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1.  Origin and Proliferation of Multiple-Drug Resistance in Bacterial Pathogens 
Many studies report the high prevalence of multiply drug-resistant (MDR) strains. Because MDR infections are often significantly harder and more expensive to treat, they represent a growing public health threat. However, for different pathogens, different underlying mechanisms are traditionally used to explain these observations, and it is unclear whether each bacterial taxon has its own mechanism(s) for multidrug resistance or whether there are common mechanisms between distantly related pathogens. In this review, we provide a systematic overview of the causes of the excess of MDR infections and define testable predictions made by each hypothetical mechanism, including experimental, epidemiological, population genomic, and other tests of these hypotheses. Better understanding the cause(s) of the excess of MDR is the first step to rational design of more effective interventions to prevent the origin and/or proliferation of MDR.
PMCID: PMC4402963  PMID: 25652543
2.  Identifying the effect of patient sharing on between-hospital genetic differentiation of methicillin-resistant Staphylococcus aureus 
Genome Medicine  2016;8:18.
Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most common healthcare-associated pathogens. To examine the role of inter-hospital patient sharing on MRSA transmission, a previous study collected 2,214 samples from 30 hospitals in Orange County, California and showed by spa typing that genetic differentiation decreased significantly with increased patient sharing. In the current study, we focused on the 986 samples with spa type t008 from the same population.
We used genome sequencing to determine the effect of patient sharing on genetic differentiation between hospitals. Genetic differentiation was measured by between-hospital genetic diversity, FST, and the proportion of nearly identical isolates between hospitals.
Surprisingly, we found very similar genetic diversity within and between hospitals, and no significant association between patient sharing and genetic differentiation measured by FST. However, in contrast to FST, there was a significant association between patient sharing and the proportion of nearly identical isolates between hospitals. We propose that the proportion of nearly identical isolates is more powerful at determining transmission dynamics than traditional estimators of genetic differentiation (FST) when gene flow between populations is high, since it is more responsive to recent transmission events. Our hypothesis was supported by the results from coalescent simulations.
Our results suggested that there was a high level of gene flow between hospitals facilitated by patient sharing, and that the proportion of nearly identical isolates is more sensitive to population structure than FST when gene flow is high.
Electronic supplementary material
The online version of this article (doi:10.1186/s13073-016-0274-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4752745  PMID: 26873713
Genetic differentiation; Patient sharing; Gene flow; Transmission; Staphylococcus aureus
3.  Population genomic datasets describing the post-vaccine evolutionary epidemiology of Streptococcus pneumoniae  
Scientific Data  2015;2:150058.
Streptococcus pneumoniae is common nasopharyngeal commensal bacterium and important human pathogen. Vaccines against a subset of pneumococcal antigenic diversity have reduced rates of disease, without changing the frequency of asymptomatic carriage, through altering the bacterial population structure. These changes can be studied in detail through using genome sequencing to characterise systematically-sampled collections of carried S. pneumoniae. This dataset consists of 616 annotated draft genomes of isolates collected from children during routine visits to primary care physicians in Massachusetts between 2001, shortly after the seven valent polysaccharide conjugate vaccine was introduced, and 2007. Also made available are a core genome alignment and phylogeny describing the overall population structure, clusters of orthologous protein sequences, software for inferring serotype from Illumina reads, and whole genome alignments for the analysis of closely-related sets of pneumococci. These data can be used to study both bacterial evolution and the epidemiology of a pathogen population under selection from vaccine-induced immunity.
PMCID: PMC4622223  PMID: 26528397
Bacterial genetics; Molecular evolution; Genetic variation; Respiratory tract diseases
5.  Effect of Serotype on Pneumococcal Competition in a Mouse Colonization Model 
mBio  2015;6(5):e00902-15.
