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.

Role of social networks in shaping disease transmission during a community outbreak of 2009 H1N1 pandemic influenza.

Evaluating the impact of different social networks on the spread of respiratory diseases has been limited by a lack of detailed data on transmission outside the household setting as well as appropriate statistical methods. Here, from data collected during a H1N1 pandemic (pdm) influenza outbreak that started in an elementary school and spread in a semirural community in Pennsylvania, we quantify how transmission of influenza is affected by social networks. We set up a transmission model for which parameters are estimated from the data via Markov chain Monte Carlo sampling. Sitting next to a case or being the playmate of a case did not significantly increase the risk of infection; but the structuring of the school into classes and grades strongly affected spread. There was evidence that boys were more likely to transmit influenza to other boys than to girls (and vice versa), which mimicked the observed assortative mixing among playmates. We also investigated the presence of abnormally high transmission occurring on specific days of the outbreak. Late closure of the school (i.e., when 27% of students already had symptoms) had no significant impact on spread. School-aged individuals (6-18 y) facilitated the introduction and spread of influenza in households, but only about one in five cases aged >18 y was infected by a school-aged household member. This analysis shows the extent to which clearly defined social networks affect influenza transmission, revealing strong between-place interactions with back-and-forth waves of transmission between the school, the community, and the household.

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.

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.

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.

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 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.

Viral shedding duration of pandemic influenza A H1N1 virus during an elementary school outbreak--Pennsylvania, May-June 2009.

We report shedding duration of 2009 pandemic influenza A (pH1N1) virus from a school-associated outbreak in Pennsylvania during May through June 2009. Outbreak-associated students or household contacts with influenza-like illness (ILI) onset within 7 days of interview were recruited. Nasopharyngeal specimens, collected every 48 hours until 2 consecutive nonpositive tests, underwent real-time reverse transcriptase polymerase chain reaction (rRT-PCR) and culture for pH1N1 virus. Culture-positive specimens underwent virus titrations. Twenty-six (median age, 8 years) rRT-PCR-positive persons, for pH1N1 virus, were included in analysis. Median shedding duration from fever onset by rRT-PCR was 6 days (range, 1-13) and 5 days (range, 1-7) by culture. Following fever resolution virus was isolated for a median of 2 days (range, 0-5). Highest and lowest virus titers detected, 2 and 5 days following fever onset, were 3.2 and 1.2 log(10) TCID(50)/mL respectively. Overall, shedding duration in children and adults were similar to seasonal influenza viruses.

An outbreak of 2009 pandemic influenza A (H1N1) virus infection in an elementary school in Pennsylvania.

In May 2009, one of the earliest outbreaks of 2009 pandemic influenza A virus (pH1N1) infection resulted in the closure of a semi-rural Pennsylvania elementary school. Two sequential telephone surveys were administered to 1345 students (85% of the students enrolled in the school) and household members in 313 households to collect data on influenza-like illness (ILI). A total of 167 persons (12.4%) among those in the surveyed households, including 93 (24.0%) of the School A students, reported ILI. Students were 3.1 times more likely than were other household members to develop ILI (95% confidence interval [CI], 2.3-4.1). Fourth-grade students were more likely to be affected than were students in other grades (relative risk, 2.2; 95% CI, 1.2-3.9). pH1N1 was confirmed in 26 (72.2%) of the individuals tested by real-time reverse-transcriptase polymerase chain reaction. The outbreak did not resume upon the reopening of the school after the 7-day closure. This investigation found that pH1N1 outbreaks at schools can have substantial attack rates; however, grades and classrooms are affected variably. Additional study is warranted to determine the effectiveness of school closure during outbreaks.

Description and evaluation of the 2009-2010 Pennsylvania Influenza Sentinel School Monitoring System.

OBJECTIVES: We described and evaluated the 2009-2010 Pennsylvania Influenza Sentinel School Monitoring System, a voluntary sentinel network of schools that report data on school absenteeism and visits to the school nurse for influenza-like illness (ILI). METHODS: Participating schools provided daily absenteeism and ILI data on a weekly basis through an online survey. We used participation and weekly response rates to determine acceptability, timeliness, and simplicity. We assessed representativeness by comparing participating schools with nonparticipating schools. We compared monitoring system data with statewide reports of laboratory-confirmed influenza. RESULTS: Of the 3244 Pennsylvania public schools, 367 (11%) enrolled in the system. On average, 79% of enrolled schools completed the survey each week. Although the peak week of elevated absenteeism coincided with the peak of statewide laboratory-confirmed influenza cases, the correlation between absenteeism and state data was nonsignificant (correlation coefficient = 0.10; P = .56). Trends in ILI correlated significantly with state data (correlation coefficient = 0.67; P < .001). CONCLUSIONS: The school-based sentinel system is a simple, acceptable, reliable device for tracking absenteeism and ILI in schools. Further analyses are necessary to determine the comparative value of this system and other influenza surveillance systems.

