Papers by Jeffrey Townsend
PNAS Nexus
Quarantine and serial testing strategies for a disease depend principally on its incubation perio... more Quarantine and serial testing strategies for a disease depend principally on its incubation period and infectiousness profile. In the context of COVID-19, these primary public health tools must be modulated with successive SARS CoV-2 variants of concern that dominate transmission. Our analysis shows that (1) vaccination status of an individual makes little difference to the determination of the appropriate quarantine duration of an infected case, whereas vaccination coverage of the population can have a substantial effect on this duration, (2) successive variants can challenge disease control efforts by their earlier and increased transmission in the disease time course relative to prior variants, and (3) sufficient vaccine boosting of a population substantially aids the suppression of local transmission through frequent serial testing. For instance, with Omicron, increasing immunity through vaccination and boosters—for instance with 100% of the population is fully immunized and at ...
Communications Medicine
Background Rapid antigen (RA) tests are being increasingly employed to detect SARS-CoV-2 infectio... more Background Rapid antigen (RA) tests are being increasingly employed to detect SARS-CoV-2 infections in quarantine and surveillance. Prior research has focused on RT-PCR testing, a single RA test, or generic diagnostic characteristics of RA tests in assessing testing strategies. Methods We have conducted a comparative analysis of the post-quarantine transmission, the effective reproduction number during serial testing, and the false-positive rates for 18 RA tests with emergency use authorization from The United States Food and Drug Administration and an RT-PCR test. To quantify the extent of transmission, we developed an analytical mathematical framework informed by COVID-19 infectiousness, test specificity, and temporal diagnostic sensitivity data. Results We demonstrate that the relative effectiveness of RA tests and RT-PCR testing in reducing post-quarantine transmission depends on the quarantine duration and the turnaround time of testing results. For quarantines of two days or s...
Frontiers in cellular and infection microbiology, 2018
Leptospirosis is an emerging zoonotic disease with more than 1 million cases annually. Currently ... more Leptospirosis is an emerging zoonotic disease with more than 1 million cases annually. Currently there is lack of evidence for signaling pathways involved during the infection process of . In our comprehensive genomic analysis of 20 spp. we identified seven pathogen-specific Two-Component System (TCS) proteins. Disruption of two these TCS genes in pathogenic strain resulted in loss-of-virulence in a hamster model of leptospirosis. Corresponding genes and ) are juxtaposed in an operon and are predicted to encode a hybrid histidine kinase and a hybrid response regulator, respectively. Transcriptome analysis of mutant strains with disruption of one () or both genes () revealed global transcriptional regulation of 850 differentially expressed genes. Phosphotransfer assays demonstrated that LvrA phosphorylates LvrB and predicted further signaling downstream to one or more DNA-binding response regulators, suggesting that it is a branched pathway. Phylogenetic analyses indicated that and e...
Fungal Biology, 2016
Mycological research, especially research on fungal evolution and ecology, requires a robust and ... more Mycological research, especially research on fungal evolution and ecology, requires a robust and detailed fungal classification and phylogeny to facilitate efficient and informative communication among mycologists as well as for comparative biology relevant to the larger bioscience community. The field of fungal systematics has undergone numerous revisions recently, from early morphological classifications to an integrative taxonomy that is increasingly reliant on molecular phylogeny. These revisions have taken place at a range of taxonomic ranks, fueled by advances surmounting two major challenges, namely, adequate and balanced sampling of genetic markers and taxa and reinterpretation of phylogenetic informativeness of numerous morphological and ecological characters. The Assembling the Fungal Tree of Life (AFTOL) projects reflected a corresponding surge of collaborative effort in fungal molecular phylogeny using PCR and Sanger sequencing. Here we review recent progress in fungal systematics after AFTOL, in the post-Sanger age, and discuss the future fungal systematics that is emerging as a result of the extraordinary volume of data being gathered by high-throughput sequencing. We examine how environmental DNA surveys, sequence-based classification, and phylogenomics and phylotranscriptomics can impact fungal systematics and point out that sequenced fungal genomes could significantly improve multi-marker phylogenetic inference at a range of levels of fungal systematics by facilitating application of phylogenetically informative experimental design. We argue that it is time to integrate fungal systematics, genome-enabled mycology, and other dimensions of fungal research within the framework of evolutionary biology.