Competitive interactions between Streptococcus pneumoniae strains during host colonization could influence the serotype distribution in nasopharyngeal carriage and pneumococcal disease. We evaluated the competitive fitness of strains of serotypes 6B, 14, 19A, 19F, 23F, and 35B in a mouse model of multiserotype carriage. Isogenic variants were constructed using clinical strains as the capsule gene donors. Animals were intranasally inoculated with a mixture of up to six pneumococcal strains of different serotypes, with separate experiments involving either clinical isolates or isogenic capsule-switch variants of clinical strain TIGR4. Upper-respiratory-tract samples were repeatedly collected from animals in order to monitor changes in the serotype ratios using quantitative PCR. A reproducible hierarchy of capsular types developed in the airways of mice inoculated with multiple strains. Serotype ranks in this hierarchy were similar among pneumococcal strains of different genetic backgrounds in different strains of mice and were not altered when tested under a range of host conditions. This rank correlated with the measure of the metabolic cost of capsule synthesis and in vitro measure of pneumococcal cell surface charge, both parameters considered to be predictors of serotype-specific fitness in carriage. This study demonstrates the presence of a robust competitive hierarchy of pneumococcal serotypes in vivo that is driven mainly, but not exclusively, by the capsule itself.
Streptococcus pneumoniae (pneumococcus) is the leading cause of death due to respiratory bacterial infections but also a commensal frequently carried in upper airways. Available vaccines induce immune responses against polysaccharides coating pneumococcal cells, but with over 90 different capsular types (serotypes) identified, they can only target strains of the selected few serotypes most prevalent in disease. Vaccines not only protect vaccinated individuals against disease but also protect by reducing carriage of vaccine-targeted strains to induce herd effects across whole populations. Unfortunately, reduction in the circulation of vaccine-type strains is offset by increase in carriage and disease from nonvaccine strains, indicating the importance of competitive interactions between pneumococci in shaping the population structure of this pathogen. Here, we showed that the competitive ability of pneumococcal strains to colonize the host strongly depends on the type of capsular polysaccharide expressed by pneumococci and only to a lesser degree on strain or host genetic backgrounds or on variation in host immune responses.
PMCID: PMC4600102  PMID: 26374118
6.  Estimating the hospitalization burden associated with influenza and respiratory syncytial virus in New York City, 2003–2011 
Hospitalization burden associated with influenza and respiratory syncytial virus (RSV) is uncertain due to ambiguity in the inference methodologies employed for its estimation.
Utilization of a new method to quantitate the above burden.
Weekly hospitalization rates for several principal diagnoses from 2003 to 2011 in New York City by age group were regressed linearly against incidence proxies for the major influenza subtypes and RSV adjusting for temporal trends and seasonal baselines.
Average annual rates of influenza-associated respiratory hospitalizations per 100 000 were estimated to be 129 [95% CI (79, 179)] for age <1, 36·3 (21·6, 51·4) for ages 1–4, 10·6 (7·5, 13·7) for ages 5–17, 25·6 (21·3, 29·8) for ages 18–49, 65·5 (54·0, 76·9) for ages 50–64, 125 (105, 147) for ages 65–74, and 288 (244, 331) for ages ≥75. Additionally, influenza had a significant contribution to hospitalization rates with a principal diagnosis of septicemia for ages 5–17 [0·76 (0·1, 1·4)], 18–49 [1·02 (0·3, 1·7)], 50–64 [4·0 (1·7, 6·3)], 65–74 [8·8 (2·2, 15·6)], and ≥75 [38·7 (25·7, 52·9)]. RSV had a significant contribution to the rates of respiratory hospitalizations for age <1 [1900 (1740, 2060)], ages 1–4 [117 (70, 167)], and ≥75 [175 (44, 312)] [including chronic lower respiratory disease, 90 (43, 140)] as well as pneumonia & influenza hospitalizations for ages 18–49 [6·2 (1·1, 11·3)] and circulatory hospitalizations for ages ≥75 [199 (13, 375)].
The high burden of RSV hospitalizations among young children and seniors age ≥75 suggests the need for additional control measures such as vaccination to mitigate the impact of annual RSV epidemics. Our estimates for influenza-associated hospitalizations provide further evidence of the burden of morbidity associated with influenza, supporting current guidelines regarding influenza vaccination and antiviral treatment.
PMCID: PMC4548992  PMID: 25980600
Hospitalization; influenza; New York City; respiratory syncytial virus
7.  STAMP: Sequence tag-based analysis of microbial population dynamics 
Nature methods  2015;12(3):223-226.
We describe a new method (STAMP) for characterization of pathogen population dynamics during infection. STAMP analyzes the frequency changes of genetically “barcoded” organisms to quantify population bottlenecks and infer the founding population size. Analyses of intra-intestinal Vibrio cholerae revealed infection-stage and region-specific host barriers to infection, and unexpectedly showed V. cholerae migration counter to intestinal flow. STAMP provides a robust, widely applicable analytical framework for high confidence characterization of in vivo microbial dissemination.
