Regulatory bioinformatics for food and drug safety.

"Regulatory Bioinformatics" strives to develop and implement a standardized and transparent bioinformatic framework to support the implementation of existing and emerging technologies in regulatory decision-making. It has great potential to improve public health through the development and use of clinically important medical products and tools to manage the safety of the food supply. However, the application of regulatory bioinformatics also poses new challenges and requires new knowledge and skill sets. In the latest Global Coalition on Regulatory Science Research (GCRSR) governed conference, Global Summit on Regulatory Science (GSRS2015), regulatory bioinformatics principles were presented with respect to global trends, initiatives and case studies. The discussion revealed that datasets, analytical tools, skills and expertise are rapidly developing, in many cases via large international collaborative consortia. It also revealed that significant research is still required to realize the potential applications of regulatory bioinformatics. While there is significant excitement in the possibilities offered by precision medicine to enhance treatments of serious and/or complex diseases, there is a clear need for further development of mechanisms to securely store, curate and share data, integrate databases, and standardized quality control and data analysis procedures. A greater understanding of the biological significance of the data is also required to fully exploit vast datasets that are becoming available. The application of bioinformatics in the microbiological risk analysis paradigm is delivering clear benefits both for the investigation of food borne pathogens and for decision making on clinically important treatments. It is recognized that regulatory bioinformatics will have many beneficial applications by ensuring high quality data, validated tools and standardized processes, which will help inform the regulatory science community of the requirements necessary to ensure the safe introduction and effective use of these applications.

Genomics in the land of regulatory science.

Genomics science has played a major role in the generation of new knowledge in the basic research arena, and currently question arises as to its potential to support regulatory processes. However, the integration of genomics in the regulatory decision-making process requires rigorous assessment and would benefit from consensus amongst international partners and research communities. To that end, the Global Coalition for Regulatory Science Research (GCRSR) hosted the fourth Global Summit on Regulatory Science (GSRS2014) to discuss the role of genomics in regulatory decision making, with a specific emphasis on applications in food safety and medical product development. Challenges and issues were discussed in the context of developing an international consensus for objective criteria in the analysis, interpretation and reporting of genomics data with an emphasis on transparency, traceability and "fitness for purpose" for the intended application. It was recognized that there is a need for a global path in the establishment of a regulatory bioinformatics framework for the development of transparent, reliable, reproducible and auditable processes in the management of food and medical product safety risks. It was also recognized that training is an important mechanism in achieving internationally consistent outcomes. GSRS2014 provided an effective venue for regulators andresearchers to meet, discuss common issues, and develop collaborations to address the challenges posed by the application of genomics to regulatory science, with the ultimate goal of wisely integrating novel technical innovations into regulatory decision-making.

Invasive group A Streptococcus infections associated with liposuction surgery at outpatient facilities not subject to state or federal regulation.

