Noise in neurons is message-dependent

Neuronal responses are conspicuously variable. We focus on one particular aspect of that variability: the precision of action potential timing. We show that for common models of noisy spike generation, elementary considerations imply that such variability is a function of the input, and can be made arbitrarily large or small by a suitable choice of inputs. Our considerations are expected to extend to virtually any mechanism of spike generation, and we illustrate them with data from the visual pathway. Thus, a simplification usually made in the application of information theory to neural processing is violated: noise {\sl is not independent of the message}. However, we also show the existence of {\sl error-correcting} topologies, which can achieve better timing reliability than their components.Comment: 6 pages,6 figures. Proceedings of the National Academy of Sciences (in press

Impact of variance components on reliability of absolute quantification using digital PCR

Background: Digital polymerase chain reaction (dPCR) is an increasingly popular technology for detecting and quantifying target nucleic acids. Its advertised strength is high precision absolute quantification without needing reference curves. The standard data analytic approach follows a seemingly straightforward theoretical framework but ignores sources of variation in the data generating process. These stem from both technical and biological factors, where we distinguish features that are 1) hard-wired in the equipment, 2) user-dependent and 3) provided by manufacturers but may be adapted by the user. The impact of the corresponding variance components on the accuracy and precision of target concentration estimators presented in the literature is studied through simulation. Results: We reveal how system-specific technical factors influence accuracy as well as precision of concentration estimates. We find that a well-chosen sample dilution level and modifiable settings such as the fluorescence cut-off for target copy detection have a substantial impact on reliability and can be adapted to the sample analysed in ways that matter. User-dependent technical variation, including pipette inaccuracy and specific sources of sample heterogeneity, leads to a steep increase in uncertainty of estimated concentrations. Users can discover this through replicate experiments and derived variance estimation. Finally, the detection performance can be improved by optimizing the fluorescence intensity cut point as suboptimal thresholds reduce the accuracy of concentration estimates considerably. Conclusions: Like any other technology, dPCR is subject to variation induced by natural perturbations, systematic settings as well as user-dependent protocols. Corresponding uncertainty may be controlled with an adapted experimental design. Our findings point to modifiable key sources of uncertainty that form an important starting point for the development of guidelines on dPCR design and data analysis with correct precision bounds. Besides clever choices of sample dilution levels, experiment-specific tuning of machine settings can greatly improve results. Well-chosen data-driven fluorescence intensity thresholds in particular result in major improvements in target presence detection. We call on manufacturers to provide sufficiently detailed output data that allows users to maximize the potential of the method in their setting and obtain high precision and accuracy for their experiments

Reliability-based design optimization of shells with uncertain geometry using adaptive Kriging metamodels

Optimal design under uncertainty has gained much attention in the past ten years due to the ever increasing need for manufacturers to build robust systems at the lowest cost. Reliability-based design optimization (RBDO) allows the analyst to minimize some cost function while ensuring some minimal performances cast as admissible failure probabilities for a set of performance functions. In order to address real-world engineering problems in which the performance is assessed through computational models (e.g., finite element models in structural mechanics) metamodeling techniques have been developed in the past decade. This paper introduces adaptive Kriging surrogate models to solve the RBDO problem. The latter is cast in an augmented space that "sums up" the range of the design space and the aleatory uncertainty in the design parameters and the environmental conditions. The surrogate model is used (i) for evaluating robust estimates of the failure probabilities (and for enhancing the computational experimental design by adaptive sampling) in order to achieve the requested accuracy and (ii) for applying a gradient-based optimization algorithm to get optimal values of the design parameters. The approach is applied to the optimal design of ring-stiffened cylindrical shells used in submarine engineering under uncertain geometric imperfections. For this application the performance of the structure is related to buckling which is addressed here by means of a finite element solution based on the asymptotic numerical method

Probabilistic classification of acute myocardial infarction from multiple cardiac markers

Logistic regression and Gaussian mixture model (GMM) classifiers have been trained to estimate the probability of acute myocardial infarction (AMI) in patients based upon the concentrations of a panel of cardiac markers. The panel consists of two new markers, fatty acid binding protein (FABP) and glycogen phosphorylase BB (GPBB), in addition to the traditional cardiac troponin I (cTnI), creatine kinase MB (CKMB) and myoglobin. The effect of using principal component analysis (PCA) and Fisher discriminant analysis (FDA) to preprocess the marker concentrations was also investigated. The need for classifiers to give an accurate estimate of the probability of AMI is argued and three categories of performance measure are described, namely discriminatory ability, sharpness, and reliability. Numerical performance measures for each category are given and applied. The optimum classifier, based solely upon the samples take on admission, was the logistic regression classifier using FDA preprocessing. This gave an accuracy of 0.85 (95% confidence interval: 0.78–0.91) and a normalised Brier score of 0.89. When samples at both admission and a further time, 1–6 h later, were included, the performance increased significantly, showing that logistic regression classifiers can indeed use the information from the five cardiac markers to accurately and reliably estimate the probability AMI

Error Estimation of Bathymetric Grid Models Derived from Historic and Contemporary Data Sets

The past century has seen remarkable advances in technologies associated with positioning and the measurement of depth. Lead lines have given way to single beam echo sounders, which in turn are being replaced by multibeam sonars and other means of remotely and rapidly collecting dense bathymetric datasets. Sextants were replaced by radio navigation, then transit satellite, GPS and now differential GPS. With each new advance comes tremendous improvement in the accuracy and resolution of the data we collect. Given these changes and given the vastness of the ocean areas we must map, the charts we produce are mainly compilations of multiple data sets collected over many years and representing a range of technologies. Yet despite our knowledge that the accuracy of the various technologies differs, our compilations have traditionally treated each sounding with equal weight. We address these issues in the context of generating regularly spaced grids containing bathymetric values. Gridded products are required for a number of earth sciences studies and for generating the grid we are often forced to use a complex interpolation scheme due to the sparseness and irregularity of the input data points. Consequently, we are faced with the difficult task of assessing the confidence that we can assign to the final grid product, a task that is not usually addressed in most bathymetric compilations. Traditionally the hydrographic community has considered each sounding equally accurate and there has been no error evaluation of the bathymetric end product. This has important implications for use of the gridded bathymetry, especially when it is used for generating further scientific interpretations. In this paper we approach the problem of assessing the confidence of the final bathymetry gridded product via a direct-simulation Monte Carlo method. We start with a small subset of data from the International Bathymetric Chart of the Arctic Ocean (IBCAO) grid model [Jakobsson et al., 2000]. This grid is compiled from a mixture of data sources ranging from single beam soundings with available metadata, to spot soundings with no available metadata, to digitized contours; the test dataset shows examples of all of these types. From this database, we assign a priori error variances based on available meta-data, and when this is not available, based on a worst-case scenario in an essentially heuristic manner. We then generate a number of synthetic datasets by randomly perturbing the base data using normally distributed random variates, scaled according to the predicted error model. These datasets are next re-gridded using the same methodology as the original product, generating a set of plausible grid models of the regional bathymetry that we can use for standard deviation estimates. Finally, we repeat the entire random estimation process and analyze each run’s standard deviation grids in order to examine sampling bias and standard error in the predictions. The final products of the estimation are a collection of standard deviation grids, which we combine with the source data density in order to create a grid that contains information about the bathymetric model’s reliability