PMCID: PMC4344388  PMID: 25599549
8.  Examining the role of different age groups, and of vaccination during the 2012 Minnesota pertussis outbreak 
Scientific Reports  2015;5:13182.
There is limited information on the roles of different age groups during pertussis outbreaks. Little is known about vaccine effectiveness against pertussis infection (both clinically apparent and subclinical), which is different from effectiveness against reportable pertussis disease, with the former influencing the impact of vaccination on pertussis transmission in the community. For the 2012 pertussis outbreak in Minnesota, we estimated odds ratios for case counts in pairs of population groups before vs. after the epidemic’s peak. We found children aged 11–12y, 13–14y and 8–10y experienced the greatest rates of depletion of susceptible individuals during the outbreak’s ascent, with all ORs for each of those age groups vs. groups outside this age range significantly above 1, with the highest ORs for ages 11–12y. Receipt of the fifth dose of DTaP was associated with a decreased relative role during the outbreak’s ascent compared to non-receipt [OR 0.16 (0.01, 0.84) for children aged 5, 0.13 (0.003, 0.82) for ages 8–10y, indicating a protective effect of DTaP against pertussis infection. No analogous effect of Tdap was detected. Our results suggest that children aged 8–14y played a key role in propagating this outbreak. The impact of immunization with Tdap on pertussis infection requires further investigation.
PMCID: PMC4538373  PMID: 26278132
9.  Potential Biases in Estimating Absolute and Relative Case-Fatality Risks during Outbreaks 
PLoS Neglected Tropical Diseases  2015;9(7):e0003846.
Estimating the case-fatality risk (CFR)—the probability that a person dies from an infection given that they are a case—is a high priority in epidemiologic investigation of newly emerging infectious diseases and sometimes in new outbreaks of known infectious diseases. The data available to estimate the overall CFR are often gathered for other purposes (e.g., surveillance) in challenging circumstances. We describe two forms of bias that may affect the estimation of the overall CFR—preferential ascertainment of severe cases and bias from reporting delays—and review solutions that have been proposed and implemented in past epidemics. Also of interest is the estimation of the causal impact of specific interventions (e.g., hospitalization, or hospitalization at a particular hospital) on survival, which can be estimated as a relative CFR for two or more groups. When observational data are used for this purpose, three more sources of bias may arise: confounding, survivorship bias, and selection due to preferential inclusion in surveillance datasets of those who are hospitalized and/or die. We illustrate these biases and caution against causal interpretation of differential CFR among those receiving different interventions in observational datasets. Again, we discuss ways to reduce these biases, particularly by estimating outcomes in smaller but more systematically defined cohorts ascertained before the onset of symptoms, such as those identified by forward contact tracing. Finally, we discuss the circumstances in which these biases may affect non-causal interpretation of risk factors for death among cases.
PMCID: PMC4504518  PMID: 26181387
10.  How could preventive therapy affect the prevalence of drug resistance? Causes and consequences 
Various forms of preventive and prophylactic antimicrobial therapies have been proposed to combat HIV (e.g. pre-exposure prophylaxis), tuberculosis (e.g. isoniazid preventive therapy) and malaria (e.g. intermittent preventive treatment). However, the potential population-level effects of preventative therapy (PT) on the prevalence of drug resistance are not well understood. PT can directly affect the rate at which resistance is acquired among those receiving PT. It can also indirectly affect resistance by altering the rate at which resistance is acquired through treatment for active disease and by modifying the level of competition between transmission of drug-resistant and drug-sensitive pathogens. We propose a general mathematical model to explore the ways in which PT can affect the long-term prevalence of drug resistance. Depending on the relative contributions of these three mechanisms, we find that increasing the level of coverage of PT may result in increases, decreases or non-monotonic changes in the overall prevalence of drug resistance. These results demonstrate the complexity of the relationship between PT and drug resistance in the population. Care should be taken when predicting population-level changes in drug resistance from small pilot studies of PT or estimates based solely on its direct effects.