IMPORTANCE: Liposuction is one of the most common cosmetic surgery procedures in the United States. Tumescent liposuction, in which crystalloid fluids, lidocaine, and epinephrine are infused subcutaneously before cannula-assisted aspiration of fat, can be performed without intravenous or general anesthesia, often at outpatient facilities. However, some of these facilities are not subject to state or federal regulation and may not adhere to appropriate infection control practices. OBJECTIVE: To describe an outbreak of severe group A Streptococcus (GAS) infections among persons undergoing tumescent liposuction at 2 outpatient cosmetic surgery facilities not subject to state or federal regulation. DESIGN: Outbreak investigation (including cohort analysis of at-risk patients), interviews using a standardized questionnaire, medical record review, facility assessment, and laboratory analysis of GAS isolates. SETTING AND PARTICIPANTS: Patients undergoing liposuction at 2 outpatient facilities, one in Maryland and the other in Pennsylvania, between July 1 and September 14, 2012. MAIN OUTCOMES AND MEASURES: Confirmed invasive GAS infections (isolation of GAS from a normally sterile site or wound of a patient with necrotizing fasciitis or streptococcal toxic shock syndrome), suspected GAS infections (inflamed surgical site and either purulent discharge or fever and chills in a patient with no alternative diagnosis), postsurgical symptoms and patient-reported experiences related to his or her procedure, and emm types, T-antigen types, and antimicrobial susceptibility of GAS isolates. RESULTS: We identified 4 confirmed cases and 9 suspected cases, including 1 death (overall attack rate, 20% [13 of 66]). One instance of likely secondary GAS transmission to a household member occurred. All confirmed case patients had necrotizing fasciitis and had undergone surgical debridement. Procedures linked to illness were performed by a single surgical team that traveled between the 2 locations; 2 team members (1 of whom reported recent cellulitis) were colonized with a GAS strain that was indistinguishable by laboratory analysis of the isolates from the case patients. Facility assessments and patient reports indicated substandard infection control, including errors in equipment sterilization and infection prevention training. CONCLUSIONS AND RELEVANCE: This outbreak of severe GAS infections was likely caused by transmission from colonized health care workers to patients during liposuction procedures. Additional oversight of outpatient cosmetic surgery facilities is needed to assure that they maintain appropriate infection control practices and other patient protections.

A comparison of non-typhoidal Salmonella from humans and food animals using pulsed-field gel electrophoresis and antimicrobial susceptibility patterns.

Salmonellosis is one of the most important foodborne diseases affecting humans. To characterize the relationship between Salmonella causing human infections and their food animal reservoirs, we compared pulsed-field gel electrophoresis (PFGE) and antimicrobial susceptibility patterns of non-typhoidal Salmonella isolated from ill humans in Pennsylvania and from food animals before retail. Human clinical isolates were received from 2005 through 2011 during routine public health operations in Pennsylvania. Isolates from cattle, chickens, swine and turkeys were recovered during the same period from federally inspected slaughter and processing facilities in the northeastern United States. We found that subtyping Salmonella isolates by PFGE revealed differences in antimicrobial susceptibility patterns and, for human Salmonella, differences in sources and invasiveness that were not evident from serotyping alone. Sixteen of the 20 most common human Salmonella PFGE patterns were identified in Salmonella recovered from food animals. The most common human Salmonella PFGE pattern, Enteritidis pattern JEGX01.0004 (JEGX01.0003ARS), was associated with more cases of invasive salmonellosis than all other patterns. In food animals, this pattern was almost exclusively (99%) found in Salmonella recovered from chickens and was present in poultry meat in every year of the study. Enteritidis pattern JEGX01.0004 (JEGX01.0003ARS) was associated with susceptibility to all antimicrobial agents tested in 94.7% of human and 97.2% of food animal Salmonella isolates. In contrast, multidrug resistance (resistance to three or more classes of antimicrobial agents) was observed in five PFGE patterns. Typhimurium patterns JPXX01.0003 (JPXX01.0003 ARS) and JPXX01.0018 (JPXX01.0002 ARS), considered together, were associated with resistance to five or more classes of antimicrobial agents: ampicillin, chloramphenicol, streptomycin, sulfonamides and tetracycline (ACSSuT), in 92% of human and 80% of food animal Salmonella isolates. The information from our study can assist in source attribution, outbreak investigations, and tailoring of interventions to maximize their impact on prevention.

Use of interrupted time-series method to evaluate the impact of cigarette excise tax increases in Pennsylvania, 2000-2009.