Frontiers in cellular and infection microbiology, 2018
Leptospirosis is a worldwide zoonosis, responsible for more than 1 million cases and 60,000 death... more Leptospirosis is a worldwide zoonosis, responsible for more than 1 million cases and 60,000 deaths every year. Among the 13 pathogenic species of the genus , serovars belonging to serogroup Icterohaemorrhagiae are considered to be the most virulent strains, and responsible for majority of the reported severe cases. Serovars Copenhageni and Icterohaemorrhagiae are major representatives of this serogroup and despite their public health relevance, little is known regarding the genetic differences between these two serovars. In this study, we analyzed the genome sequences of 67 isolates belonging to serovars Copenhageni and Icterohaemorrhagiae to investigate the influence of spatial and temporal variations on DNA sequence diversity. Out of the 1072 SNPs identified, 276 were in non-coding regions and 796 in coding regions. Indel analyses identified 258 indels, out of which 191 were found in coding regions and 67 in non-coding regions. Our phylogenetic analyses based on SNP dataset reveal...
Immunoepidemiology, 2019
Transmission could result from direct contact between hosts, could require host-environment inter... more Transmission could result from direct contact between hosts, could require host-environment interaction, or could be mediated by a vector-often a phlebotomine insect-that transmits a pathogen between different hosts. Transmission can also vary across strata of the host population, as subgroups determined by behavioral, genetic, demographic, environmental, or other characteristics may result in differential exposure or susceptibility to specific diseases. Much of the art and science of modeling rides on critically evaluating which factors are essential to include in order to generate quantitative understanding of a focal research question. Beyond accounting for the change in number of infected individuals over time, it can be important to also incorporate the course of infection during which microbial load, symptom severity, and contact behavior may all vary. Infection progression, or "age of infection," is associated with temporal changes in infectiousness. Microbiological studies that measure the change in pathogen load over the course of an infection are integral to parameterization of dynamic models of disease, particularly evaluating interventions as the timing of intervention during the infection period could impact predicted effectiveness. The behaviors of human hosts, reservoir hosts, and vectors are fundamental to risks of both infection and transmission to others. For nonhuman hosts and vectors, the geographical distribution of habitat, feeding preferences, and proximity to humans affect the rate of transmission. For human hosts, contact patterns, belief systems, attitudes about public health recommendations, and propensity to seek care impact the real-world effectiveness of infection control measures, including quarantining, school closures, handwashing, and vaccination. To some extent, behavioral effects are implicit in the measures of transmission that are used in and estimated by models. However, in many cases it can be more appropriate to treat the transmission rate as a dynamic variable that evolves in concert with behaviors associated with the epidemic. This approach has been increasingly adopted when changes in willingness to accept interventions, in public health policy, or in disease awareness are expected to impact a component (i.e., contact rate, probability of transmission given contact, or frequencies of susceptible and infectious individuals) of overall transmission [2-6].
Model systems to investigate oncogene-driven cancer have played an essential role in the developm... more Model systems to investigate oncogene-driven cancer have played an essential role in the development of therapies for cancer. However, not all systems are appropriate for all therapeutic targets. Knowing where and when proto-oncogenes and their interactors originated in evolutionary history is key to understanding which organisms can serve as models. Here we investigate two tyrosine kinase receptors that underlie tumorigenesis in cancer: anaplastic lymphoma kinase (ALK) and leukocyte tyrosine kinase (LTK). In Drosophila melanogaster, Caenorhabitis elegans, and Homo sapiens, the discovery of putative ligands Jeb, Hen-1, and AUG has the potential to accelerate the development of novel therapeutics. However, homology of these ligands and receptors is unclear. We performed an exhaustive search for their homologs spanning the metazoan tree of life. Jeb and Hen-1 were restricted to species that diverged prior to the origin of all vertebrates. No non-vertebrate species had ligands ortholog...
JNCI: Journal of the National Cancer Institute, 2018
Frontiers in oncology, 2018
HPV infection is associated with high p16 expression and good prognosis in head and neck squamous... more HPV infection is associated with high p16 expression and good prognosis in head and neck squamous cell carcinomas (HNSCCs). Analysis of CDKN2A, the gene encoding p16, may further elucidate the association between p16 expression and prognosis. We sought to determine whether CDKN2A copy number loss was associated with poor survival in HPV-negative HNSCCs. The Cancer Genome Atlas HNSCC clinical and genomic data were obtained and integrated. Patients <80 years old with a primary tumor in the oral cavity, oropharynx, hypopharynx, or larynx were included. Stratifying by copy number loss status, CDKN2A mRNA and p16 protein expression levels were examined and overall survival (OS) and disease-free survival (DFS) were evaluated. 401 patients with HPV-negative HNSCC were identified. 146 patients demonstrated CDKN2A copy number loss. The CDKN2A copy number loss group expressed significantly lower levels of CDKN2A mRNA and p16 protein than did the non-copy number loss group. Median OS for pa...