PMCID: PMC4424438  PMID: 25918446
prophylaxis; preventive; mathematical model; antibiotic resistance; indirect effects; competition
11.  Carriage burden, multiple colonization and antibiotic pressure promote emergence of resistant vaccine escape pneumococci 
Pneumococcal conjugate vaccines target the limited subset of the more than 90 known serotypes of Streptococcus pneumoniae responsible for the greatest burden of pneumococcal disease and antibiotic resistance. Following the introduction of these vaccines, serotypes not targeted were able to expand and resistance became more common within these types. Here we use a stochastic dynamic model of pediatric pneumococcal carriage to evaluate potential influences on the emergence of new resistant lineages following the introduction of a vaccine targeting more common resistant types. Antibiotic pressure was the strongest driver, with no emergence at low levels and universal emergence at high levels. At intermediate levels of antibiotic pressure, higher carriage burden and a greater degree of dual carriage promoted emergence. This may have implications for current plans to introduce childhood pneumococcal vaccination in several high-burden countries.
PMCID: PMC4424439  PMID: 25918447
Streptococcus pneumoniae; vaccination; emergence; model; resistance
12.  Utilizing Syndromic Surveillance Data for Estimating Levels of Influenza Circulation 
American Journal of Epidemiology  2014;179(11):1394-1401.
The availability of weekly Web-based participatory surveillance data on self-reported influenza-like illness (ILI), defined here as self-reported fever and cough/sore throat, over several influenza seasons allows for estimation of the incidence of influenza infection in population cohorts. We demonstrate this using syndromic data reported through the Influenzanet surveillance platform in the Netherlands. We used the 2011–2012 influenza season, a low-incidence season that began late, to assess the baseline rates of self-reported ILI during periods of low influenza circulation, and we used ILI rates above that baseline level from the 2012–1013 season, a major influenza season, to estimate influenza attack rates for that period. The latter conversion required estimates of age-specific probabilities of self-reported ILI given influenza (Flu) infection (P(ILI | Flu)), which were obtained from separate data (extracted from Hong Kong, China, household studies). For the 2012–2013 influenza season in the Netherlands, we estimated combined influenza A/B attack rates of 29.2% (95% credible interval (CI): 21.6, 37.9) among survey participants aged 20–49 years, 28.3% (95% CI: 20.7, 36.8) among participants aged 50–60 years, and 5.9% (95% CI: 0.4, 11.8) among participants aged ≥61 years. Estimates of influenza attack rates can be obtained in other settings using analogous, multiseason surveillance data on self-reported ILI together with separate, context-specific estimates of P(ILI | Flu).
PMCID: PMC4036214  PMID: 24748609
attack rate; influenza; influenza-like illness; participatory surveillance
13.  Identification of pneumococcal colonization determinants in the stringent response pathway facilitated by genomic diversity 
BMC Genomics  2015;16(1):369.
Understanding genetic determinants of a microbial phenotype generally involves creating and comparing isogenic strains differing at the locus of interest, but the naturally existing genomic and phenotypic diversity of microbial populations has rarely been exploited. Here we report use of a diverse collection of 616 carriage isolates of Streptococcus pneumoniae and their genome sequences to help identify a novel determinant of pneumococcal colonization.
A spontaneously arising laboratory variant (SpnYL101) of a capsule-switched TIGR4 strain (TIGR4:19F) showed reduced ability to establish mouse nasal colonization and lower resistance to non-opsonic neutrophil-mediated killing in vitro, a phenotype correlated with in vivo success. Whole genome sequencing revealed 5 single nucleotide polymorphisms (SNPs) affecting 4 genes in SpnYL101 relative to its ancestor. To evaluate the effect of variation in each gene, we performed an in silico screen of 616 previously published genome sequences to identify pairs of closely-related, serotype-matched isolates that differ at the gene of interest, and compared their resistance to neutrophil-killing. This method allowed rapid examination of multiple candidate genes and found phenotypic differences apparently associated with variation in SP_1645, a RelA/ SpoT homolog (RSH) involved in the stringent response. To establish causality, the alleles corresponding to SP_1645 were switched between the TIGR4:19F and SpnYL101. The wild-type SP_1645 conferred higher resistance to neutrophil-killing and competitiveness in mouse colonization. Using a similar strategy, variation in another RSH gene (TIGR4 locus tag SP_1097) was found to alter resistance to neutrophil-killing.
These results indicate that analysis of naturally existing genomic diversity complements traditional genetics approaches to accelerate genotype-phenotype analysis.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1573-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4424882  PMID: 25956132
Genomic diversity; Pneumococcal colonization; RelA/ SpoT homolog
14.  In Vitro Selection of Neisseria gonorrhoeae Mutants with Elevated MIC Values and Increased Resistance to Cephalosporins 
Antimicrobial Agents and Chemotherapy  2014;58(11):6986-6989.