INTRODUCTION: Scientific evidence shows that cigarette price increases can significantly reduce smoking prevalence and smoking initiation among adolescents and young adults. However, data are lacking regarding the effectiveness of increasing Pennsylvania's cigarette tax to reduce smoking and/or adverse health effects of smoking. The objective of our study was to assess the impact of cigarette tax increases and resulting price increases on smoking prevalence, acute myocardial infarction (AMI) and asthma hospitalization rates, and sudden cardiac death (SCD) rates in Pennsylvania. METHODS: We used segmented regression analyses of interrupted time series to evaluate the level and trend changes in Pennsylvania adults' current smoking prevalence, age-adjusted AMI and asthma hospitalization rates, age-specific asthma hospitalization rates, and age-adjusted SCD rates following 2 cigarette excise tax increases. RESULTS: After the first excise tax increase, no beneficial effects were noted on the outcomes of interest. The second tax increase was associated with significant declines in smoking prevalence for people aged 18 to 39, age-adjusted AMI hospitalization rates for men, age-adjusted asthma hospitalizations rates, and SCD rates among men. Overall smoking prevalence declined by 5.2% (P = .01), with a quarterly decrease of 1.4% (P = .01) for people aged 18 to 39 years. The age-adjusted AMI hospitalization rate for men showed a decline of 3.87/100,000 population (P = .04). The rate of age-adjusted asthma hospitalizations decreased by 10.05/100,000 population (P < .001), and the quarterly trend decreased by 3.21/100,000 population (P < .001). Quarterly SCD rates for men decreased by 1.34/100,000 population (P < .001). CONCLUSION: An increase in the price of cigarettes to more than $4 per 20-cigarette pack was associated with a significant decrease in smoking among younger people (aged 18-39). Decreases were also seen in asthma hospitalizations and men's age-adjusted AMI hospitalization and SCD rates. Further research and policy development regarding the effect of cigarette taxes on tobacco consumption should be cognizant of the psychological tipping points at which overall price affects smoking patterns.

Outbreak of variant influenza A(H3N2) virus in the United States.

BACKGROUND: Variant influenza virus infections are rare but may have pandemic potential if person-to-person transmission is efficient. We describe the epidemiology of a multistate outbreak of an influenza A(H3N2) variant virus (H3N2v) first identified in 2011. METHODS: We identified laboratory-confirmed cases of H3N2v and used a standard case report form to characterize illness and exposures. We considered illness to result from person-to-person H3N2v transmission if swine contact was not identified within 4 days prior to illness onset. RESULTS: From 9 July to 7 September 2012, we identified 306 cases of H3N2v in 10 states. The median age of all patients was 7 years. Commonly reported signs and symptoms included fever (98%), cough (85%), and fatigue (83%). Sixteen patients (5.2%) were hospitalized, and 1 fatal case was identified. The majority of those infected reported agricultural fair attendance (93%) and/or contact with swine (95%) prior to illness. We identified 15 cases of possible person-to-person transmission of H3N2v. Viruses recovered from patients were 93%-100% identical and similar to viruses recovered from previous cases of H3N2v. All H3N2v viruses examined were susceptible to oseltamivir and zanamivir and resistant to adamantane antiviral medications. CONCLUSIONS: In a large outbreak of variant influenza, the majority of infected persons reported exposures, suggesting that swine contact at an agricultural fair was a risk for H3N2v infection. We identified limited person-to-person H3N2v virus transmission, but found no evidence of efficient or sustained person-to-person transmission. Fair managers and attendees should be aware of the risk of swine-to-human transmission of influenza viruses in these settings.

Transmissibility of variant influenza from Swine to humans: a modeling approach.

BACKGROUND: Respiratory illness was reported among humans and swine at an agricultural fair in 2011; 3 human infections with an influenza A(H3N2) variant (H3N2v) virus were confirmed. Using epidemiologic investigation data, we sought to estimate H3N2v transmissibility from swine to humans. METHODS: We developed a model of H3N2v transmission among swine and humans and fit it to data from a cohort of 100 agricultural club members reporting swine contact to estimate transmissibility. A sensitivity analysis was performed varying H3N2v prevalence in the club cohort. Using the best-fit transmission probability, we simulated the number of swine-acquired infections among all fair attendees. RESULTS: We estimated the best-fit probability of swine-to-human H3N2v transmission per minute of swine contact. Applying this probability to 14 910 people with swine contact at the fair, we estimate that there were 80 (95% confidence interval [CI], 40-133) H3N2v infections among persons aged <20 years and 58 (95% CI, 29-96) H3N2v infections among person aged ≥20 years. CONCLUSIONS: Using early data from investigation of a new virus with unclear transmission properties, we estimated the transmissibility of H3N2v from swine to humans and the burden of H3N2v among fair attendees. Although the risk of H3N2v virus infection is small for fair attendees with minimal swine contact, large populations attend agricultural events each year, and human cases will likely occur when infected swine are present.

