Tail-Robust Quantile Normalization.

High-throughput biological data-such as mass spectrometry (MS)-based proteomics data-suffer from systematic non-biological variance due to systematic errors. This hinders the estimation of "real" biological signals and, in turn, decreases the power of statistical tests and biases the identification of differentially expressed proteins. To remove such unintended variation, while retaining the biological signal of interest, analysis workflows for quantitative MS data typically comprise normalization prior to their statistical analysis. Several normalization methods, such as quantile normalization (QN), have originally been developed for microarray data. In contrast to microarray data proteomics data may contain features, in the form of protein intensities that are consistently high across experimental conditions and, hence, are encountered in the tails of the protein intensity distribution. If QN is applied in the presence of such proteins statistical inferences of the features' intensity profiles are impeded due to the biased estimation of their variance. A freely available, novel approach is introduced which serves as an improvement of the classical QN by preserving the biological signals of features in the tails of the intensity distribution and by accounting for sample-dependent missing values (MVs): The "tail-robust quantile normalization" (TRQN).

Inferring direct directed-information flow from multivariate nonlinear time series.

Estimating the functional topology of a network from multivariate observations is an important task in nonlinear dynamics. We introduce the nonparametric partial directed coherence that allows disentanglement of direct and indirect connections and their directions. We illustrate the performance of the nonparametric partial directed coherence by means of a simulation with data from synchronized nonlinear oscillators and apply it to real-world data from a patient suffering from essential tremor.

Application of a multivariate seizure detection and prediction method to non-invasive and intracranial long-term EEG recordings.

OBJECTIVE: Retrospective evaluation and comparison of performances of a multivariate method for seizure detection and prediction on simultaneous long-term EEG recordings from scalp and intracranial electrodes. METHODS: Two multivariate techniques based on simulated leaky integrate-and-fire neurons were investigated in order to detect and predict seizures. Both methods were applied and assessed on 423h of EEG and 26 seizures in total, recorded simultaneously from the scalp and intracranially continuously over several days from six patients with pharmacorefractory epilepsy. RESULTS: Features generated from simultaneous scalp and intracranial EEG data showed a similar dynamical behavior. Significant performances with sensitivities of up to 73%/62% for scalp/invasive EEG recordings given an upper limit of 0.15 false detections per hour were obtained. Up to 59%/50% of all seizures could be predicted from scalp/invasive EEG, given a maximum number of 0.15 false predictions per hour. A tendency to better performances for scalp EEG was obtained for the detection algorithm. CONCLUSIONS: The investigated methods originally developed for non-invasive EEG were successfully applied to intracranial EEG. Especially, concerning seizure detection the method shows a promising performance which is appropriate for practical applications in EEG monitoring. Concerning seizure prediction a significant prediction performance is indicated and a modification of the method is suggested. SIGNIFICANCE: This study evaluates simultaneously recorded non-invasive and intracranial continuous long-term EEG data with respect to seizure detection and seizure prediction for the first time.

Spatio-temporal patient-individual assessment of synchronization changes for epileptic seizure prediction.

OBJECTIVE: Abnormal synchronization of neurons plays a central role for the generation of epileptic seizures. Therefore, multivariate time series analysis techniques investigating relationships between the dynamics of different neural populations may offer advantages in predicting epileptic seizures. METHODS: We applied a phase and a lag synchronization measure to a selected subset of multicontact intracranial EEG recordings and assessed changes in synchronization with respect to seizure prediction. RESULTS: Patient individual results, group results, spatial aspects using focal and extra-focal electrode contacts as well as two evaluation schemes analyzing decreases and increases in synchronization were examined. Averaged sensitivity values of 60% are observed for a false prediction rate of 0.15 false predictions per hour, a seizure occurrence period of half an hour, and a prediction horizon of 10 min. For approximately half of all 21 patients, a statistically significant prediction performance is observed for at least one synchronization measure and evaluation scheme. CONCLUSIONS: The results indicate that synchronization changes in the EEG dynamics preceding seizures can be used for seizure prediction. Nevertheless, the underlying pathogenic mechanisms differ and both decreases and increases in synchronization may precede epileptic seizures depending on the structures investigated. SIGNIFICANCE: The prediction method, optimized values of intervention times, as well as preferred brain structures for the EEG recordings have to be determined for each patient individually offering the chance of a better patient-individual prediction performance.

Testing statistical significance of multivariate time series analysis techniques for epileptic seizure prediction.

Nonlinear time series analysis techniques have been proposed to detect changes in the electroencephalography dynamics prior to epileptic seizures. Their applicability in practice to predict seizure onsets is hampered by the present lack of generally accepted standards to assess their performance. We propose an analytic approach to judge the prediction performance of multivariate seizure prediction methods. Statistical tests are introduced to assess patient individual results, taking into account that prediction methods are applied to multiple time series and several seizures. Their performance is illustrated utilizing a bivariate seizure prediction method based on synchronization theory.

Do false predictions of seizures depend on the state of vigilance? A report from two seizure-prediction methods and proposed remedies.

PURPOSE: Available seizure-prediction algorithms are accompanied by high numbers of false predictions to achieve high sensitivity. Little is known about the extent to which changes in EEG dynamics contribute to false predictions. This study addresses potential causes and the circadian distribution of false predictions as well as their relation to the sleep-wake cycle. METHODS: In 21 patients, each with 24 h of interictal invasive EEG recordings, two methods, the dynamic similarity index and the mean phase coherence, were assessed with respect to time points of false predictions. Visual inspection of the invasive EEG data and additional scalp electroencephalogram data was performed at times of false predictions to identify possible correlates of changes in the EEG dynamics. RESULTS: A dependency of false predictions on the time of day is shown. Renormalized to the duration of the period patients are asleep and awake, 86% of all false predictions occurred during sleep for the dynamic similarity index and 68% for the mean phase coherence, respectively. Combining two reference intervals, one during sleep and one in an awake state, the dynamic similarity index increases its performance by reducing the number of false predictions by almost 50% without major changes in sensitivity. No obvious dependence of false predictions was noted on visible epileptic activity, such as spikes, sharp waves, or subclinical ictal patterns. CONCLUSIONS: Changes in the EEG dynamics related to the sleep-wake cycle contribute to limits of specificity of both seizure-prediction methods investigated. This may provide a clue for improving prediction methods in general. The combination of reference states yields promising results and may offer opportunities to increase further the performance of prediction methods.