Strains of Neisseria gonorrhoeae with mosaic penA genes bearing novel point mutations in penA have been isolated from ceftriaxone treatment failures. Such isolates exhibit significantly higher MIC values to third-generation cephalosporins. Here we report the in vitro isolation of two mutants with elevated MICs to cephalosporins. The first possesses a point mutation in the transpeptidase region of the mosaic penA gene, and the second contains an insertion mutation in pilQ.
PMCID: PMC4249396  PMID: 25199775
15.  Selective and Genetic Constraints on Pneumococcal Serotype Switching 
PLoS Genetics  2015;11(3):e1005095.
Streptococcus pneumoniae isolates typically express one of over 90 immunologically distinguishable polysaccharide capsules (serotypes), which can be classified into “serogroups” based on cross-reactivity with certain antibodies. Pneumococci can alter their serotype through recombinations affecting the capsule polysaccharide synthesis (cps) locus. Twenty such “serotype switching” events were fully characterised using a collection of 616 whole genome sequences from systematic surveys of pneumococcal carriage. Eleven of these were within-serogroup switches, representing a highly significant (p < 0.0001) enrichment based on the observed serotype distribution. Whereas the recombinations resulting in between-serogroup switches all spanned the entire cps locus, some of those that caused within-serogroup switches did not. However, higher rates of within-serogroup switching could not be fully explained by either more frequent, shorter recombinations, nor by genetic linkage to genes involved in β–lactam resistance. This suggested the observed pattern was a consequence of selection for preserving serogroup. Phenotyping of strains constructed to express different serotypes in common genetic backgrounds was used to test whether genotypes were physiologically adapted to particular serogroups. These data were consistent with epistatic interactions between the cps locus and the rest of the genome that were specific to serotype, but not serogroup, meaning they were unlikely to account for the observed distribution of capsule types. Exclusion of these genetic and physiological hypotheses suggested future work should focus on alternative mechanisms, such as host immunity spanning multiple serotypes within the same serogroup, which might explain the observed pattern.
Author Summary
Streptococcus pneumoniae is a major respiratory pathogen responsible for a high burden of morbidity and mortality worldwide. Current anti-pneumococcal vaccines target the bacterium’s polysaccharide capsule, of which at least 95 different variants (‘serotypes’) are known, which are classified into ‘serogroups’. Bacteria can change their serotype through genetic recombination, termed ‘switching’, which can allow strains to evade vaccine-induced immunity. By combining epidemiological data with whole genome sequencing, this work finds a robust and unexpected pattern of serotype switching in a sample of bacteria collected following the introduction of routine anti-pneumococcal vaccination: switching was much more likely to exchange one serotype for another within the same serogroup than expected by chance. Several hypotheses are presented and tested to explain this pattern, including limitations of genetic recombination, interactions between the genes that determine serotype and the rest of the genome, and the constraints imposed by bacterial metabolism. This provides novel information on the evolution of S. pneumoniae, particularly regarding how the bacterium might diversify as newer vaccines are introduced.
PMCID: PMC4380333  PMID: 25826208
16.  The US 2009 A/H1N1 influenza epidemic: Quantifying the impact of school openings on the reproductive number 
Epidemiology (Cambridge, Mass.)  2014;25(2):203-206.
There is limited information on differences in the dynamics of influenza transmission during time periods when schools are open compared with periods when they are closed.
Data on school openings, influenza surveillance, and absolute humidity were incorporated into a regression model to estimate the increase in the reproductive number for the 2009 A(H1N1) influenza pandemic associated with the opening of school in 10 US states.
The estimate for the average increase in the reproductive number for the 2009 A(H1N1) influenza pandemic associated with the beginning of the school year was 19.5% (95% credible interval (10% to 29%)).
Whether schools are open or closed can have a major impact on community transmission dynamics of influenza.
PMCID: PMC3960948  PMID: 24434751
17.  Antibiotics in agriculture and the risk to human health: how worried should we be? 
Evolutionary Applications  2014;8(3):240-247.