Campylobacter jejuni infections associated with unpasteurized milk--multiple States, 2012.

In 2012, a multistate outbreak of Campylobacter infections associated with unpasteurized milk resulted in 148 illnesses. A dairy with a Pennsylvania Department of Agriculture unpasteurized milk permit and minimal deficiencies identified during inspection was the outbreak source, demonstrating the ongoing hazards of unpasteurized dairy products.

Use of nonpharmaceutical interventions to reduce transmission of 2009 pandemic influenza A (pH1N1) in Pennsylvania public schools.

BACKGROUND: School-based recommendations for nonpharmaceutical interventions (NPIs) were issued in response to the threat of 2009 pandemic influenza A (pH1N1). The implementation and effectiveness of these recommendations has not been assessed. METHODS: In November 2009, a Web-based survey of all Pennsylvania public schools was conducted to assess the use of recommended NPIs. RESULTS: Overall, 1040 (31%) of 3351 schools participated in the survey. By fall 2009, 820 (84%) of 979 respondents reported that their school had an influenza plan in place, a 44% higher proportion than in the spring 2009 (p < .01). Most schools communicated health messages (eg, staying home when sick), implemented return to school requirements, and made hand sanitizer available. Schools with a spring influenza plan (N = 568) were less likely to report substantial influenza-like illness (ILI) during the fall wave of influenza than the 299 schools without a spring influenza plan (63% vs 71%, p = .02). This association persisted after controlling for schools with substantial ILI in the spring. CONCLUSION: The reported use of NPIs in participating Pennsylvania public schools improved substantially from spring to fall and was generally consistent with issued recommendations. The proactive implementation of a number of NPIs and the early implementation of communication and education initiatives might have cumulatively reduced the impact of pH1N1 in some schools.

Investigating systematic misclassification of central line-associated bloodstream infection (CLABSI) to secondary bloodstream infection during health care-associated infection reporting.

Central line-associated bloodstream infection (CLABSI) rates are an important measure of health care quality. However, reputational or financial risks associated with public reporting and disclosure of hospital CLABSI rates may introduce reporting biases, including intentional underreporting. To assess systematic case misclassification of CLABSI to secondary bloodstream infection (BSI; ie, intentional underreporting of CLABSI), the authors assessed data reported to the National Healthcare Safety Network by hospitals in Pennsylvania, the only state in which both CLABSI and secondary BSI reporting are mandatory. CLABSI rates decreased over the 2-year analysis period, but the authors found no evidence of increasing secondary BSI rates, suggesting that systematic case misclassification is not widespread.

Outbreak of influenza A (H3N2) variant virus infection among attendees of an agricultural fair, Pennsylvania, USA, 2011.

During August 2011, influenza A (H3N2) variant [A(H3N2)v] virus infection developed in a child who attended an agricultural fair in Pennsylvania, USA; the virus resulted from reassortment of a swine influenza virus with influenza A(H1N1)pdm09. We interviewed fair attendees and conducted a retrospective cohort study among members of an agricultural club who attended the fair. Probable and confirmed cases of A(H3N2)v virus infection were defined by serology and genomic sequencing results, respectively. We identified 82 suspected, 4 probable, and 3 confirmed case-patients who attended the fair. Among 127 cohort study members, the risk for suspected case status increased as swine exposure increased from none (4%; referent) to visiting swine exhibits (8%; relative risk 2.1; 95% CI 0.2-53.4) to touching swine (16%; relative risk 4.4; 95% CI 0.8-116.3). Fairs may be venues for zoonotic transmission of viruses with epidemic potential; thus, health officials should investigate respiratory illness outbreaks associated with agricultural events.

