Open-target sparse sensing of biological agents using DNA microarray.

BACKGROUND: Current biosensors are designed to target and react to specific nucleic acid sequences or structural epitopes. These 'target-specific' platforms require creation of new physical capture reagents when new organisms are targeted. An 'open-target' approach to DNA microarray biosensing is proposed and substantiated using laboratory generated data. The microarray consisted of 12,900 25 bp oligonucleotide capture probes derived from a statistical model trained on randomly selected genomic segments of pathogenic prokaryotic organisms. Open-target detection of organisms was accomplished using a reference library of hybridization patterns for three test organisms whose DNA sequences were not included in the design of the microarray probes. RESULTS: A multivariate mathematical model based on the partial least squares regression (PLSR) was developed to detect the presence of three test organisms in mixed samples. When all 12,900 probes were used, the model correctly detected the signature of three test organisms in all mixed samples (mean(R²)) = 0.76, CI = 0.95), with a 6% false positive rate. A sampling algorithm was then developed to sparsely sample the probe space for a minimal number of probes required to capture the hybridization imprints of the test organisms. The PLSR detection model was capable of correctly identifying the presence of the three test organisms in all mixed samples using only 47 probes (mean(R²)) = 0.77, CI = 0.95) with nearly 100% specificity. CONCLUSIONS: We conceived an 'open-target' approach to biosensing, and hypothesized that a relatively small, non-specifically designed, DNA microarray is capable of identifying the presence of multiple organisms in mixed samples. Coupled with a mathematical model applied to laboratory generated data, and sparse sampling of capture probes, the prototype microarray platform was able to capture the signature of each organism in all mixed samples with high sensitivity and specificity. It was demonstrated that this new approach to biosensing closely follows the principles of sparse sensing.

VX hydrolysis by human serum paraoxonase 1: a comparison of experimental and computational results.

Human Serum paraoxonase 1 (HuPON1) is an enzyme that has been shown to hydrolyze a variety of chemicals including the nerve agent VX. While wildtype HuPON1 does not exhibit sufficient activity against VX to be used as an in vivo countermeasure, it has been suggested that increasing HuPON1's organophosphorous hydrolase activity by one or two orders of magnitude would make the enzyme suitable for this purpose. The binding interaction between HuPON1 and VX has recently been modeled, but the mechanism for VX hydrolysis is still unknown. In this study, we created a transition state model for VX hydrolysis (VX(ts)) in water using quantum mechanical/molecular mechanical simulations, and docked the transition state model to 22 experimentally characterized HuPON1 variants using AutoDock Vina. The HuPON1-VX(ts) complexes were grouped by reaction mechanism using a novel clustering procedure. The average Vina interaction energies for different clusters were compared to the experimentally determined activities of HuPON1 variants to determine which computational procedures best predict how well HuPON1 variants will hydrolyze VX. The analysis showed that only conformations which have the attacking hydroxyl group of VX(ts) coordinated by the sidechain oxygen of D269 have a significant correlation with experimental results. The results from this study can be used for further characterization of how HuPON1 hydrolyzes VX and design of HuPON1 variants with increased activity against VX.

Empirical evidence for synchrony in the evolution of TB cases and HIV+ contacts among the San Francisco homeless.

The re-emergence of tuberculosis (TB) in the mid-1980s in many parts of the world, including the United States, is often attributed to the emergence and rapid spread of human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS). Although it is well established that TB transmission is particularly amplified in populations with high HIV prevalence, the epidemiology of interaction between TB and HIV is not well understood. This is partly due to the scarcity of HIV-related data, a consequence of the voluntary nature of HIV status reporting and testing, and partly due to current practices of screening high risk populations through separate surveillance programs for HIV and TB. The San Francisco Department of Public Health, TB Control Program, has been conducting active surveillance among the San Francisco high-risk populations since the early 1990s. We present extensive TB surveillance data on HIV and TB infection among the San Francisco homeless to investigate the association between the TB cases and their HIV+ contacts. We applied wavelet coherence and phase analyses to the TB surveillance data from January 1993 through December 2005, to establish and quantify statistical association and synchrony in the highly non-stationary and ostensibly non-periodic waves of TB cases and their HIV+ contacts in San Francisco. When stratified by homelessness, we found that the evolution of TB cases and their HIV+ contacts is highly coherent over time and locked in phase at a specific periodic scale among the San Francisco homeless, but no significant association was observed for the non-homeless. This study confirms the hypothesis that the dynamics of HIV and TB are significantly intertwined and that HIV is likely a key factor in the sustenance of TB transmission among the San Francisco homeless. The findings of this study underscore the importance of contact tracing in detection of HIV+ individuals that may otherwise remain undetected, and thus highlights the ever-increasing need for HIV-related data and an integrative approach to monitoring high-risk populations with respect to HIV and TB transmission.

Early detection of tuberculosis outbreaks among the San Francisco homeless: trade-offs between spatial resolution and temporal scale.

