Publications by authors named "Katherine E Atkins"

53 Publications

Importance of patient bed pathways and length of stay differences in predicting COVID-19 hospital bed occupancy in England.

BMC Health Serv Res 2021 Jun 9;21(1):566. Epub 2021 Jun 9.

Centre for Mathematical Modelling of Infectious Diseases, Department of Infectious Disease Epidemiology, Faculty of Epidemiology & Population Health, London School of Hygiene & Tropical Medicine, London, UK.

Background: Predicting bed occupancy for hospitalised patients with COVID-19 requires understanding of length of stay (LoS) in particular bed types. LoS can vary depending on the patient's "bed pathway" - the sequence of transfers of individual patients between bed types during a hospital stay. In this study, we characterise these pathways, and their impact on predicted hospital bed occupancy.

Methods: We obtained data from University College Hospital (UCH) and the ISARIC4C COVID-19 Clinical Information Network (CO-CIN) on hospitalised patients with COVID-19 who required care in general ward or critical care (CC) beds to determine possible bed pathways and LoS. We developed a discrete-time model to examine the implications of using either bed pathways or only average LoS by bed type to forecast bed occupancy. We compared model-predicted bed occupancy to publicly available bed occupancy data on COVID-19 in England between March and August 2020.

Results: In both the UCH and CO-CIN datasets, 82% of hospitalised patients with COVID-19 only received care in general ward beds. We identified four other bed pathways, present in both datasets: "Ward, CC, Ward", "Ward, CC", "CC" and "CC, Ward". Mean LoS varied by bed type, pathway, and dataset, between 1.78 and 13.53 days. For UCH, we found that using bed pathways improved the accuracy of bed occupancy predictions, while only using an average LoS for each bed type underestimated true bed occupancy. However, using the CO-CIN LoS dataset we were not able to replicate past data on bed occupancy in England, suggesting regional LoS heterogeneities.

Conclusions: We identified five bed pathways, with substantial variation in LoS by bed type, pathway, and geography. This might be caused by local differences in patient characteristics, clinical care strategies, or resource availability, and suggests that national LoS averages may not be appropriate for local forecasts of bed occupancy for COVID-19.

Trial Registration: The ISARIC WHO CCP-UK study ISRCTN66726260 was retrospectively registered on 21/04/2020 and designated an Urgent Public Health Research Study by NIHR.
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http://dx.doi.org/10.1186/s12913-021-06509-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188158PMC
June 2021

Respiratory syncytial virus seasonality and prevention strategy planning for passive immunisation of infants in low-income and middle-income countries: a modelling study.

Lancet Infect Dis 2021 May 6. Epub 2021 May 6.

Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, UK; Respiratory Syncytial Virus Network (ReSViNET) Foundation, Zeist, Netherlands. Electronic address:

Background: Respiratory syncytial virus (RSV) represents a substantial burden of disease in young infants in low-income and middle-income countries (LMICs). Because RSV passive immunisations, including maternal vaccination and monoclonal antibodies, can only grant a temporary period of protection, their effectiveness and efficiency will be determined by the timing of the immunisation relative to the underlying RSV seasonality. We aimed to assess the potential effect of different approaches for passive RSV immunisation of infants in LMICs.

Methods: We included 52 LMICs in this study on the basis of the availability of RSV seasonality data and developed a mathematical model to compare the effect of different RSV passive immunisation approaches (seasonal approaches vs a year-round approach). For each candidate approach, we calculated the expected annual proportion of RSV incidence among infants younger than 6 months averted (effectiveness) and the ratio of per-dose cases averted between that approach and the year-round approach (relative efficiency).

Findings: 39 (75%) of 52 LMICs included in the study had clear RSV seasonality, defined as having more than 75% of annual RSV cases occurring in 5 or fewer months. In these countries with clear RSV seasonality, the seasonal approach in which monoclonal antibody administration began 3 months before RSV season onset was only a median of 16% (IQR 13-18) less effective in averting RSV-associated acute lower respiratory infection (ALRI) hospital admissions than a year-round approach, but was a median of 70% (50-97) more efficient in reducing RSV-associated hospital admissions per dose. The seasonal approach that delivered maternal vaccination 1 month before the season onset was a median of 27% (25-33) less effective in averting hospital admissions associated with RSV-ALRI than a year-round approach, but was a median of 126% (87-177) more efficient at averting these hospital admissions per dose.

Interpretation: In LMICs with clear RSV seasonality, seasonal approaches to monoclonal antibody and maternal vaccine administration might optimise disease prevention by dose given compared with year-round administration. More data are needed to clarify if seasonal administration of RSV monoclonal antibodies or maternal immunisation is programmatically suitable and cost effective in LMICs.

Funding: The Bill & Melinda Gates Foundation, World Health Organization.
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http://dx.doi.org/10.1016/S1473-3099(20)30703-9DOI Listing
May 2021

Implication of backward contact tracing in the presence of overdispersed transmission in COVID-19 outbreaks.

Wellcome Open Res 2020 31;5:239. Epub 2021 Mar 31.

Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, WC1E 7HT, UK.