Capacity of public health surveillance to comply with revised international health regulations, USA.

Public health surveillance is essential for detecting and responding to infectious diseases and necessary for compliance with the revised International Health Regulations (IHR) 2005. To assess reporting capacities and compliance with IHR of all 50 states and Washington, DC, we sent a questionnaire to respective epidemiologists; 47 of 51 responded. Overall reporting capacity was high. Eighty-one percent of respondents reported being able to transmit notifications about unknown or unexpected events to the Centers for Disease Control and Prevention (CDC) daily. Additionally, 80% of respondents reported use of a risk assessment tool to determine whether CDC should be notified of possible public health emergencies. These findings suggest that most states have systems in place to ensure compliance with IHR. However, full state-level compliance will require additional efforts.

Household effects of school closure during pandemic (H1N1) 2009, Pennsylvania, USA.

To determine the effects of school closure, we surveyed 214 households after a 1-week elementary school closure because of pandemic (H1N1) 2009. Students spent 77% of the closure days at home, 69% of students visited at least 1 other location, and 79% of households reported that adults missed no days of work to watch children.

Myopericarditis following smallpox vaccination among vaccinia-naive US military personnel.

CONTEXT: In the United States, the annual incidence of myocarditis is estimated at 1 to 10 per 100,000 population. As many as 1% to 5% of patients with acute viral infections involve the myocardium. Although many viruses have been reported to cause myopericarditis, it has been a rare or unrecognized event after vaccination with the currently used strain of vaccinia virus (New York City Board of Health). OBJECTIVE: To describe a series of probable cases of myopericarditis following smallpox vaccination among US military service members reported since the reintroduction of vaccinia vaccine. DESIGN, SETTING, PARTICIPANTS: Surveillance case definitions are presented. The cases were identified either through sentinel reporting to US military headquarters surveillance using the Defense Medical Surveillance System or reports to the Vaccine Adverse Event Reporting System using International Classification of Diseases, Ninth Revision. The cases occurred among individuals vaccinated from mid-December 2002 to March 14, 2003. MAIN OUTCOME MEASURE: Elevated serum levels of creatine kinase (MB isoenzyme), troponin I, and troponin T, usually in the presence of ST-segment elevation on electrocardiogram and wall motion abnormalities on echocardiogram. RESULTS: Among 230,734 primary vaccinees, 18 cases of probable myopericarditis after smallpox vaccination were reported (an incidence of 7.8 per 100,000 over 30 days). No cases of myopericarditis following smallpox vaccination were reported among 95,622 vaccinees who were previously vaccinated. All cases were white men aged 21 years to 33 years (mean age, 26.5 years), who presented with acute myopericarditis 7 to 19 days following vaccination. A causal relationship is supported by the close temporal clustering (7-19 days; mean, 10.5 days following vaccination), wide geographic and temporal distribution, occurrence in only primary vaccinees, and lack of evidence for alternative etiologies or other diseases associated with myopericarditis. Additional supporting evidence is the observation that the observed rate of myopericarditis among primary vaccinees is 3.6-fold (95% confidence interval, 3.33-4.11) higher than the expected rate among personnel who were not vaccinated. The background incidence of myopericarditis did not show statistical significance when stratified by age (20-34 years: 2.18 expected cases per 100,000; 95% confidence interval [CI], 1.90-2.34), race (whites: 1.82 per 100,000; 95% CI, 1.50-2.01), and sex (males: 2.28 per 100,000; 95% CI, 2.04-2.54). CONCLUSION: Among US military personnel vaccinated against smallpox, myopericarditis occurred at a rate of 1 per 12 819 primary vaccinees. Myopericarditis should be considered an expected adverse event associated with smallpox vaccination. Clinicians should consider myopericarditis in the differential diagnosis of patients presenting with chest pain 4 to 30 days following smallpox vaccination and be aware of the implications as well as the need to report this potential adverse advent.