BACKGROUND: San Francisco has the highest rate of tuberculosis (TB) in the U.S. with recurrent outbreaks among the homeless and marginally housed. It has been shown for syndromic data that when exact geographic coordinates of individual patients are used as the spatial base for outbreak detection, higher detection rates and accuracy are achieved compared to when data are aggregated into administrative regions such as zip codes and census tracts. We examine the effect of varying the spatial resolution in the TB data within the San Francisco homeless population on detection sensitivity, timeliness, and the amount of historical data needed to achieve better performance measures. METHODS AND FINDINGS: We apply a variation of space-time permutation scan statistic to the TB data in which a patient's location is either represented by its exact coordinates or by the centroid of its census tract. We show that the detection sensitivity and timeliness of the method generally improve when exact locations are used to identify real TB outbreaks. When outbreaks are simulated, while the detection timeliness is consistently improved when exact coordinates are used, the detection sensitivity varies depending on the size of the spatial scanning window and the number of tracts in which cases are simulated. Finally, we show that when exact locations are used, smaller amount of historical data is required for training the model. CONCLUSION: Systematic characterization of the spatio-temporal distribution of TB cases can widely benefit real time surveillance and guide public health investigations of TB outbreaks as to what level of spatial resolution results in improved detection sensitivity and timeliness. Trading higher spatial resolution for better performance is ultimately a tradeoff between maintaining patient confidentiality and improving public health when sharing data. Understanding such tradeoffs is critical to managing the complex interplay between public policy and public health. This study is a step forward in this direction.

Multi-syndrome analysis of time series using PCA: a new concept for outbreak investigation.

To date, despite widespread availability of time series data on multiple syndromes, multivariate analysis of syndromic data remains under-explored. We present a non-parametric multivariate framework for early detection of temporal anomalies based on principal components analysis of historical data on multiple syndromes. We introduce simulated outbreaks of different shapes and magnitudes into the historical data, and compare the detection sensitivity and timeliness of the multi-syndrome detection method with those of uni-syndrome. We find that the multi-syndrome detection framework provides a powerful tool for identifying such designated abnormalities in the data and significantly improves upon the detection sensitivity and timeliness of uni-syndrome analysis. The proposed multivariate framework requires minimal preprocessing of the data and can be easily adopted in settings where temporal information on multiple syndromes are routinely collected and processed, and thus can be an integral component of real-time surveillance systems.

A susceptible-infected model of early detection of respiratory infection outbreaks on a background of influenza.

The threat of biological warfare and the emergence of new infectious agents spreading at a global scale have highlighted the need for major enhancements to the public health infrastructure. Early detection of epidemics of infectious diseases requires both real-time data and real-time interpretation of data. Despite moderate advancements in data acquisition, the state of the practice for real-time analysis of data remains inadequate. We present a nonlinear mathematical framework for modeling the transient dynamics of influenza, applied to historical data sets of patients with influenza-like illness. We estimate the vital time-varying epidemiological parameters of infections from historical data, representing normal epidemiological trends. We then introduce simulated outbreaks of different shapes and magnitudes into the historical data, and estimate the parameters representing the infection rates of anomalous deviations from normal trends. Finally, a dynamic threshold-based detection algorithm is devised to assess the timeliness and sensitivity of detecting the irregularities in the data, under a fixed low false-positive rate. We find that the detection algorithm can identify such designated abnormalities in the data with high sensitivity with specificity held at 97%, but more importantly, early during an outbreak. The proposed methodology can be applied to a broad range of influenza-like infectious diseases, whether naturally occurring or a result of bioterrorism, and thus can be an integral component of a real-time surveillance system.

Evolution of indirect reciprocity by social information: the role of trust and reputation in evolution of altruism.

The complexity of human's cooperative behavior cannot be fully explained by theories of kin selection and group selection. If reciprocal altruism is to provide an explanation for altruistic behavior, it would have to depart from direct reciprocity, which requires dyads of individuals to interact repeatedly. For indirect reciprocity to rationalize cooperation among genetically unrelated or even culturally dissimilar individuals, information about the reputation of individuals must be assessed and propagated in a population. Here, we propose a new framework for the evolution of indirect reciprocity by social information: information selectively retrieved from and propagated through dynamically evolving networks of friends and acquaintances. We show that for indirect reciprocity to be evolutionarily stable, the differential probability of trusting and helping a reputable individual over a disreputable individual, at a point in time, must exceed the cost-to-benefit ratio of the altruistic act. In other words, the benefit received by the trustworthy must out-weigh the cost of helping the untrustworthy.

Qualitative analysis of the all-cause black-white mortality crossover.

To date, despite decades of investigations and the relative abundance of mortality data, our understanding of the phenomenon of 'mortality crossover' remains inadequate. We propose a methodology for transforming mortality data from the 'age-domain' to the 'time-domain'. We then introduce a model of selection partially offset by mobility, to simulate the dynamics of vulnerability in a population cohort that is heterogeneous in health and death. Using our model of vulnerability simulating the dynamics of mortality in the time-domain, we compare the mortality experience of the Black and White populations of the United States, identify the significance of selection and mobility as potential factors producing the crossover phenomenon, and make diagnostic use of them.