Contact tracing has the potential to control outbreaks without the need for stringent physical distancing policies, e.g. civil lockdowns. Unlike forward contact tracing, backward contact tracing identifies the source of newly detected cases. This approach is particularly valuable when there is high individual-level variation in the number of secondary transmissions (overdispersion). By using a simple branching process model, we explored the potential of combining backward contact tracing with more conventional forward contact tracing for control of COVID-19. We estimated the typical size of clusters that can be reached by backward tracing and simulated the incremental effectiveness of combining backward tracing with conventional forward tracing. Across ranges of parameter values consistent with dynamics of SARS-CoV-2, backward tracing is expected to identify a primary case generating 3-10 times more infections than a randomly chosen case, typically increasing the proportion of subsequent cases averted by a factor of 2-3. The estimated number of cases averted by backward tracing became greater with a higher degree of overdispersion. Backward contact tracing can be an effective tool for outbreak control, especially in the presence of overdispersion as is observed with SARS-CoV-2.
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http://dx.doi.org/10.12688/wellcomeopenres.16344.3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610176.3PMC
March 2021

Implications of the school-household network structure on SARS-CoV-2 transmission under school reopening strategies in England.

Nat Commun 2021 03 29;12(1):1942. Epub 2021 Mar 29.

Centre for Mathematical Modelling of Infectious Diseases, London School of Hygiene and Tropical Medicine, London, UK.

In early 2020 many countries closed schools to mitigate the spread of SARS-CoV-2. Since then, governments have sought to relax the closures, engendering a need to understand associated risks. Using address records, we construct a network of schools in England connected through pupils who share households. We evaluate the risk of transmission between schools under different reopening scenarios. We show that whilst reopening select year-groups causes low risk of large-scale transmission, reopening secondary schools could result in outbreaks affecting up to 2.5 million households if unmitigated, highlighting the importance of careful monitoring and within-school infection control to avoid further school closures or other restrictions.
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http://dx.doi.org/10.1038/s41467-021-22213-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007691PMC
March 2021

Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England.

Science 2021 04 3;372(6538). Epub 2021 Mar 3.

Centre for Mathematical Modelling of Infectious Diseases, London School of Hygiene and Tropical Medicine, London, UK.

A severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant, VOC 202012/01 (lineage B.1.1.7), emerged in southeast England in September 2020 and is rapidly spreading toward fixation. Using a variety of statistical and dynamic modeling approaches, we estimate that this variant has a 43 to 90% (range of 95% credible intervals, 38 to 130%) higher reproduction number than preexisting variants. A fitted two-strain dynamic transmission model shows that VOC 202012/01 will lead to large resurgences of COVID-19 cases. Without stringent control measures, including limited closure of educational institutions and a greatly accelerated vaccine rollout, COVID-19 hospitalizations and deaths across England in the first 6 months of 2021 were projected to exceed those in 2020. VOC 202012/01 has spread globally and exhibits a similar transmission increase (59 to 74%) in Denmark, Switzerland, and the United States.
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http://dx.doi.org/10.1126/science.abg3055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128288PMC
April 2021

Cost-effectiveness of live-attenuated influenza vaccination among school-age children.

Vaccine 2021 01 4;39(2):447-456. Epub 2020 Dec 4.

Centre for Mathematical Modelling of Infectious Diseases, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK; Respiratory Diseases Department, Public Health England, London NW9 5EQ, UK; School of Public Health, Infectious Disease Epidemiology, Imperial College London, London SW7 2AZ, UK.

The current pediatric vaccination program in England and Wales administers Live-Attenuated Influenza Vaccine (LAIV) to children ages 2-16 years old. Annual administration of LAIV to this age group is costly and poses substantial logistical issues. This study aims to evaluate the cost-effectiveness of prioritizing vaccination to age groups within the 2-16 year old age range to mitigate the operational and resource challenges of the current strategy. We performed economic evaluations comparing the influenza vaccination program from 1995-2013 to seven alternative strategies targeted at low risk individuals along the school age divisions Preschool (2-4 years old), Primary school (5-11 years old), and Secondary school (12-16 years old). These extensions are evaluated incrementally on the status quo scenario (vaccinating subgroups at high risk of influenza-related complications and individuals 65+ years old). Impact of vaccination was assessed using a transmission model from a previously published study and updated with new data. At all levels of coverage, all strategies had a 100% probability of being cost-effective at the current National Health Service threshold, £20,000/QALY gained. The incremental analysis demonstrated vaccinating Primary School children was the most cost-efficient strategy compared incrementally against others with an Incremental Cost-Effectiveness Ratio of £639 spent per QALY gained (Net Benefit: 404 M£ [155, 795]). When coverage was varied between 30%, 55%, and 70% strategies which included Primary school children had a higher probability of being cost-effective at lower willingness-to-pay levels. Although children were the vaccine target the majority of QALY gains occurred in the 25-44 years old and 65+ age groups. Influenza strain A/H3N2 incurred the greatest costs and QALYs lost regardless of which strategy was used. Improvement could be made to the current LAIV pediatric vaccination strategy by eliminating vaccination of 2-4 year olds and focusing on school-based delivery to Primary and Secondary school children in tandem.
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http://dx.doi.org/10.1016/j.vaccine.2020.10.007DOI Listing
January 2021

Evaluating the next generation of RSV intervention strategies: a mathematical modelling study and cost-effectiveness analysis.

BMC Med 2020 11 18;18(1):348. Epub 2020 Nov 18.

Department of Infectious Disease Epidemiology, Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK.

Background: With a suite of promising new RSV prophylactics on the horizon, including long-acting monoclonal antibodies and new vaccines, it is likely that one or more of these will replace the current monoclonal Palivizumab programme. However, choosing the optimal intervention programme will require balancing the costs of the programmes with the health benefits accrued.

Methods: To compare the next generation of RSV prophylactics, we integrated a novel transmission model with an economic analysis. We estimated key epidemiological parameters by calibrating the model to 7 years of historical epidemiological data using a Bayesian approach. We determined the cost-effective and affordable maximum purchase price for a comprehensive suite of intervention programmes.

