Computational multi-scale pandemic modelling remains a major and timely challenge. Here we identify specific requirements for a new class of models simulating pandemics across three scales: (1) pathogen evolution, often punctuated by the rapid emergence of new variants, (2) human interactions within a heterogeneous population, and (3) public health responses which constrain individual actions to control the disease transmission. We then present a pandemic modelling framework satisfying these requirements and capable of simulating feedback loops between dynamics unfolding at these different scales. The developed framework comprises a stochastic agent-based model of pandemic spread, coupled with a phylodynamic model that incorporates within-host pathogen evolution. It is validated with a case study, modelling the punctuated evolution of SARS-CoV-2, based on global and contemporary genomic surveillance data, which captures a large heterogeneous population. We demonstrate that the model replicates the essential features of the COVID-19 pandemic and virus evolution, while retaining computational tractability and scalability.

SUMMARY: The reliable and timely recognition of outbreaks is a key component of public health surveillance for foodborne diseases. Whole genome sequencing (WGS) offers high resolution typing of foodborne bacterial pathogens and facilitates the accurate detection of outbreaks. This detection relies on grouping WGS data into clusters at an appropriate genetic threshold. However, methods and tools for selecting and adjusting such thresholds according to the required resolution of surveillance and epidemiological context are lacking. Here we present DODGE (Dynamic Outbreak Detection for Genomic Epidemiology), an algorithm to dynamically select and compare these genetic thresholds. DODGE can analyse expanding datasets over time and clusters that are predicted to correspond to outbreaks (or "investigation clusters") can be named with established genomic nomenclature systems to facilitate integrated analysis across jurisdictions. DODGE was tested in two real-world Salmonella genomic surveillance datasets of different duration, 2 months from Australia and 9 years from the United Kingdom. In both cases only a minority of isolates were identified as investigation clusters. Two known outbreaks in the United Kingdom dataset were detected by DODGE and were recognized at an earlier timepoint than the outbreaks were reported. These findings demonstrated the potential of the DODGE approach to improve the effectiveness and timeliness of genomic surveillance for foodborne diseases and the effectiveness of the algorithm developed. AVAILABILITY AND IMPLEMENTATION: DODGE is freely available at https://github.com/LanLab/dodge and can easily be installed using Conda.

Modelling the emergence of foodborne pathogens is a crucial step in the prediction and prevention of disease outbreaks. Unfortunately, the mechanisms that drive the evolution of such continuously adapting pathogens remain poorly understood. Here, we combine molecular genotyping with network science and Bayesian inference to infer directed genotype networks-and trace the emergence and evolutionary paths-of Salmonella Typhimurium (STM) from nine years of Australian disease surveillance data. We construct networks where nodes represent STM strains and directed edges represent evolutionary steps, presenting evidence that the structural (i.e., network-based) features are relevant to understanding the functional (i.e., fitness-based) progression of co-evolving STM strains. This is argued by showing that outbreak severity, i.e., prevalence, correlates to: (i) the network path length to the most prevalent node (r = -0.613, N = 690); and (ii) the network connected-component size (r = 0.739). Moreover, we uncover distinct exploration-exploitation pathways in the genetic space of STM, including a strong evolutionary drive through a transition region. This is examined via the 6,897 distinct evolutionary paths in the directed network, where we observe a dominant 66% of these paths decrease in network centrality, whilst increasing in prevalence. Furthermore, 72.4% of all paths originate in the transition region, with 64% of those following the dominant direction. Further, we find that the length of an evolutionary path strongly correlates to its increase in prevalence (r = 0.497). Combined, these findings indicate that longer evolutionary paths result in genetically rare and virulent strains, which mostly evolve from a single transition point. Our results not only validate our widely-applicable approach for inferring directed genotype networks from data, but also provide a unique insight into the elusive functional and structural drivers of STM bacteria.

