Estimating the population-level impact of vaccines using synthetic controls.

When a new vaccine is introduced, it is critical to monitor trends in disease rates to ensure that the vaccine is effective and to quantify its impact. However, estimates from observational studies can be confounded by unrelated changes in healthcare utilization, changes in the underlying health of the population, or changes in reporting. Other diseases are often used to detect and adjust for these changes, but choosing an appropriate control disease a priori is a major challenge. The "synthetic controls" (causal impact) method, which was originally developed for website analytics and social sciences, provides an appealing solution. With this approach, potential comparison time series are combined into a composite and are used to generate a counterfactual estimate, which can be compared with the time series of interest after the intervention. We sought to estimate changes in hospitalizations for all-cause pneumonia associated with the introduction of pneumococcal conjugate vaccines (PCVs) in five countries in the Americas. Using synthetic controls, we found a substantial decline in hospitalizations for all-cause pneumonia in infants in all five countries (average of 20%), whereas estimates for young and middle-aged adults varied by country and were potentially influenced by the 2009 influenza pandemic. In contrast to previous reports, we did not detect a decline in all-cause pneumonia in older adults in any country. Synthetic controls promise to increase the accuracy of studies of vaccine impact and to increase comparability of results between populations compared with alternative approaches.

Challenges in Estimating the Impact of Vaccination with Sparse Data.

BACKGROUND: The synthetic control model is a powerful tool to quantify the population-level impact of vaccines because it can adjust for trends unrelated to vaccination using a composite of control diseases. Because vaccine impact studies are often conducted using smaller, subnational datasets, we evaluated the performance of synthetic control models with sparse time series data. To obtain more robust estimates of vaccine impacts from noisy time series, we proposed a possible alternative approach, STL+PCA method (seasonal-trend decomposition plus principal component analysis), which first extracts smoothed trends from the control time series and uses them to adjust the outcome. METHODS: Using both the synthetic control and STL+PCA models, we estimated the impact of 10-valent pneumococcal conjugate vaccine on pneumonia hospitalizations among cases <12 months and 80+ years of age during 2004-2014 at the subnational level in Brazil. We compared the performance of these models using simulation analyses. RESULTS: The synthetic control model was able to adjust for trends unrelated to 10-valent pneumococcal conjugate vaccine in larger states but not in smaller states. Simulation analyses showed that the estimates obtained with the synthetic control approach were biased when there were fewer cases, and only 4% of simulations had credible intervals covering the true estimate. In contrast, the STL+PCA analysis had 90% lower bias and had 95% of simulations, with credible intervals covering the true estimate. CONCLUSIONS: Estimates from the synthetic control model might be biased when data are sparse. The STL+PCA model provides more accurate evaluations of vaccine impact in smaller populations.

Impact of Pneumococcal Conjugate Vaccines on Pneumonia Hospitalizations in High- and Low-Income Subpopulations in Brazil.

BACKGROUND: Pneumococcal conjugate vaccines (PCVs) are being used worldwide. A key question is whether the impact of PCVs on pneumonia is similar in low- and high-income populations. However, most low-income countries, where the burden of disease is greatest, lack reliable data that can be used to evaluate the impact. Data from middle-income countries that have both low- and high-income subpopulations can provide a proxy measure for the impact of the vaccine in low-income countries. METHODS: We evaluated the impact of PCV10 on hospitalizations for all-cause pneumonia in Brazil, a middle-income country with localities that span a broad range of human development index (HDI) levels. We used complementary time series and spatiotemporal methods (synthetic controls and hierarchical Bayesian spatial regression) to test whether the decline in pneumonia hospitalizations associated with vaccine introduction varied across the socioeconomic spectrum. RESULTS: We found that the declines in all-cause pneumonia hospitalizations in children and young and middle-aged adults did not vary substantially across low and high HDI subpopulations. Moreover, the estimated declines seen in infants and young adults were associated with higher levels of uptake of the vaccine at a local level. CONCLUSIONS: These results suggest that PCVs have an important impact on hospitalizations for all-cause pneumonia in both low- and high-income populations.

Bayesian Model Averaging with Change Points to Assess the Impact of Vaccination and Public Health Interventions.

BACKGROUND: Pneumococcal conjugate vaccines (PCVs) prevent invasive pneumococcal disease and pneumonia. However, some low-and middle-income countries have yet to introduce PCV into their immunization programs due, in part, to lack of certainty about the potential impact. Assessing PCV benefits is challenging because specific data on pneumococcal disease are often lacking, and it can be difficult to separate the effects of factors other than the vaccine that could also affect pneumococcal disease rates. METHODS: We assess PCV impact by combining Bayesian model averaging with change-point models to estimate the timing and magnitude of vaccine-associated changes, while controlling for seasonality and other covariates. We applied our approach to monthly time series of age-stratified hospitalizations related to pneumococcal infection in children younger 5 years of age in the United States, Brazil, and Chile. RESULTS: Our method accurately detected changes in data in which we knew true and noteworthy changes occurred, i.e., in simulated data and for invasive pneumococcal disease. Moreover, 24 months after the vaccine introduction, we detected reductions of 14%, 9%, and 9% in the United States, Brazil, and Chile, respectively, in all-cause pneumonia (ACP) hospitalizations for age group 0 to <1 years of age. CONCLUSIONS: Our approach provides a flexible and sensitive method to detect changes in disease incidence that occur after the introduction of a vaccine or other intervention, while avoiding biases that exist in current approaches to time-trend analyses.