Findings: Our transmission model suggests that maternal protection of infants is seasonal, with 38-62% of infants born with protection against RSV. Our economic analysis found that to cost-effectively and affordably replace the current monoclonal antibody Palivizumab programme with long-acting monoclonal antibodies, the purchase price per dose would have to be less than around £4350 but dropping to £200 for vaccinated heightened risk infants or £90 for all infants. A seasonal maternal vaccine would have to be priced less than £85 to be cost-effective and affordable. While vaccinating pre-school and school-age children is likely not cost-effective relative to elderly vaccination programmes, vaccinating the elderly is not likely to be affordable. Conversely, vaccinating infants at 2 months seasonally would be cost-effective and affordable if priced less than £80.

Conclusions: In a setting with seasonal RSV epidemiology, maternal protection conferred to newborns is also seasonal, an assumption not previously incorporated in transmission models of RSV. For a country with seasonal RSV dynamics like England, seasonal programmes rather than year-round intervention programmes are always optimal.
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http://dx.doi.org/10.1186/s12916-020-01802-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672821PMC
November 2020

Acquisition of extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE) carriage after exposure to systemic antimicrobials during travel: Systematic review and meta-analysis.

Travel Med Infect Dis 2020 Sep - Oct;37:101823. Epub 2020 Aug 2.

Centre for Mathematical Modelling of Infectious Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom; Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, Edinburgh Medical School, The University of Edinburgh, UK.

Background: International travel is an important risk factor for colonization with extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE). Antimicrobial use during travel likely amplifies this risk, yet to what extent, and whether it varies by antimicrobial class, has not been established.

Methods: We conducted a systematic review that included prospective cohorts reporting both receipt of systemic antimicrobials and acquired ESBL-PE isolated from stool or rectum during international travel. We performed a random effects meta-analysis to estimate odds of acquiring ESBL-PE due to antimicrobials during travel, overall and by antimicrobial class.

Results: Fifteen studies were included. The study population was mainly female travellers from high income countries recruited primarily from travel clinics. Participants travelled most frequently to Asia and Africa with 10% reporting antimicrobial use during travel. The combined odds ratio (OR) for ESBL-PE acquisition during travel was 2.37 for antimicrobial use overall (95% confidence interval [CI], 1.69 to 3.33), but there was substantial heterogeneity between studies. Fluoroquinolones were the antibiotic class associated with the highest combined OR of ESBL-PE acquisition, compared to no antimicrobial use (OR 4.68, 95% CI, 2.34 to 9.37).

Conclusions: The risk of ESBL-PE colonization during travel is increased substantially with exposure to antimicrobials, especially fluoroquinolones. While a small proportion of colonized individuals will develop a resistant infection, there remains the potential for onward spread among returning travellers. Public health efforts to decrease inappropriate antimicrobial usage during travel are warranted.
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http://dx.doi.org/10.1016/j.tmaid.2020.101823DOI Listing
August 2020

Number of HIV-1 founder variants is determined by the recency of the source partner infection.

Science 2020 07;369(6499):103-108

Department of Infectious Disease Epidemiology, Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK.

During sexual transmission, the high genetic diversity of HIV-1 within an individual is frequently reduced to one founder variant that initiates infection. Understanding the drivers of this bottleneck is crucial to developing effective infection control strategies. Little is known about the importance of the source partner during this bottleneck. To test the hypothesis that the source partner affects the number of HIV founder variants, we developed a phylodynamic model calibrated using genetic and epidemiological data on all existing transmission pairs for whom the direction of transmission and the infection stage of the source partner are known. Our results suggest that acquiring infection from someone in the acute (early) stage of infection increases the risk of multiple-founder variant transmission compared with acquiring infection from someone in the chronic (later) stage of infection. This study provides the first direct test of source partner characteristics to explain the low frequency of multiple-founder strain infections.
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http://dx.doi.org/10.1126/science.aba5443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116289PMC
July 2020

Cost-effectiveness of introducing national seasonal influenza vaccination for adults aged 60 years and above in mainland China: a modelling analysis.

BMC Med 2020 04 14;18(1):90. Epub 2020 Apr 14.

School of Public Health, Fudan University, Key Laboratory of Public Health Safety, Ministry of Education, Shanghai, China.

Background: China has an aging population with an increasing number of adults aged ≥ 60 years. Influenza causes a heavy disease burden in older adults, but can be alleviated by vaccination. We assessed the cost-effectiveness of a potential government-funded seasonal influenza vaccination program in older adults in China.

Methods: We characterized the health and economic impact of a fully funded influenza vaccination program for older adults using China-specific influenza disease burden, and related cost data, etc. Using a decision tree model, we calculated the incremental costs per quality-adjusted life year (QALY) gained of vaccination from the societal perspective, at a willingness-to-pay threshold equivalent to GDP per capita (US$8840). Moreover, we estimated the threshold vaccination costs, under which the fully funded vaccination program is cost-effective using GDP per capita as the willingness-to-pay threshold.

Results: Compared to current self-paid vaccination, a fully funded vaccination program is expected to prevent 19,812 (95% uncertainty interval, 7150-35,783) influenza-like-illness outpatient consultations per year, 9418 (3386-17,068) severe acute respiratory infection hospitalizations per year, and 8800 (5300-11,667) respiratory excess deaths due to influenza per year, and gain 70,212 (42,106-93,635) QALYs per year. Nationally, the incremental costs per QALY gained of the vaccination program is US$4832 (3460-8307), with a 98% probability of being cost-effective. The threshold vaccination cost is US$10.19 (6.08-13.65). However, variations exist between geographical regions, with Northeast and Central China having lower probabilities of cost-effectiveness.