BACKGROUND: High-throughput sequencing can identify numerous potential genomic targets for microbial strain typing, but identification of the most informative combinations requires the use of computational screening tools. This paper describes novel software-- Automated Selection of Typing Target Subsets (AuSeTTS)--that allows intelligent selection of optimal targets for pathogen strain typing. The objective of this software is to maximise both discriminatory power, using Simpson's index of diversity (D), and concordance with existing typing methods, using the adjusted Wallace coefficient (AW). The program interrogates molecular typing results for panels of isolates, based on large target sets, and iteratively examines each target, one-by-one, to determine the most informative subset. RESULTS: AuSeTTS was evaluated using three target sets: 51 binary targets (13 toxin genes, 16 phage-related loci and 22 SCCmec elements), used for multilocus typing of 153 methicillin-resistant Staphylococcus aureus (MRSA) isolates; 17 MLVA loci in 502 Streptococcus pneumoniae isolates from the MLVA database (http://www.mlva.eu) and 12 MLST loci for 98 Cryptococcus spp. isolates.The maximum D for MRSA, 0.984, was achieved with a subset of 20 targets and a D value of 0.954 with 7 targets. Twelve targets predicted MLST with a maximum AW of 0.9994. All 17 S. pneumoniae MLVA targets were required to achieve maximum D of 0.997, but 4 targets reached D of 0.990. Twelve targets predicted pneumococcal serotype with a maximum AW of 0.899 and 9 predicted MLST with maximum AW of 0.963. Eight of the 12 MLST loci were sufficient to achieve the maximum D of 0.963 for Cryptococcus spp. CONCLUSIONS: Computerised analysis with AuSeTTS allows rapid selection of the most discriminatory targets for incorporation into typing schemes. Output of the program is presented in both tabular and graphical formats and the software is available for free download from http://www.cidmpublichealth.org/pages/ausetts.html.

OBJECTIVE: To assess the impact of a web-based personally controlled health management system (PCHMS) on the uptake of seasonal influenza vaccine and primary care service utilization among university students and staff. MATERIALS AND METHODS: A PCHMS called Healthy.me was developed and evaluated in a 2010 CONSORT-compliant two-group (6-month waitlist vs PCHMS) parallel randomized controlled trial (RCT) (allocation ratio 1:1). The PCHMS integrated an untethered personal health record with consumer care pathways, social forums, and messaging links with a health service provider. RESULTS: 742 university students and staff met inclusion criteria and were randomized to a 6-month waitlist (n=372) or the PCHMS (n=370). Amongst the 470 participants eligible for primary analysis, PCHMS users were 6.7% (95% CI: 1.46 to 12.30) more likely than the waitlist to receive an influenza vaccine (waitlist: 4.9% (12/246, 95% CI 2.8 to 8.3) vs PCHMS: 11.6% (26/224, 95% CI 8.0 to 16.5); χ(2)=7.1, p=0.008). PCHMS participants were also 11.6% (95% CI 3.6 to 19.5) more likely to visit the health service provider (waitlist: 17.9% (44/246, 95% CI 13.6 to 23.2) vs PCHMS: 29.5% (66/224, 95% CI: 23.9 to 35.7); χ(2)=8.8, p=0.003). A dose-response effect was detected, where greater use of the PCHMS was associated with higher rates of vaccination (p=0.001) and health service provider visits (p=0.003). DISCUSSION: PCHMS can significantly increase consumer participation in preventive health activities, such as influenza vaccination. CONCLUSIONS: Integrating a PCHMS into routine health service delivery systems appears to be an effective mechanism for enhancing consumer engagement in preventive health measures. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12610000386033. http://www.anzctr.org.au/trial_view.aspx?id=335463.

To take advantage of the various high performance computer (HPC) architectures for multithreaded and distributed computing, this paper parallelizes the dynamic programming algorithm for multiple sequence alignment (MSA). A novel definition of a hyper-diagonal through a tensor space is used to reduce the search space. Experiments demonstrate that scoring less than 1% of the search space produces the same optimal results as scoring the full search space. The alignment scores are often better than other heuristic methods and are capable of aligning more divergent sequences.

BACKGROUND: In silico candidate gene prioritisation (CGP) aids the discovery of gene functions by ranking genes according to an objective relevance score. While several CGP methods have been described for identifying human disease genes, corresponding methods for prokaryotic gene function discovery are lacking. Here we present two prokaryotic CGP methods, based on phylogenetic profiles, to assist with this task. RESULTS: Using gene occurrence patterns in sample genomes, we developed two CGP methods (statistical and inductive CGP) to assist with the discovery of bacterial gene functions. Statistical CGP exploits the differences in gene frequency against phenotypic groups, while inductive CGP applies supervised machine learning to identify gene occurrence pattern across genomes. Three rediscovery experiments were designed to evaluate the CGP frameworks. The first experiment attempted to rediscover peptidoglycan genes with 417 published genome sequences. Both CGP methods achieved best areas under receiver operating characteristic curve (AUC) of 0.911 in Escherichia coli K-12 (EC-K12) and 0.978 Streptococcus agalactiae 2603 (SA-2603) genomes, with an average improvement in precision of >3.2-fold and a maximum of >27-fold using statistical CGP. A median AUC of >0.95 could still be achieved with as few as 10 genome examples in each group of genome examples in the rediscovery of the peptidoglycan metabolism genes. In the second experiment, a maximum of 109-fold improvement in precision was achieved in the rediscovery of anaerobic fermentation genes in EC-K12. The last experiment attempted to rediscover genes from 31 metabolic pathways in SA-2603, where 14 pathways achieved AUC >0.9 and 28 pathways achieved AUC >0.8 with the best inductive CGP algorithms. CONCLUSION: Our results demonstrate that the two CGP methods can assist with the study of functionally uncategorised genomic regions and discovery of bacterial gene-function relationships. Our rediscovery experiments also provide a set of standard tasks against which future methods may be compared.

