, assessing generalizability may be useful when defining relevant variables and can be used to partially compensate for the lack of interventional data.

Absence of EEG correlates of self-referential processing depth in ALS.

Self-referential processing is a key cognitive process, associated with the serotonergic system and the default mode network (DMN). Decreased levels of serotonin and reduced activations of the DMN observed in amyotrophic lateral sclerosis (ALS) suggest that self-referential processing might be altered in patients with ALS. Here, we investigate the effects of ALS on the electroencephalography correlates of self-referential thinking. We find that electroencephalography (EEG) correlates of self-referential thinking are present in healthy individuals, but not in those with ALS. In particular, thinking about themselves or others significantly modulates the bandpower in the medial prefrontal cortex in healthy individuals, but not in ALS patients. This finding supports the view of ALS as a complex multisystem disorder which, as shown here, includes dysfunctional processing of the medial prefrontal cortex. It points towards possible alterations of self-consciousness in ALS patients, which might have important consequences for patients' self-conceptions, personal relations, and decision-making.

Causal interpretation rules for encoding and decoding models in neuroimaging.

Causal terminology is often introduced in the interpretation of encoding and decoding models trained on neuroimaging data. In this article, we investigate which causal statements are warranted and which ones are not supported by empirical evidence. We argue that the distinction between encoding and decoding models is not sufficient for this purpose: relevant features in encoding and decoding models carry a different meaning in stimulus- and in response-based experimental paradigms.We show that only encoding models in the stimulus-based setting support unambiguous causal interpretations. By combining encoding and decoding models trained on the same data, however, we obtain insights into causal relations beyond those that are implied by each individual model type. We illustrate the empirical relevance of our theoretical findings on EEG data recorded during a visuo-motor learning task.