The use of antibiotics in agriculture is routinely described as a major contributor to the clinical problem of resistant disease in human medicine. While a link is plausible, there are no data conclusively showing the magnitude of the threat emerging from agriculture. Here, we define the potential mechanisms by which agricultural antibiotic use could lead to human disease and use case studies to critically assess the potential risk from each. The three mechanisms considered are as follows 1: direct infection with resistant bacteria from an animal source, 2: breaches in the species barrier followed by sustained transmission in humans of resistant strains arising in livestock, and 3: transfer of resistance genes from agriculture into human pathogens. Of these, mechanism 1 is the most readily estimated, while significant is small in comparison with the overall burden of resistant disease. Several cases of mechanism 2 are known, and we discuss the likely livestock origins of resistant clones of Staphylococcus aureus and Enterococcus faecium, but while it is easy to show relatedness the direction of transmission is hard to assess in robust fashion. More difficult yet to study is the contribution of mechanism 3, which may be the most important of all.
PMCID: PMC4380918  PMID: 25861382
agriculture; antibiotic resistance; Enterococcus; food; resistance transfer; Staphylococcus aureus
18.  Stability of the pneumococcal population structure in Massachusetts as PCV13 was introduced 
The success of 7-valent pneumococcal conjugate vaccination (PCV-7) introduced to the US childhood immunization schedule in 2000 was partially offset by increases in invasive pneumococcal disease (IPD) and pneumococcal carriage due to non-vaccine serotypes, in particular 19A, in the years that followed. A 13-valent conjugate vaccine (PCV-13) was introduced in 2010. As part of an ongoing study of the response of the Massachusetts pneumococcal population to conjugate vaccination, we report the findings from the samples collected in 2011, as PCV-13 was introduced.
We used multilocus sequence typing (MLST) to analyze 367 pneumococcal isolates carried by Massachusetts children (aged 3 months-7 years) collected during the winter of 2010–11 and used eBURST software to compare the pneumococcal population structure with that found in previous years.
One hundred and four distinct sequence types (STs) were found, including 24 that had not been previously recorded. Comparison with a similar sample collected in 2009 revealed no significant overall difference in the ST composition (p = 0.39, classification index). However, we describe clonal dynamics within the important replacement serotypes 19A, 15B/C, and 6C, and clonal expansion of ST 433 and ST 432, which are respectively serotype 22F and 21 clones.
While little overall change in serotypes or STs was evident, multiple changes in the frequency of individual STs and or serotypes may plausibly be ascribed to the introduction of PCV-13. This 2011 sample documents the initial impact of PCV-13 and will be important for comparison with future studies of the evolution of the pneumococcal population in Massachusetts.
Electronic supplementary material
The online version of this article (doi:10.1186/s12879-015-0797-z) contains supplementary material, which is available to authorized users.
PMCID: PMC4336693  PMID: 25887323
Pneumococcal conjugate vaccine; Streptococcus pneumoniae; Colonization; Molecular epidemiology; MLST
21.  Age- and Sex-related Risk Factors for Influenza-associated Mortality in the United States Between 1997–2007 
American Journal of Epidemiology  2013;179(2):156-167.
Limited information on age- and sex-specific estimates of influenza-associated death with different underlying causes is currently available. We regressed weekly age- and sex-specific US mortality outcomes underlying several causes between 1997 and 2007 to incidence proxies for influenza A/H3N2, A/H1N1, and B that combine data on influenzalike illness consultations and respiratory specimen testing, adjusting for seasonal baselines and time trends. Adults older than 75 years of age had the highest average annual rate of influenza-associated mortality, with 141.15 deaths per 100,000 people (95% confidence interval (CI): 118.3, 163.9), whereas children under 18 had the lowest average mortality rate, with 0.41 deaths per 100,000 people (95% CI: 0.23, 0.60). In addition to respiratory and circulatory causes, mortality with underlying cancer, diabetes, renal disease, and Alzheimer disease had a contribution from influenza in adult age groups, whereas mortality with underlying septicemia had a contribution from influenza in children. For adults, within several age groups and for several underlying causes, the rate of influenza-associated mortality was somewhat higher in men than in women. Of note, in men 50–64 years of age, our estimate for the average annual rate of influenza-associated cancer mortality per 100,000 persons (1.90, 95% CI: 1.20, 2.62) is similar to the corresponding rate of influenza-associated respiratory deaths (1.81, 95% CI: 1.42, 2.21). Age, sex, and underlying health conditions should be considered when planning influenza vaccination and treatment strategies.
