Win-loss parameters for right-censored event data, with application to recurrent events.

The win ratio has become a popular method for comparing multiple event data between two groups in clinical cohort studies. The win ratio compares the event data in prioritized order, where the first prioritized event is death and a typical example for the second prioritized event is hospitalization. Literature is sparse on inference for win and loss parameters, including the win ratio, for censored event data. Inference for two prioritized censored event times has been developed for independent right-censoring. Many clinical studies include recurrent event data such as hospitalizations. In this article, we suggest inference for win-loss parameters for death and a recurrent event outcome under independent right-censoring. The small sample properties of the proposed method are studied in a simulation study showing that the variance formula is accurate even for small samples. The method is applied on a data set from a randomized clinical trial.

Regression models for censored time-to-event data using infinitesimal jack-knife pseudo-observations, with applications to left-truncation.

Jack-knife pseudo-observations have in recent decades gained popularity in regression analysis for various aspects of time-to-event data. A limitation of the jack-knife pseudo-observations is that their computation is time consuming, as the base estimate needs to be recalculated when leaving out each observation. We show that jack-knife pseudo-observations can be closely approximated using the idea of the infinitesimal jack-knife residuals. The infinitesimal jack-knife pseudo-observations are much faster to compute than jack-knife pseudo-observations. A key assumption of the unbiasedness of the jack-knife pseudo-observation approach is on the influence function of the base estimate. We reiterate why the condition on the influence function is needed for unbiased inference and show that the condition is not satisfied for the Kaplan-Meier base estimate in a left-truncated cohort. We present a modification of the infinitesimal jack-knife pseudo-observations that provide unbiased estimates in a left-truncated cohort. The computational speed and medium and large sample properties of the jack-knife pseudo-observations and infinitesimal jack-knife pseudo-observation are compared and we present an application of the modified infinitesimal jack-knife pseudo-observations in a left-truncated cohort of Danish patients with diabetes.

Bivariate pseudo-observations for recurrent event analysis with terminal events.

The analysis of recurrent events in the presence of terminal events requires special attention. Several approaches have been suggested for such analyses either using intensity models or marginal models. When analysing treatment effects on recurrent events in controlled trials, special attention should be paid to competing deaths and their impact on interpretation. This paper proposes a method that formulates a marginal model for recurrent events and terminal events simultaneously. Estimation is based on pseudo-observations for both the expected number of events and survival probabilities. Various relevant hypothesis tests in the framework are explored. Theoretical derivations and simulation studies are conducted to investigate the behaviour of the method. The method is applied to two real data examples. The bivariate marginal pseudo-observation model carries the strength of a two-dimensional modelling procedure and performs well in comparison with available models. Finally, an extension to a three-dimensional model, which decomposes the terminal event per death cause, is proposed and exemplified.

Can neurofeedback provide evidence of direct brain-behavior causality?

Neurofeedback is a procedure that measures brain activity in real-time and presents it as feedback to an individual, thus allowing them to self-regulate brain activity with effects on cognitive processes inferred from behavior. One common argument is that neurofeedback studies can reveal how the measured brain activity causes a particular cognitive process. The causal claim is often made regarding the measured brain activity being manipulated as an independent variable, similar to brain stimulation studies. However, this causal inference is vulnerable to the argument that other upstream brain activities change concurrently and cause changes in the brain activity from which feedback is derived. In this paper, we outline the inference that neurofeedback may causally affect cognition by indirect means. We further argue that researchers should remain open to the idea that the trained brain activity could be part of a "causal network" that collectively affects cognition rather than being necessarily causally primary. This particular inference may provide a better translation of evidence from neurofeedback studies to the rest of neuroscience. We argue that the recent advent of multivariate pattern analysis, when combined with implicit neurofeedback, currently comprises the strongest case for causality. Our perspective is that although the burden of inferring direct causality is difficult, it may be triangulated using a collection of various methods in neuroscience. Finally, we argue that the neurofeedback methodology provides unique advantages compared to other methods for revealing changes in the brain and cognitive processes but that researchers should remain mindful of indirect causal effects.

Task requirements affect the neural correlates of consciousness.