ABSTRACTSummaryPathScore quantifies the level of enrichment of somatic mutations within curated p... more ABSTRACTSummaryPathScore quantifies the level of enrichment of somatic mutations within curated pathways, applying a novel approach that identifies pathways enriched across patients. The application provides several user-friendly, interactive graphic interfaces for data exploration, including tools for comparing pathway effect sizes, significance, gene-set overlap and enrichment differences between projects.Availability and ImplementationWeb application available at pathscore.publichealth.yale.edu. Site implemented in Python and MySQL, with all major browsers supported. Source code available at github.com/sggaffney/pathscore with a GPLv3 license.Contactstephen.gaffney@yale.eduSupplementary InformationAdditional documentation can be found at http://pathscore.publichealth.yale.edu/faq.
Vaccine, 2016
Cytomegalovirus (CMV) infection is the leading cause of congential cognitive deficit, visual impa... more Cytomegalovirus (CMV) infection is the leading cause of congential cognitive deficit, visual impairment and hearing loss in the US. Clinical trials are underway to evaluate the efficacy of CMV vaccine candidates in seronegative females. The optimal age of such vaccination depends on the interplay among age-specific transmission dynamics, vaccine efficacy and vaccine waning. We developed an age-structured model of CMV transmission dynamics in the US and estimated age-specific transmission rates of CMV based on age-stratified CMV prevalence, congenital infections per birth, breastfeeding patterns and demographic data. We found that the optimal age of vaccination depended on the duration of vaccine protection. For most scenarios, the optimal age of vaccination was between 19 and 21 years of age. However, for a rapidly waning vaccine, the optimal age of vaccination can shift to infants under 1 year. This shift arises when the duration of vaccine efficacy is too brief to offer appreciable protection during the child-bearing years. In this case, it becomes more effective to achieve indirect protection by reducing transmission from infants, the transmissibility from whom was estimated to be an order of magnitude higher than other age classes. Knowledge of vaccine waning is paramount to optimizing CMV vaccination and is thus a key parameter for longitudinal clinical evaluation.
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, Jan 30, 2015
The effectiveness of interferon-free direct-acting antivirals (DAA) in treating chronic hepatiti... more The effectiveness of interferon-free direct-acting antivirals (DAA) in treating chronic hepatitis C virus (HCV) is limited by low screening and treatment rates, particularly among people who inject drugs (PWIDs). To evaluate the levels of screening and treatment with interferon-free DAAs that are required to control HCV incidence and HCV-associated morbidity and mortality, we developed a transmission model, stratified by age and by injection drug use, and calibrated it to epidemiological data in the United States from 1992 to 2014. We quantified the impact of administration of DAAs at current and at enhanced screening and treatment rates, focusing on outcomes of HCV incidence, prevalence, compensated and decompensated cirrhosis, hepatocellular carcinoma, liver transplants, and mortality from 2015 to 2040. Increasing annual treatment of patients 4-fold-from the approximately 100 000 treated historically to 400 000-is predicted to prevent 526 084 (95% confidence interval, 466 615-5...
PloS one, 2015
The WHO recommends integrating interventions to address the devastating TB/HIV co-epidemics in So... more The WHO recommends integrating interventions to address the devastating TB/HIV co-epidemics in South Africa, yet integration has been poorly implemented and TB/HIV control efforts need strengthening. Identifying infected individuals is particularly difficult in rural settings. We used mathematical modeling to predict the impact of community-based, integrated TB/HIV case finding and additional control strategies on South Africa's TB/HIV epidemics. We developed a model incorporating TB and HIV transmission to evaluate the effectiveness of integrating TB and HIV interventions in rural South Africa over 10 years. We modeled the impact of a novel screening program that integrates case finding for TB and HIV in the community, comparing it to status quo and recommended TB/HIV control strategies, including GeneXpert, MDR-TB treatment decentralization, improved first-line TB treatment cure rate, isoniazid preventive therapy, and expanded ART. Combining recommended interventions averted 2...