PMCID: PMC3873104  PMID: 24190951
age; influenza; mortality; sex; underlying cause
22.  Within-Host Whole-Genome Deep Sequencing and Diversity Analysis of Human Respiratory Syncytial Virus Infection Reveals Dynamics of Genomic Diversity in the Absence and Presence of Immune Pressure 
Journal of Virology  2014;88(13):7286-7293.
Human respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract disease in infants and young children and an important respiratory pathogen in the elderly and immunocompromised. While population-wide molecular epidemiology studies have shown multiple cocirculating RSV genotypes and revealed antigenic and genetic change over successive seasons, little is known about the extent of viral diversity over the course of an individual infection, the origins of novel variants, or the effect of immune pressure on viral diversity and potential immune-escape mutations. To investigate viral population diversity in the presence and absence of selective immune pressures, we studied whole-genome deep sequencing of RSV in upper airway samples from an infant with severe combined immune deficiency syndrome and persistent RSV infection. The infection continued over several months before and after bone marrow transplant (BMT) from his RSV-immune father. RSV diversity was characterized in 26 samples obtained over 78 days. Diversity increased after engraftment, as defined by T-cell presence, and populations reflected variation mostly within the G protein, the major surface antigen. Minority populations with known palivizumab resistance mutations emerged after its administration. The viral population appeared to diversify in response to selective pressures, showing a statistically significant growth in diversity in the presence of pressure from immunity. Defining escape mutations and their dynamics will be useful in the design and application of novel therapeutics and vaccines. These data can contribute to future studies of the relationship between within-host and population-wide RSV phylodynamics.
IMPORTANCE Human RSV is an important cause of respiratory disease in infants, the elderly, and the immunocompromised. RSV circulating in a community appears to change season by season, but the amount of diversity generated during an individual infection and the impact of immunity on this viral diversity has been unclear. To address this question, we described within-host RSV diversity by whole-genome deep sequencing in a unique clinical case of an RSV-infected infant with severe combined immunodeficiency and effectively no adaptive immunity who then gained adaptive immunity after undergoing bone marrow transplantation. We found that viral diversity increased in the presence of adaptive immunity and was primarily within the G protein, the major surface antigen. These data will be useful in designing RSV treatments and vaccines and to help understand the relationship between the dynamics of viral diversification within individual hosts and the viral populations circulating in a community.
PMCID: PMC4054443  PMID: 24741088
23.  Estimating the per-exposure effect of infectious disease interventions 
Epidemiology (Cambridge, Mass.)  2014;25(1):134-138.
The average effect of an infectious disease intervention (e.g., a vaccine) varies across populations with different degrees of exposure to the pathogen. As a result, many investigators favor a per-exposure effect measure that is considered independent of the population level of exposure and that can be used in simulations to estimate the total disease burden averted by an intervention across different populations. However, while per-exposure effects are frequently estimated, the quantity of interest is often poorly defined, and assumptions in its calculation are typically left implicit. In this paper, we build upon work by Halloran and Struchiner (Epidemiology. 1995; 6:172-151) to develop a formal definition of the per-exposure effect and discuss conditions necessary for its unbiased estimation. With greater care paid to the parameterization of transmission models, their results can be better understood and can thereby be of greater value to decision-makers.
PMCID: PMC3898464  PMID: 24240656
24.  Moratorium on Research Intended To Create Novel Potential Pandemic Pathogens 
mBio  2014;5(6):e02366-14.
PMCID: PMC4271556  PMID: 25505122
25.  Epidemiologic data and pathogen genome sequences: a powerful synergy for public health 
Genome Biology  2014;15(11):538.
Epidemiologists aim to inform the design of public health interventions with evidence on the evolution, emergence and spread of infectious diseases. Sequencing of pathogen genomes, together with date, location, clinical manifestation and other relevant data about sample origins, can contribute to describing nearly every aspect of transmission dynamics, including local transmission and global spread. The analyses of these data have implications for all levels of clinical and public health practice, from institutional infection control to policies for surveillance, prevention and treatment. This review highlights the range of epidemiological questions that can be addressed from the combination of genome sequence and traditional ‘line lists’ (tables of epidemiological data where each line includes demographic and clinical features of infected individuals). We identify opportunities for these data to inform interventions that reduce disease incidence and prevalence. By considering current limitations of, and challenges to, interpreting these data, we aim to outline a research agenda to accelerate the genomics-driven transformation in public health microbiology.
PMCID: PMC4282151  PMID: 25418119

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