In the search for the neural correlates of consciousness, it is often assumed that there is a stable set within the relevant sensory modality. Within the visual modality, the debate has centred upon whether frontal or occipital activations are the best predictors of perceptual awareness. Although not accepted by all as definitive evidence, no-report and decoding studies have indicated that occipital activity is the most consistently correlated with perceptual awareness whereas frontal activity might be closely related to aspects of cognition typically related to reports. However, perception is rarely just passive perception of something, but more or less always perception for something. That is, the task at hand for the perceiver may influence what is being perceived. This suggests an alternative view: that consciousness is not one specific 'function' that can be localized consistently to one area or event-related component and that the specific attributes of the neural correlates of consciousness depend on the task at hand. To investigate whether and how tasks may influence the neural correlates of consciousness, we here contrasted two tasks, a perceptual task and a conceptual task, using identical stimuli in both tasks. Using magnetoencephalography, we found that the perceptual task recruited more occipital resources than the conceptual task. Furthermore, we found that between the two conditions, the amount of frontal resources recruited differed between different gradations of perceptual awareness partly in an unexpected manner. These findings support a view of task affecting the neural correlates of consciousness.

Doubting the double-blind: Introducing a questionnaire for awareness of experimental purposes in neurofeedback studies.

Double-blinding subjects to the experiment's purpose is an important standard in neurofeedback studies. However, it is difficult to provide evidence that humans are entirely unaware of certain information. This study used insights from consciousness studies and neurophenomenology to develop a contingency awareness questionnaire for neurofeedback. We assessed whether participants had an awareness of experimental purposes to manipulate their attention and multisensory perception. A subset of subjects (5 out of 20) gained a degree of awareness of experimental purposes as evidenced by their correct guess about the purposes of the experiment to affect their attention and multisensory perceptions specific to their double-blinded group assignment. The results warrant replication before they are applied to clinical neurofeedback studies, given the considerable time taken to perform the questionnaire (∼25 min). We discuss the strengths and limitations of our contingency awareness questionnaire and the growing appeal of the double-blinded standard in clinical neurofeedback studies.

Investigating the validity of the Perceptual Awareness Scale - The effect of task-related difficulty on subjective rating.

The Perceptual Awareness Scale (PAS) is often used to probe conscious experience, but the assumptions behind the scale and its validity are rarely tested. Using a continuous colour estimation task to assess perceptual quality, we focus on how well PAS follows perceptual quality and how the presence of the estimation task affects PAS ratings. We varied the number and presentation time of stimuli in a simultaneous presentation and target position in a sequential presentation. In all experiments, PAS rating closely followed colour precision. However, it was affected by task-induced response bias, even when the possible task difficulty was judged, without performing the task itself. Still, this bias was only observed on the absolute rating level rather than the scale's ability to capture changes in perceptual quality. Reported studies shed light on factors influencing scales outside of the scale formulation and construction.

Comparing theories of consciousness: Object position, not probe modality, reliably influences experience and accuracy in object recognition tasks.

People often claim seeing images completely despite performing poorly. This highlights an issue with conscious representations. We introduce an experimental manipulation aiming to disentangle two prevalent positions: Rich views posit that people virtually represent the external world with unlimited capacity; Sparse views state that representations are reconstructed from expectations and information. In two experiments using the object recognition task, we tested two probe types: Images, which should aid reconstruction more, and Words, which should aid it less. From a sparse view, one should expect that Images lead to greater accuracy and reported experience. We found no reliable differences in accuracy and reported experience across probe types; however, we observed that the object positions influenced both accuracy and reported experience, which is surprising from a Rich view as it seemingly requires assumptions of different access across the visual field. Both theoretical positions thus currently need further development to explain our results.

Cumulative risk regression in case-cohort studies using pseudo-observations.

Case-cohort studies are useful when information on certain risk factors is difficult or costly to ascertain. Particularly, a case-cohort study may be well suited in situations where several case series are of interest, e.g. in studies with competing risks, because the same sub-cohort may serve as a comparison group for all case series. Previous analyses of this kind of sampled cohort data most often involved estimation of rate ratios based on a Cox regression model. However, with competing risks this method will not provide parameters that directly describe the association between covariates and cumulative risks. In this paper, we study regression analysis of cause-specific cumulative risks in case-cohort studies using pseudo-observations. We focus mainly on the situation with competing risks. However, as a by-product, we also develop a method by which absolute mortality risks may be analyzed directly from case-cohort survival data. We adjust for the case-cohort sampling by inverse sampling probabilities applied to a generalized estimation equation. The large-sample properties of the proposed estimator are developed and small-sample properties are evaluated in a simulation study. We apply the methodology to study the effect of a specific diet component and a specific gene on the absolute risk of atrial fibrillation.