Conclusions: Our results support the implementation of a government fully funded older adult vaccination program in China. The regional analysis provides results across settings that may be relevant to other countries with similar disease burden and economic status, especially for low- and middle-income countries where such analysis is limited.
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http://dx.doi.org/10.1186/s12916-020-01545-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7155276PMC
April 2020

Quantifying the economic cost of antibiotic resistance and the impact of related interventions: rapid methodological review, conceptual framework and recommendations for future studies.

BMC Med 2020 03 6;18(1):38. Epub 2020 Mar 6.

Modelling and Economics Unit, National Infections Service, Public Health England, London, UK.

Background: Antibiotic resistance (ABR) poses a major threat to health and economic wellbeing worldwide. Reducing ABR will require government interventions to incentivise antibiotic development, prudent antibiotic use, infection control and deployment of partial substitutes such as rapid diagnostics and vaccines. The scale of such interventions needs to be calibrated to accurate and comprehensive estimates of the economic cost of ABR.

Methods: A conceptual framework for estimating costs attributable to ABR was developed based on previous literature highlighting methodological shortcomings in the field and additional deductive epidemiological and economic reasoning. The framework was supplemented by a rapid methodological review.

Results: The review identified 110 articles quantifying ABR costs. Most were based in high-income countries only (91/110), set in hospitals (95/110), used a healthcare provider or payer perspective (97/110), and used matched cohort approaches to compare costs of patients with antibiotic-resistant infections and antibiotic-susceptible infections (or no infection) (87/110). Better use of methods to correct biases and confounding when making this comparison is needed. Findings also need to be extended beyond their limitations in (1) time (projecting present costs into the future), (2) perspective (from the healthcare sector to entire societies and economies), (3) scope (from individuals to communities and ecosystems), and (4) space (from single sites to countries and the world). Analyses of the impact of interventions need to be extended to examine the impact of the intervention on ABR, rather than considering ABR as an exogeneous factor.

Conclusions: Quantifying the economic cost of resistance will require greater rigour and innovation in the use of existing methods to design studies that accurately collect relevant outcomes and further research into new techniques for capturing broader economic outcomes.
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http://dx.doi.org/10.1186/s12916-020-1507-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059710PMC
March 2020

The impact of vector migration on the effectiveness of strategies to control gambiense human African trypanosomiasis.

PLoS Negl Trop Dis 2019 12 5;13(12):e0007903. Epub 2019 Dec 5.

Center for Infectious Disease Modeling and Analysis, Yale School of Public Health, New Haven, CT, United States of America.

Background: Several modeling studies have been undertaken to assess the feasibility of the WHO goal of eliminating gambiense human African trypanosomiasis (g-HAT) by 2030. However, these studies have generally overlooked the effect of vector migration on disease transmission and control. Here, we evaluated the impact of vector migration on the feasibility of interrupting transmission in different g-HAT foci.

Methods: We developed a g-HAT transmission model of a single tsetse population cluster that accounts for migration of tsetse fly into this population. We used a model calibration approach to constrain g-HAT incidence to ranges expected for high, moderate and low transmission settings, respectively. We used the model to evaluate the effectiveness of current intervention measures, including medical intervention through enhanced screening and treatment, and vector control, for interrupting g-HAT transmission in disease foci under each transmission setting.

Results: We showed that, in low transmission settings, under enhanced medical intervention alone, at least 70% treatment coverage is needed to interrupt g-HAT transmission within 10 years. In moderate transmission settings, a combination of medical intervention and a vector control measure with a daily tsetse mortality greater than 0.03 is required to achieve interruption of disease transmission within 10 years. In high transmission settings, interruption of disease transmission within 10 years requires a combination of at least 70% medical intervention coverage and at least 0.05 tsetse daily mortality rate from vector control. However, the probability of achieving elimination in high transmission settings decreases with an increased tsetse migration rate.

Conclusion: Our results suggest that the WHO 2030 goal of G-HAT elimination is, at least in theory, achievable. But the presence of tsetse migration may reduce the probability of interrupting g-HAT transmission in moderate and high transmission foci. Therefore, optimal vector control programs should incorporate monitoring and controlling of vector density in buffer areas around foci of g-HAT control efforts.
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http://dx.doi.org/10.1371/journal.pntd.0007903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894748PMC
December 2019

Mathematical modelling for antibiotic resistance control policy: do we know enough?

BMC Infect Dis 2019 Nov 29;19(1):1011. Epub 2019 Nov 29.

Department of Infectious Disease Epidemiology, Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine (LSHTM), London, UK.

Background: Antibiotics remain the cornerstone of modern medicine. Yet there exists an inherent dilemma in their use: we are able to prevent harm by administering antibiotic treatment as necessary to both humans and animals, but we must be mindful of limiting the spread of resistance and safeguarding the efficacy of antibiotics for current and future generations. Policies that strike the right balance must be informed by a transparent rationale that relies on a robust evidence base.

Main Text: One way to generate the evidence base needed to inform policies for managing antibiotic resistance is by using mathematical models. These models can distil the key drivers of the dynamics of resistance transmission from complex infection and evolutionary processes, as well as predict likely responses to policy change in silico. Here, we ask whether we know enough about antibiotic resistance for mathematical modelling to robustly and effectively inform policy. We consider in turn the challenges associated with capturing antibiotic resistance evolution using mathematical models, and with translating mathematical modelling evidence into policy.