BACKGROUND: This paper proposes a novel framework for bioinformatics assisted biosurveillance and early warning to address the inefficiencies in traditional surveillance as well as the need for more timely and comprehensive infection monitoring and control. It leverages on breakthroughs in rapid, high-throughput molecular profiling of microorganisms and text mining. RESULTS: This framework combines the genetic and geographic data of a pathogen to reconstruct its history and to identify the migration routes through which the strains spread regionally and internationally. A pilot study of Salmonella typhimurium genotype clustering and temporospatial outbreak analysis demonstrated better discrimination power than traditional phage typing. Half of the outbreaks were detected in the first half of their duration. CONCLUSION: The microbial profiling and biosurveillance focused text mining tools can enable integrated infectious disease outbreak detection and response environments based upon bioinformatics knowledge models and measured by outcomes including the accuracy and timeliness of outbreak detection.

OBJECTIVE: This study assessed the effect of a handheld computer-based decision support system (DSS) on antibiotic use and patient outcomes in a critical care unit. DESIGN: A DSS containing four types of evidence (patient microbiology reports, local antibiotic guidelines, unit-specific antibiotic susceptibility data for common bacterial pathogens, and a clinical pulmonary infection score calculator) was developed and implemented on a handheld computer for use in the intensive care unit at a tertiary referral hospital. System impact was assessed in a prospective "before/after" cohort trial lasting 12 months. Outcome measures were defined daily doses (DDDs) of antibiotics per 1,000 patient-days, patient length of stay, and mortality. RESULTS: The number of admissions, APACHE (Acute Physiology, Age, and Chronic Health Evaluation) II and SAPS (Simplified Acute Physiology Score) II for patients in preintervention, and intervention (DSS use) periods were statistically comparable. The mean patient length of stay and the use of antibiotics in the unit during six months of the DSS use decreased from 7.15 to 6.22 bed-days (p = 0.02) and from 1,767 DDD to 1,458 DDD per 1,000 patient-days (p = 0.04), respectively, with no change in mortality. The DSS was accessed 674 times during 168 days of the trial. Microbiology reports and antibiotic guidelines were the two most commonly used (53% and 22.5%, respectively) types of evidence. The greatest reduction was observed in the use of beta-lactamase-resistant penicillins and vancomycin. CONCLUSION: Handheld computer-based decision support contributed to a significant reduction in patient length of stay and antibiotic prescribing in a critical care unit.

OBJECTIVE: The aim of this study was to compare the clinical impact of computerized decision support with and without electronic access to clinical guidelines and laboratory data on antibiotic prescribing decisions. DESIGN: A crossover trial was conducted of four levels of computerized decision support-no support, antibiotic guidelines, laboratory reports, and laboratory reports plus a decision support system (DSS), randomly allocated to eight simulated clinical cases accessed by the Web. MEASUREMENTS: Rate of intervention adoption was measured by frequency of accessing information support, cost of use was measured by time taken to complete each case, and effectiveness of decision was measured by correctness of and self-reported confidence in individual prescribing decisions. Clinical impact score was measured by adoption rate and decision effectiveness. RESULTS: Thirty-one intensive care and infectious disease specialist physicians (ICPs and IDPs) participated in the study. Ventilator-associated pneumonia treatment guidelines were used in 24 (39%) of the 62 case scenarios for which they were available, microbiology reports in 36 (58%), and the DSS in 37 (60%). The use of all forms of information support did not affect clinicians' confidence in their decisions. Their use of the DSS plus microbiology report improved the agreement of decisions with those of an expert panel from 65% to 97% (p=0.0002), or to 67% (p=0.002) when antibiotic guidelines only were accessed. Significantly fewer IDPs than ICPs accessed information support in making treatment decisions. On average, it took 245 seconds to make a decision using the DSS compared with 113 seconds for unaided prescribing (p<0.001). The DSS plus microbiology reports had the highest clinical impact score (0.58), greater than that of electronic guidelines (0.26) and electronic laboratory reports (0.45). CONCLUSION: When used, computer-based decision support significantly improved decision quality. In measuring the impact of decision support systems, both their effectiveness in improving decisions and their likely rate of adoption in the clinical environment need to be considered. Clinicians chose to use antibiotic guidelines for one third and microbiology reports or the DSS for about two thirds of cases when they were available to assist their prescribing decisions.