Visual expectations change subjective experience without changing performance.

It is widely believed that visual expectations can change the subjective experiences of humans. We investigated how visual expectations in a recognition task affected objective performance and subjective perception. Using a 2-alternative-forced-choice task based on digit recognition of briefly presented and visually masked digits, we found over two experiments that expectations changed the quality of the experiences without changing the performance capabilities associated with the quality of experience. Expectations were manipulated by providing a cue indicating the set of possible digits that might appear on each trial. The results also inform the debate about whether subjective experiences can be categorized in a dichotomous manner or in a graded manner. We found that subjective experiences were graded near the objective threshold and more dichotomous away from the threshold. Furthermore, distinct expectations resulted in a more dichotomous distribution of subjective experience. We also provide evidence of an interesting relationship between stimulus duration, objective performance and subjective ratings. Only experiences that were rated as evoking some degree of perception showed systematic improvements in objective performance as a function of stimulus duration. These findings suggest that subjective experience cannot be understood without considering the broader cognitive context, namely that the quality of subjective experiences is dependent on a multitude of factors such as attention, task requirements and cognitive expectations.

Measuring Blood Pulse Wave Velocity with Bioimpedance in Different Age Groups.

In this project, we have studied the use of electrical impedance cardiography as a possible method for measuring blood pulse wave velocity, and hence be an aid in the assessment of the degree of arteriosclerosis. Using two different four-electrode setups, we measured the timing of the systolic pulse at two locations, the upper arm and the thorax, and found that the pulse wave velocity was in general higher in older volunteers and furthermore that it was also more heart rate dependent for older subjects. We attribute this to the fact that the degree of arteriosclerosis typically increases with age and that stiffening of the arterial wall will make the arteries less able to comply with increased heart rate (and corresponding blood pressure), without leading to increased pulse wave velocity. In view of these findings, we conclude that impedance cardiography seems to be well suited and practical for pulse wave velocity measurements and possibly for the assessment of the degree of arteriosclerosis. However, further studies are needed for comparison between this approach and reference methods for pulse wave velocity and assessment of arteriosclerosis before any firm conclusions can be drawn.

Nitrite and S-Nitrosohemoglobin Exchange Across the Human Cerebral and Femoral Circulation: Relationship to Basal and Exercise Blood Flow Responses to Hypoxia.

BACKGROUND: The mechanisms underlying red blood cell (RBC)-mediated hypoxic vasodilation remain controversial, with separate roles for nitrite () and S-nitrosohemoglobin (SNO-Hb) widely contested given their ability to transduce nitric oxide bioactivity within the microcirculation. To establish their relative contribution in vivo, we quantified arterial-venous concentration gradients across the human cerebral and femoral circulation at rest and during exercise, an ideal model system characterized by physiological extremes of O2 tension and blood flow. METHODS: Ten healthy participants (5 men, 5 women) aged 24±4 (mean±SD) years old were randomly assigned to a normoxic (21% O2) and hypoxic (10% O2) trial with measurements performed at rest and after 30 minutes of cycling at 70% of maximal power output in hypoxia and equivalent relative and absolute intensities in normoxia. Blood was sampled simultaneously from the brachial artery and internal jugular and femoral veins with plasma and RBC nitric oxide metabolites measured by tri-iodide reductive chemiluminescence. Blood flow was determined by transcranial Doppler ultrasound (cerebral blood flow) and constant infusion thermodilution (femoral blood flow) with net exchange calculated via the Fick principle. RESULTS: Hypoxia was associated with a mild increase in both cerebral blood flow and femoral blood flow (P<0.05 versus normoxia) with further, more pronounced increases observed in femoral blood flow during exercise (P<0.05 versus rest) in proportion to the reduction in RBC oxygenation (r=0.680-0.769, P<0.001). Plasma gradients reflecting consumption (arterial>venous; P<0.05) were accompanied by RBC iron nitrosylhemoglobin formation (venous>arterial; P<0.05) at rest in normoxia, during hypoxia (P<0.05 versus normoxia), and especially during exercise (P<0.05 versus rest), with the most pronounced gradients observed across the bioenergetically more active, hypoxemic, and acidotic femoral circulation (P<0.05 versus cerebral). In contrast, we failed to observe any gradients consistent with RBC SNO-Hb consumption and corresponding delivery of plasma S-nitrosothiols (P>0.05). CONCLUSIONS: These findings suggest that hypoxia and, to a far greater extent, exercise independently promote arterial-venous delivery gradients of intravascular nitric oxide, with deoxyhemoglobin-mediated reduction identified as the dominant mechanism underlying hypoxic vasodilation.