Conclusions: We suggest that in spite of promising advances, we lack a complete understanding of key principles. From this we advocate for priority areas of future empirical and theoretical research.
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http://dx.doi.org/10.1186/s12879-019-4630-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6884858PMC
November 2019

Estimates for quality of life loss due to Respiratory Syncytial Virus.

Influenza Other Respir Viruses 2020 01 18;14(1):19-27. Epub 2019 Oct 18.

Respiratory Diseases Department, Public Health England, London, UK.

Background: In children aged <5 years in whom severe respiratory syncytial virus (RSV) episodes predominantly occur, there are currently no appropriate standardised instruments to estimate quality of life years (QALY) loss.

Objectives: We estimated the age-specific QALY loss due to RSV by developing a regression model which predicts the QALY loss without the use of standardised instruments.

Methods: We conducted a surveillance study which targeted confirmed RSV episodes in children aged <5 years (confirmed cases) and their household members who experienced symptoms of RSV during the same time (suspected cases). All participants were asked to complete questions regarding their health during the infection, with the suspected cases additionally providing health-related quality of life (HR-QoL) loss estimates by completing EQ-5D-3L-Y or EQ-5D-3L instruments. We used the responses from the suspected cases to calibrate a regression model which estimates the HR-QoL and QALY loss due to infection.

Findings: For confirmed RSV cases in children under 5 years of age who sought health care, our model predicted a QALY loss per RSV episode of 3.823 × 10 (95% CI 0.492-12.766 × 10 ), compared with 3.024 × 10 (95% CI 0.329-10.098 × 10 ) for under fives who did not seek health care. Quality of life years loss per episode was less for older children and adults, estimated as 1.950 × 10 (0.185-9.578 × 10 ) and 1.543 × 10 (0.136-6.406 × 10 ) for those who seek or do not seek health care, respectively.

Conclusion: Evaluations of potential RSV vaccination programmes should consider their impact across the whole population, not just young child children.
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http://dx.doi.org/10.1111/irv.12686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928035PMC
January 2020

Effect of Pediatric Influenza Vaccination on Antibiotic Resistance, England and Wales.

Emerg Infect Dis 2020 01;26(1):138-142

Vaccines against viral infections have been proposed to reduce prescribing of antibiotics and thereby help control resistant bacterial infections. However, by combining published data sources, we predict that pediatric live attenuated influenza vaccination in England and Wales will not substantially reduce antibiotic consumption or adverse health outcomes associated with antibiotic resistance.
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http://dx.doi.org/10.3201/eid2601.191110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6924886PMC
January 2020

Quantifying the public's view on social value judgments in vaccine decision-making: A discrete choice experiment.

Soc Sci Med 2019 05 20;228:181-193. Epub 2019 Mar 20.

Department of Infectious Disease Epidemiology, Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, United Kingdom; Centre for Infectious Diseases, National Institute for Public Health and the Environment, Antonie van Leeuwenhoeklaan 9, 3721 MA, Bilthoven, the Netherlands. Electronic address:

Vaccination programs generate direct protection, herd protection and, occasionally, side effects, distributed over different age groups. This study elicits the general public's view on how to balance these outcomes in funding decisions for vaccines. We performed an optimal design discrete choice experiment with partial profiles in a representative sample (N = 1499) of the population in the United Kingdom in November 2016. Using a panel mixed logit model, we quantified, for four different types of infectious disease, the importance of a person's age during disease, how disease was prevented-via direct vaccine protection or herd protection-and whether the vaccine induced side effects. Our study shows clear patterns in how the public values vaccination programs. These diverge from the assumptions made in public health and cost-effectiveness models that inform decision-making. We found that side effects and infections in newborns and children were of primary importance to the perceived value of a vaccination program. Averting side effects was, in any age group, weighted three times as important as preventing an identical natural infection in a child whereas the latter was weighted six times as important as preventing the same infection in elderly aged 65-75 years. These findings were independent of the length or severity of the disease, and were robust across respondents' backgrounds. We summarize these patterns in a set of preference weights that can be incorporated into future models. Although the normative significance of these weights remains a matter open for debate, our study can, hopefully, contribute to the evaluation of vaccination programs beyond cost-effectiveness.
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http://dx.doi.org/10.1016/j.socscimed.2019.03.025DOI Listing
May 2019

Within-host dynamics shape antibiotic resistance in commensal bacteria.

Nat Ecol Evol 2019 03 11;3(3):440-449. Epub 2019 Feb 11.

Centre for Mathematical Modelling of Infectious Diseases, London School of Hygiene and Tropical Medicine, London, UK.

The spread of antibiotic resistance, a major threat to human health, is poorly understood. Simple population-level models of bacterial transmission predict that above a certain rate of antibiotic consumption in a population, resistant bacteria should completely eliminate non-resistant strains, while below this threshold they should be unable to persist at all. This prediction stands at odds with empirical evidence showing that resistant and non-resistant strains coexist stably over a wide range of antibiotic consumption rates. Not knowing what drives this long-term coexistence is a barrier to developing evidence-based strategies for managing the spread of resistance. Here, we argue that competition between resistant and sensitive pathogens within individual hosts gives resistant pathogens a relative fitness benefit when they are rare, promoting coexistence between strains at the population level. To test this hypothesis, we embed mechanistically explicit within-host dynamics in a structurally neutral pathogen transmission model. Doing so allows us to reproduce patterns of resistance observed in the opportunistic pathogens Escherichia coli and Streptococcus pneumoniae across European countries and to identify factors that may shape resistance evolution in bacteria by modulating the intensity and outcomes of within-host competition.
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http://dx.doi.org/10.1038/s41559-018-0786-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6420107PMC
March 2019

Quantifying the impact of social groups and vaccination on inequalities in infectious diseases using a mathematical model.