Successive waves of infection by SARS-CoV-2 have left little doubt that this virus will transitio... more Successive waves of infection by SARS-CoV-2 have left little doubt that this virus will transition to an endemic disease 1,2. Projections of the endemic seasonality of SARS-CoV-2 transmission are crucial to informed public health policy 3. Such projections are not only essential to well-timed interventions and the preparation of healthcare systems for synchronous surges with other respiratory viruses 4, but also to the elimination of seasonality as a confounder in the identification of surges that are occurring due to viral evolution, changes in host immunity, or other non-seasonal factors. However, the less than two-year duration of SARS-CoV-2 circulation, pandemic dynamics, and heterogeneous implementation of interventions have grievously complicated evaluations of its seasonality 5. Here we estimate the impending endemic seasonality of SARS-CoV-2 in global population centers via a novel phylogenetic ancestral and descendent states approach 6 that leverages long-term data on the i...
A major policy tool used by governments during the COVID-19 pandemic has been the imposition of q... more A major policy tool used by governments during the COVID-19 pandemic has been the imposition of quarantine and testing requirements on international travel, extending even to the extreme approach of closing national borders. However, both approaches have far-reaching socioeconomic implications. Therefore, we evaluated the implications of quarantine and testing compared to the reductions achieved by border closure on in-country imminent transmission based on country-specific prevalence, daily incidence, vaccine coverage, immunity, age-demographics, and travel flow. We considered travel quarantines of 0-14 days with and without RT-PCR or antigen testing for COVID-19 in 31 European countries. Our analysis demonstrates that for the vast majority of origin-destination country pairs, there are combinations of short-duration quarantine and testing that are as effective as border closure. Furthermore, for most origin-destination country pairs, travel with testing and no quarantine will redu...
We were pleased to see that Dr. Schmidt recommended acceptance of our manuscript. While we agree ... more We were pleased to see that Dr. Schmidt recommended acceptance of our manuscript. While we agree with Dr. Schmidt that changing from a narrative to systematic review would strengthen our manuscript, we feel such a review is beyond our current scope. We hope to work on such a systematic review in the future. We have revised the current manuscript to ensure that the coverage of previous literature is even-handed and extensive.
The progression of cancer--including the acquisition of therapeutic resistance and the fatal meta... more The progression of cancer--including the acquisition of therapeutic resistance and the fatal metastatic spread of therapy-resistant cell populations--is an evolutionary process that is challenging to monitor between sampling timepoints. Here we apply mutational signature analysis to clinically correlated cancer chronograms to detect and describe the shifting mutational processes caused by both endogenous (e.g. mutator mutation) and exogenous (e.g. therapeutic) factors between tumor sampling timepoints. In one patient, we find that cisplatin therapy can introduce mutations that increase the likelihood of genetic adaptation to subsequent targeted therapeutics. In another patient, we trace the emergence of known driver mutation CTNNB1 S37C to specific detection of defective mismatch repair associated mutational signature SBS3. Metastatic lineages were found to emerge from a single ancestral lineage arising during therapy--a finding that argues for the consideration of local consolidati...
Uploads
Papers by Jeffrey Townsend
A major analytical challenge in computational biology is the detection and description of clusters of specified site types, such as polymorphic or substituted sites within DNA or protein sequences. Progress has been stymied by a lack of suitable methods to detect clusters and to estimate the extent of clustering in discrete linear sequences, particularly when there is no a priori specification of cluster size or cluster count. Here we derive and demonstrate a maximum likelihood method of hierarchical clustering. Our method incorporates a tripartite divide-and-conquer strategy that models sequence heterogeneity, delineates clusters, and yields a profile of the level of clustering associated with each site. The clustering model may be evaluated via model selection using the Akaike Information Criterion, the corrected Akaike Information Criterion, and the Bayesian Information Criterion. Furthermore, model averaging using weighted model likelihoods may be applied to incorporate model uncertainty into the profile of heterogeneity across sites. We evaluated our method by examining its performance on a number of simulated datasets as well as on empirical polymorphism data from diverse natural alleles of the Drosophila alcohol dehydrogenase gene. Our method yielded greater power for the detection of clustered sites across a breadth of parameter ranges, and achieved better accuracy and precision of estimation of clusters, than did the existing empirical cumulative distribution function statistics.