Improving working memory performance in brain-injured patients using hypnotic suggestion.

Working memory impairment is prevalent in brain injured patients across lesion aetiologies and severities. Unfortunately, rehabilitation efforts for this impairment have hitherto yielded small or no effects. Here we show in a randomized actively controlled trial that working memory performance can be effectively restored by suggesting to hypnotized patients that they have regained their pre-injury level of working memory functioning. Following four 1-h sessions, 27 patients had a medium-sized improvement relative to 22 active controls (Bayes factors of 342 and 37.5 on the two aggregate outcome measures) and a very large improvement relative to 19 passive controls (Bayes factor = 1.7 × 1013). This was a long-term effect as revealed by no deterioration following a 6.7 week no-contact period (Bayes factors = 7.1 and 1.3 in favour of no change). To control for participant-specific effects, the active control group was crossed over to the working memory suggestion and showed superior improvement. By the end of the study, both groups reached a performance level at or above the healthy population mean with standardized mean differences between 1.55 and 2.03 relative to the passive control group. We conclude that, if framed correctly, hypnotic suggestion can effectively improve working memory following acquired brain injury. The speed and consistency with which this improvement occurred, indicate that there may be a residual capacity for normal information processing in the injured brain.

Estimating a population cumulative incidence under calendar time trends.

BACKGROUND: The risk of a disease or psychiatric disorder is frequently measured by the age-specific cumulative incidence. Cumulative incidence estimates are often derived in cohort studies with individuals recruited over calendar time and with the end of follow-up governed by a specific date. It is common practice to apply the Kaplan-Meier or Aalen-Johansen estimator to the total sample and report either the estimated cumulative incidence curve or just a single point on the curve as a description of the disease risk. METHODS: We argue that, whenever the disease or disorder of interest is influenced by calendar time trends, the total sample Kaplan-Meier and Aalen-Johansen estimators do not provide useful estimates of the general risk in the target population. We present some alternatives to this type of analysis. RESULTS: We show how a proportional hazards model may be used to extrapolate disease risk estimates if proportionality is a reasonable assumption. If not reasonable, we instead advocate that a more useful description of the disease risk lies in the age-specific cumulative incidence curves across strata given by time of entry or perhaps just the end of follow-up estimates across all strata. Finally, we argue that a weighted average of these end of follow-up estimates may be a useful summary measure of the disease risk within the study period. CONCLUSIONS: Time trends in a disease risk will render total sample estimators less useful in observational studies with staggered entry and administrative censoring. An analysis based on proportional hazards or a stratified analysis may be better alternatives.

Occipital MEG Activity in the Early Time Range (<300 ms) Predicts Graded Changes in Perceptual Consciousness.

Two electrophysiological components have been extensively investigated as candidate neural correlates of perceptual consciousness: An early, occipitally realized component occurring 130-320 ms after stimulus onset and a late, frontally realized component occurring 320-510 ms after stimulus onset. Recent studies have suggested that the late component may not be uniquely related to perceptual consciousness, but also to sensory expectations, task associations, and selective attention. We conducted a magnetoencephalographic study; using multivariate analysis, we compared classification accuracies when decoding perceptual consciousness from the 2 components using sources from occipital and frontal lobes. We found that occipital sources during the early time range were significantly more accurate in decoding perceptual consciousness than frontal sources during both the early and late time ranges. These results are the first of its kind where the predictive values of the 2 components are quantitatively compared, and they provide further evidence for the primary importance of occipital sources in realizing perceptual consciousness. The results have important consequences for current theories of perceptual consciousness, especially theories emphasizing the role of frontal sources.