BMC Med 2018 09 26;16(1):162. Epub 2018 Sep 26.

Centre for Mathematical Modelling of Infectious Diseases, London School of Hygiene & Tropical Medicine, London, UK.

Background: Social and cultural disparities in infectious disease burden are caused by systematic differences between communities. Some differences have a direct and proportional impact on disease burden, such as health-seeking behaviour and severity of infection. Other differences-such as contact rates and susceptibility-affect the risk of transmission, where the impact on disease burden is indirect and remains unclear. Furthermore, the concomitant impact of vaccination on such inequalities is not well understood.

Methods: To quantify the role of differences in transmission on inequalities and the subsequent impact of vaccination, we developed a novel mathematical framework that integrates a mechanistic model of disease transmission with a demographic model of social structure, calibrated to epidemiologic and empirical social contact data.

Results: Our model suggests realistic differences in two key factors contributing to the rates of transmission-contact rate and susceptibility-between two social groups can lead to twice the risk of infection in the high-risk population group relative to the low-risk population group. The more isolated the high-risk group, the greater this disease inequality. Vaccination amplified this inequality further: equal vaccine uptake across the two population groups led to up to seven times the risk of infection in the high-risk group. To mitigate these inequalities, the high-risk population group would require disproportionately high vaccination uptake.

Conclusion: Our results suggest that differences in contact rate and susceptibility can play an important role in explaining observed inequalities in infectious diseases. Importantly, we demonstrate that, contrary to social policy intentions, promoting an equal vaccine uptake across population groups may magnify inequalities in infectious disease risk.
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http://dx.doi.org/10.1186/s12916-018-1152-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156851PMC
September 2018

Can antibiotic resistance be reduced by vaccinating against respiratory disease?

Lancet Respir Med 2018 11 31;6(11):820-821. Epub 2018 Jul 31.

Center for Communicable Disease Dynamics, Department of Epidemiology and Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

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http://dx.doi.org/10.1016/S2213-2600(18)30328-XDOI Listing
November 2018

Balancing Benefits and Risks of Antibiotic Use.

J Infect Dis 2018 09;218(9):1351-1353

Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, United Kingdom.

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http://dx.doi.org/10.1093/infdis/jiy344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904291PMC
September 2018

Assessing Strategies Against Gambiense Sleeping Sickness Through Mathematical Modeling.

Clin Infect Dis 2018 06;66(suppl_4):S286-S292

Zeeman Institute for Systems Biology and Infectious Disease Epidemiology Research, Coventry, United Kingdom.

Background: Control of gambiense sleeping sickness relies predominantly on passive and active screening of people, followed by treatment.

Methods: Mathematical modeling explores the potential of 3 complementary interventions in high- and low-transmission settings.

Results: Intervention strategies that included vector control are predicted to halt transmission most quickly. Targeted active screening, with better and more focused coverage, and enhanced passive surveillance, with improved access to diagnosis and treatment, are both estimated to avert many new infections but, when used alone, are unlikely to halt transmission before 2030 in high-risk settings.

Conclusions: There was general model consensus in the ranking of the 3 complementary interventions studied, although with discrepancies between the quantitative predictions due to differing epidemiological assumptions within the models. While these predictions provide generic insights into improving control, the most effective strategy in any situation depends on the specific epidemiology in the region and the associated costs.
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http://dx.doi.org/10.1093/cid/ciy018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5982708PMC
June 2018

Cholera epidemic in Yemen, 2016-18: an analysis of surveillance data.

Lancet Glob Health 2018 06 3;6(6):e680-e690. Epub 2018 May 3.

Epicentre, Paris, France.

Background: In war-torn Yemen, reports of confirmed cholera started in late September, 2016. The disease continues to plague Yemen today in what has become the largest documented cholera epidemic of modern times. We aimed to describe the key epidemiological features of this epidemic, including the drivers of cholera transmission during the outbreak.

Methods: The Yemen Health Authorities set up a national cholera surveillance system to collect information on suspected cholera cases presenting at health facilities. Individual variables included symptom onset date, age, severity of dehydration, and rapid diagnostic test result. Suspected cholera cases were confirmed by culture, and a subset of samples had additional phenotypic and genotypic analysis. We first conducted descriptive analyses at national and governorate levels. We divided the epidemic into three time periods: the first wave (Sept 28, 2016, to April 23, 2017), the increasing phase of the second wave (April 24, 2017, to July 2, 2017), and the decreasing phase of the second wave (July 3, 2017, to March 12, 2018). We reconstructed the changes in cholera transmission over time by estimating the instantaneous reproduction number, R. Finally, we estimated the association between rainfall and the daily cholera incidence during the increasing phase of the second epidemic wave by fitting a spatiotemporal regression model.

Findings: From Sept 28, 2016, to March 12, 2018, 1 103 683 suspected cholera cases (attack rate 3·69%) and 2385 deaths (case fatality risk 0·22%) were reported countrywide. The epidemic consisted of two distinct waves with a surge in transmission in May, 2017, corresponding to a median R of more than 2 in 13 of 23 governorates. Microbiological analyses suggested that the same Vibrio cholerae O1 Ogawa strain circulated in both waves. We found a positive, non-linear, association between weekly rainfall and suspected cholera incidence in the following 10 days; the relative risk of cholera after a weekly rainfall of 25 mm was 1·42 (95% CI 1·31-1·55) compared with a week without rain.