Local variations in spatial synchrony of influenza epidemics.

BACKGROUND: Understanding the mechanism of influenza spread across multiple geographic scales is not complete. While the mechanism of dissemination across regions and states of the United States has been described, understanding the determinants of dissemination between counties has not been elucidated. The paucity of high resolution spatial-temporal influenza incidence data to evaluate disease structure is often not available. METHODOLOGY AND FINDINGS: We report on the underlying relationship between the spread of influenza and human movement between counties of one state. Significant synchrony in the timing of epidemics exists across the entire state and decay with distance (regional correlation=62%). Synchrony as a function of population size display evidence of hierarchical spread with more synchronized epidemics occurring among the most populated counties. A gravity model describing movement between two populations is a stronger predictor of influenza spread than adult movement to and from workplaces suggesting that non-routine and leisure travel drive local epidemics. CONCLUSIONS: These findings highlight the complex nature of influenza spread across multiple geographic scales.

Local spatial and temporal processes of influenza in Pennsylvania, USA: 2003-2009.

BACKGROUND: Influenza is a contagious respiratory disease responsible for annual seasonal epidemics in temperate climates. An understanding of how influenza spreads geographically and temporally within regions could result in improved public health prevention programs. The purpose of this study was to summarize the spatial and temporal spread of influenza using data obtained from the Pennsylvania Department of Health's influenza surveillance system. METHODOLOGY AND FINDINGS: We evaluated the spatial and temporal patterns of laboratory-confirmed influenza cases in Pennsylvania, United States from six influenza seasons (2003-2009). Using a test of spatial autocorrelation, local clusters of elevated risk were identified in the South Central region of the state. Multivariable logistic regression indicated that lower monthly precipitation levels during the influenza season (OR = 0.52, 95% CI: 0.28, 0.94), fewer residents over age 64 (OR = 0.27, 95% CI: 0.10, 0.73) and fewer residents with more than a high school education (OR = 0.76, 95% CI: 0.61, 0.95) were significantly associated with membership in this cluster. In addition, time series analysis revealed a temporal lag in the peak timing of the influenza B epidemic compared to the influenza A epidemic. CONCLUSIONS: These findings illustrate a distinct spatial cluster of cases in the South Central region of Pennsylvania. Further examination of the regional transmission dynamics within these clusters may be useful in planning public health influenza prevention programs.

Evaluation of healthcare-associated infection surveillance in Pennsylvania hospitals.

OBJECTIVE: In Pennsylvania, reporting of healthcare-associated infections (HAIs) was mandated in 2007, and hospitals were encouraged to implement qualified electronic surveillance (QES) systems to assist HAI detection. This study evaluated the usefulness of these systems in reducing HAIs. DESIGN: Online survey and retrospective cohort study. Eligible facilities had a QES or manual system in place for the entire study period and sufficient data in selected hospital units. METHODS: Surveys were sent to infection preventionists (IPs) in all Pennsylvania hospitals to gather qualitative information about their systems. National Healthcare Safety Network data from Pennsylvania hospitals for July 2008 through June 2010 were used to compare catheter-associated urinary tract infection (CAUTI) rates in facilities with and without a QES system. PARTICIPANTS: IPs from 174 facilities responded to the survey. Data from 119 of 234 hospitals were analyzed. RESULTS: IPs in facilities with a QES system reported spending as much time on data management and education as IPs in hospitals with manual surveillance. Significant interaction was observed in CAUTI rates over time between groups of facilities with and without a QES system after controlling for device-utilization ratio, location within hospital, and licensed bed size (P < .01). QES hospitals showed a significant decline in CAUTI rates (P < .01) manual surveillance facilities showed no change in rates (P > .05). CONCLUSIONS: Over the 2-year period, a significant decline in CAUTI rates was observed in facilities with a QES system. This suggests that electronic systems may aid in reducing HAI rates. Additional data are needed to see whether these improvements and trends persist.