Early visual processing allows for selective behavior, shifts of attention, and conscious visual experience in spite of masking.

Object-substitution masking (OSM) occurs when a briefly displayed target in a search array is surrounded by a mask, which remains onscreen after the target has disappeared. It has been suggested that OSM results from a specific interference with reentrant visual processing, while the initial feedforward processing is left intact. Here, we tested the prediction that the fastest saccadic responses towards a masked target, supposedly triggered before the onset of reentrant processing, are not impaired by OSM. Indeed, saccades faster than 350ms "escaped" the influence of the mask. Notably, participants' judgements of subjective awareness indicated that stimulus processing during this early stage is not entirely devoid of conscious awareness. Furthermore, the N2pc event-related potential component indicated shifts of spatial attention towards the masked targets on trials with correct fast saccades, suggesting that both target detection and spatial attention can be based on the computations accomplished during the initial feedforward sweep.

Discriminating between first- and second-order cognition in first-episode paranoid schizophrenia.

INTRODUCTION: An impairment of visually perceiving backward masked stimuli is commonly observed in patients with schizophrenia, yet it is unclear whether this impairment is the result of a deficiency in first or higher order processing and for which subtypes of schizophrenia it is present. METHODS: Here, we compare identification (first order) and metacognitive (higher order) performance in a visual masking paradigm between a highly homogenous group of young first-episode patients diagnosed with paranoid schizophrenia (N = 11) to that of carefully matched healthy controls (N = 13). RESULTS: We find no difference across groups in first-order performance, but find a difference in metacognitive performance, particularly for stimuli with relatively high visibility. CONCLUSIONS: These results indicate that the masking deficit is present in first-episode patients with paranoid schizophrenia, but that it is primarily an impairment of metacognition.

Risk of epilepsy and autism in full and half siblings-A population-based cohort study.

OBJECTIVE: Epilepsy and autism spectrum disorder (ASD) often occur together in the same individual. However, it remains unknown whether siblings of children with ASD have an increased risk of epilepsy and vice versa. This study determines the risk of ASD and epilepsy among younger siblings of children with ASD and epilepsy. DESIGN: The study included all children born in Denmark between January 1, 1980 and 31 December 2006 who participated in follow-up until December 31, 2012 (1,663,302 children). We used Cox regression to calculate the adjusted hazard ratio (aHR) and the Kaplan-Meier method to calculate the cumulative incidence. RESULTS: The overall aHR of epilepsy in younger siblings increased by 70% (aHR 1.70, 95% confidence interval [CI] 1.34-2.16%) if the older sibling had ASD compared with siblings where the older sibling did not have ASD. The cumulative incidence of epilepsy at 20 years of age was 2.54% (95% CI 1.97-3.26%) if the older sibling had ASD, whereas the cumulative incidence of epilepsy at 20 years of age was 1.63% (95% CI 1.60-1.66%) if the older sibling did not have ASD. The overall aHR of ASD in younger siblings increased by 54% if the older sibling had epilepsy (aHR 1.54, 95% CI 1.32-1.80) compared with siblings where the older sibling did not have epilepsy. The cumulative incidence of ASD at 20 years of age was 2.06% (95% CI 1.84-2.32%) if the older sibling had epilepsy, whereas the cumulative incidence of ASD at 20 years of age was 1.27% (95% CI 1.25-1.29%) if the older sibling did not have epilepsy. SIGNIFICANCE: The cross-disorder sibling risk of epilepsy and ASD was increased for the two disorders, which suggests that genes or environmental factors shared by family members may play a causal role in the co-occurrence of ASD and epilepsy.

Reconciling current approaches to blindsight.

After decades of research, blindsight is still a mysterious and controversial topic in consciousness research. Currently, many researchers tend to think of it as an ideal phenomenon to investigate neural correlates of consciousness, whereas others believe that blindsight is in fact a kind of degraded vision rather than "truly blind". This article considers both perspectives and finds that both have difficulties understanding all existing evidence about blindsight. In order to reconcile the perspectives, we suggest two specific criteria for a good model of blindsight, able to encompass all evidence. We propose that the REF-CON model (Overgaard & Mogensen, 2014) may work as such a model.