Interpretation: Our analysis suggests that the small first cholera epidemic wave seeded cholera across Yemen during the dry season. When the rains returned in April, 2017, they triggered widespread cholera transmission that led to the large second wave. These results suggest that cholera could resurge during the ongoing 2018 rainy season if transmission remains active. Therefore, health authorities and partners should immediately enhance current control efforts to mitigate the risk of a new cholera epidemic wave in Yemen.

Funding: Health Authorities of Yemen, WHO, and Médecins Sans Frontières.
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http://dx.doi.org/10.1016/S2214-109X(18)30230-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5952990PMC
June 2018

Vaccination to reduce antimicrobial resistance.

Lancet Glob Health 2018 03;6(3):e252

Centre for Mathematical Modelling of Infectious Diseases, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK; The Vaccine Centre and Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK; Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.

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http://dx.doi.org/10.1016/S2214-109X(18)30043-3DOI Listing
March 2018

Use of mathematical modelling to assess the impact of vaccines on antibiotic resistance.

Lancet Infect Dis 2018 06 13;18(6):e204-e213. Epub 2017 Nov 13.

Centre for the Mathematical Modelling of Infectious Diseases and Department of Infectious Disease Epidemiology, Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, UK; Modelling and Economics Unit, National Infection Service, Public Health England, London, UK.

Antibiotic resistance is a major global threat to the provision of safe and effective health care. To control antibiotic resistance, vaccines have been proposed as an essential intervention, complementing improvements in diagnostic testing, antibiotic stewardship, and drug pipelines. The decision to introduce or amend vaccination programmes is routinely based on mathematical modelling. However, few mathematical models address the impact of vaccination on antibiotic resistance. We reviewed the literature using PubMed to identify all studies that used an original mathematical model to quantify the impact of a vaccine on antibiotic resistance transmission within a human population. We reviewed the models from the resulting studies in the context of a new framework to elucidate the pathways through which vaccination might impact antibiotic resistance. We identified eight mathematical modelling studies; the state of the literature highlighted important gaps in our understanding. Notably, studies are limited in the range of pathways represented, their geographical scope, and the vaccine-pathogen combinations assessed. Furthermore, to translate model predictions into public health decision making, more work is needed to understand how model structure and parameterisation affects model predictions and how to embed these predictions within economic frameworks.
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http://dx.doi.org/10.1016/S1473-3099(17)30478-4DOI Listing
June 2018

Preface: 'The 2013-2016 West African Ebola epidemic: data, decision-making and disease control'.

Philos Trans R Soc Lond B Biol Sci 2017 May;372(1721)

London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.

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http://dx.doi.org/10.1098/rstb.2017.0020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5394649PMC
May 2017

The 2013-2016 Ebola epidemic: multidisciplinary success conceals a missed opportunity.

Philos Trans R Soc Lond B Biol Sci 2017 05;372(1721)

Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK

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http://dx.doi.org/10.1098/rstb.2016.0292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5394632PMC
May 2017

Effect of mass paediatric influenza vaccination on existing influenza vaccination programmes in England and Wales: a modelling and cost-effectiveness analysis.

Lancet Public Health 2017 Feb;2(2):e74-e81

Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, UK.

Background: In 2013 England and Wales began to fund a live attenuated influenza vaccine programme for individuals aged 2-16 years. Mathematical modelling predicts substantial beneficial herd effects for the entire population as a result of reduced influenza transmission. With a decreased influenza-associated disease burden, existing immunisation programmes might be less cost-effective. The aim of this study was to assess the epidemiological effect and cost-effectiveness of the existing elderly and risk group vaccination programme under the new policy of mass paediatric vaccination in England.

Methods: For this cost-effectiveness analysis, we used a transmission model of seasonal influenza calibrated to 14 seasons of weekly consultation and virology data in England and Wales. We combined this model with an economic evaluation to calculate the incremental cost-effectiveness ratios, measured in cost per quality-adjusted life-years (QALY) gained.

Findings: Our results suggest that well timed administration of paediatric vaccination would reduce the number of low-risk elderly influenza cases to a greater extent than would vaccination of the low-risk elderly themselves if the elderly uptake is achieved more slowly. Although high-risk vaccination remains cost-effective, substantial uncertainty exists as to whether low-risk elderly vaccination remains cost-effective, driven by the choice of cost-effectiveness threshold. Under base case assumptions and a cost-effectiveness threshold of £15 000 per QALY, the low-risk elderly seasonal vaccination programme will cease to be cost-effective with a mean incremental cost-effectiveness ratio of £22 000 per QALY and a probability of cost-effectiveness of 20%. However, under a £30 000 per QALY threshold, the programme will remain cost-effective with 83% probability.

Interpretation: With the likely move to decreased cost-effectiveness thresholds, reassessment of existing risk group-based vaccine programme cost-effectiveness in the presence of the paediatric vaccination programme is needed.

Funding: National Institute for Health Research, the Medical Research Council.
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http://dx.doi.org/10.1016/S2468-2667(16)30044-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5341148PMC
February 2017

Impact of the national rotavirus vaccination programme on acute gastroenteritis in England and associated costs averted.

Vaccine 2017 01 20;35(4):680-686. Epub 2016 Dec 20.

Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK; Immunisation, Hepatitis and Blood Safety Department, Centre for Infectious Disease Surveillance and Control (CIDSC), Public Health England, 61 Colindale Avenue, London NW9 5EQ, UK.

Background: Introduction of infant oral rotavirus vaccination in the UK in July 2013 has resulted in decreased hospitalisations and Emergency Department (ED) visits for acute gastroenteritis (AGE), for both adults and children. We investigated reductions in AGE incidence seen in primary care in the two years after vaccine introduction, and estimated the healthcare costs averted across healthcare settings in the first year of the vaccination programme.

Methods: We used primary care data from the Clinical Practice Research Datalink and age-stratified time-series analyses to derive adjusted incidence rate ratios (IRR) for AGE in the first two years of the post-vaccination era (July 2013-April 2015) compared to the pre-vaccination era (July 2008-June 2013). We estimated cases averted among children aged <5years in the first year of the vaccination programme by comparing observed numbers of AGE cases in 2013-2014 to numbers predicted from the time-series models. We then estimated the healthcare costs averted for general practice consultations, ED visits and hospitalisations.

Results: In general practice, AGE rates in infants (the target group for vaccination) decreased by 15% overall after vaccine introduction (IRR=0.85; 95%CI=0.76-0.95), and by 41% in the months of historically high rotavirus circulation (IRR=0.59; 95%CI=0.53-0.66). Rates also decreased in other young children and to a lesser degree in older individuals, indicating herd immunity. Across all three settings (general practice, EDs, and hospitalisations) an estimated 87,376 (95% prediction interval: 62,588-113,561) AGE visits by children aged <5years were averted in 2013-14, associated with an estimated £12.5million (9,209-16,198) reduction in healthcare costs.

Conclusions: The marked decreases in the general practice AGE burden after rotavirus vaccine introduction mirror decreases seen in other UK healthcare settings. Overall, these decreases are associated with substantial averted healthcare costs.
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http://dx.doi.org/10.1016/j.vaccine.2016.11.057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5267482PMC
January 2017

Seasonal influenza vaccination in China: Landscape of diverse regional reimbursement policy, and budget impact analysis.

Vaccine 2016 11 13;34(47):5724-5735. Epub 2016 Oct 13.

School of Public Health, Fudan University, Key Laboratory of Public Health Safety, Ministry of Education, Shanghai, China. Electronic address:

Background: To explore the current landscape of seasonal influenza vaccination across China, and estimate the budget of implementing a national "free-at-the-point-of-care" vaccination program for priority populations recommended by the World Health Organization.

Methods: In 2014 and 2016, we conducted a survey across provincial Centers for Disease Control and Prevention to collect information on regional reimbursement policies for influenza vaccination, estimated the national uptake using distributed doses of influenza vaccines, and evaluated the budget using population size and vaccine cost obtained from official websites and literatures.

Results: Regular reimbursement policies for influenza vaccination are available in 61 mutually exclusive regions, comprising 8 provinces, 45 prefectures, and 8 counties, which were reimbursed by the local Government Financial Department or Basic Social Medical Insurance (BSMI). Finance-reimbursed vaccination was offered mainly for the elderly, and school children for free in Beijing, Dongli district in Tianjin, Karamay, Shenzhen and Xinxiang cities. BSMI-reimbursement policies were limited to specific medical insurance beneficiaries with distinct differences in the reimbursement fractions. The average national vaccination coverage was just 1.5-2.2% between 2004 and 2014. A free national vaccination program for priority populations (n=416million), would cost government US$ 757million (95% CI 726-789) annually (uptake rate=20%).

Conclusions: An increasing number of regional governments have begun to pay, partially or fully, for influenza vaccination for selected groups. However, this small-scale policy approach has failed to increase national uptake. A free, nationwide vaccination program would require a substantial annual investment. A cost-effectiveness analysis is needed to identify the most efficient methods to improve coverage.
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http://dx.doi.org/10.1016/j.vaccine.2016.10.013DOI Listing
November 2016

Cost-Effectiveness of Rotavirus Vaccination in France-Accounting for Indirect Protection.

Value Health 2016 Sep - Oct;19(6):811-819. Epub 2016 Jul 15.

Center for Infectious Disease Modeling and Analysis, Yale School of Public Health, New Haven, CT, USA.

Background: Vaccination against rotavirus has shown great potential for reducing the primary cause of severe childhood gastroenteritis. Previous economic evaluations of rotavirus vaccination in France have not modeled the potential impact of vaccines on disease burden via reduced transmission.

Objective: To determine the cost-effectiveness of the introduction of pentavalent rotavirus vaccination into the French infant vaccination schedule.

Methods: We developed an age-structured model of rotavirus transmission calibrated to 6 years of French gastroenteritis incidence and vaccine clinical trial data. We evaluated the cost-effectiveness of pentavalent rotavirus vaccination considering that 75% of infants would receive the three-dose vaccine course.

Results: Our model predicts that rotavirus vaccination will decrease rotavirus gastroenteritis incidence and associated clinical outcomes in vaccinated and unvaccinated individuals, delay the seasonal peak of infection, and increase the age of infection. From the societal perspective, our base-case scenario predicts that vaccination coverage would be cost-effective at €115 or €135 per vaccine course at €28,500 and €39,500/quality-adjusted life-year (QALY) gained, respectively, and suggests that almost 95% of the financial benefits will be recouped within the first 5 years following vaccination implementation. From the third-party payer perspective, incremental cost-effectiveness ratios ranged from €12,500 to €20,000/QALY, respectively. Our uncertainty analysis suggests that findings were sensitive to various assumptions including the number of hospitalizations, outpatient visits, and the extent of QALY losses per rotavirus episode.

Conclusions: Introducing pentavalent rotavirus vaccination into the French infant vaccination schedule would significantly reduce the burden of rotavirus disease in children, and could be cost-effective under plausible conditions.
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http://dx.doi.org/10.1016/j.jval.2016.05.011DOI Listing
May 2017