Estimates of hospitalization attributable to influenza and RSV in the US during 1997-2009, by age and risk status.

BACKGROUND: Estimates of influenza and respiratory syncytial virus (RSV) burden must be periodically updated to inform public health strategies. We estimated seasonal influenza- and RSV-attributable hospitalizations in the US from 1997 to 2009 according to age and risk status (NCT01599390). METHODS: Multiple linear regression modelling was used to attribute hospitalizations to influenza or RSV using virological surveillance and hospitalization data. Hospitalization data were obtained from the US Nationwide Inpatient Sample and virology data were obtained from FluView (Centers for Disease Control and Prevention). Outcomes included any mention of ICD-coded respiratory disease and cardiorespiratory disease diagnoses. We also explored a broader definition of respiratory disease that included mention of relevant respiratory sign/symptoms and viral infection ("respiratory broad"). RESULTS: Applying the respiratory broad outcome, our model attributed ~300,000 and ~200,000 hospitalizations to influenza and RSV, respectively. Influenza A/H3N2 was the predominant cause of influenza-related hospitalizations in most seasons, except in three seasons when influenza B was dominant; likewise, A/H3N2 caused most influenza-related hospitalizations in all age segments, except in children <18 years where the relative contribution of A/H3N2 and B was similar. Most influenza A- and B-related hospitalizations occurred in seniors while approximately one half and one third of all RSV-related events occurred in children 0-4 years and seniors 65+ years, respectively. High-risk status was associated with higher risk of both influenza- and RSV-attributable hospitalizations in adults, but not in children. CONCLUSIONS: Our study assessed the burden of influenza and RSV, information that is important for both cost effectiveness studies and for prioritization of the development of antivirals and vaccines. For seniors, we found that the burdens of influenza and RSV were both substantial. Among children <18 years, about half of all influenza hospitalizations were due to influenza B, most occurring in children without noted risk conditions. RSV hospitalizations among children were confined to those 0-4 years. Our study also demonstrated the importance of the outcome used to estimate hospitalization burden. Our findings highlight the burden of influenza among children regardless of risk status and underscore the prevalence of RSV infections among both young children and older adults.

Modelling estimates of age-specific influenza-related hospitalisation and mortality in the United Kingdom.

BACKGROUND: Influenza is rarely confirmed with laboratory testing and accurate assessment of the overall burden of influenza is difficult. We used statistical modelling methods to generate updated, granular estimates of the number/rate of influenza-attributable hospitalisations and deaths in the United Kingdom. Such data are needed on a continuing basis to inform on cost-benefit analyses of treatment interventions, including vaccination. METHODS: Weekly age specific data on hospital admissions (1997-2009) and on deaths (1997-2009) were obtained from national databases. Virology reports (1996-2009) of influenza and respiratory syncytial virus detections were provided by Public Health England. We used an expanded set of ICD-codes to estimate the burden of illness attributable to influenza which we refer to as 'respiratory disease broadly defined'. These codes were chosen to optimise the balance between sensitivity and specificity. A multiple linear regression model controlled for respiratory syncytial virus circulation, with stratification by age and the presence of comorbid risk status (conditions associated with severe influenza outcomes). RESULTS: In the United Kingdom there were 28,516 hospitalisations and 7163 deaths estimated to be attributable to influenza respiratory disease in a mean season, with marked variability between seasons. The highest incidence rates of influenza-attributable hospitalisations and deaths were observed in adults aged 75+ years (252/100,000 and 131/100,000 population, respectively). Influenza B hospitalisations were highest among 5-17 year olds (12/100,000 population). Of all estimated influenza respiratory deaths in 75+ year olds, 50 % occurred out of hospital, and 25 % in 50-64 year olds. Rates of hospitalisations and death due to influenza-attributable respiratory disease were increased in adults identified as at-risk. CONCLUSIONS: Our study points to a substantial but highly variable seasonal influenza burden in all age groups, particularly affecting 75+ year olds. Effective influenza prevention or early intervention with anti-viral treatment in this age group may substantially impact the disease burden and associated healthcare costs. The high burden of influenza B hospitalisation among 5-17 year olds supports current United Kingdom vaccine policy to extend quadrivalent seasonal influenza vaccination to this age group. TRIAL REGISTRATION: ClinicalTrial.gov, NCT01520935.

Modelling estimates of the burden of Respiratory Syncytial virus infection in adults and the elderly in the United Kingdom.

BACKGROUND: Growing evidence suggests respiratory syncytial virus (RSV) is an important cause of respiratory disease in adults. However, the adult burden remains largely uncharacterized as most RSV studies focus on children, and population-based studies with laboratory-confirmation of infection are difficult to implement. Indirect modelling methods, long used for influenza, can further our understanding of RSV burden by circumventing some limitations of traditional surveillance studies that rely on direct linkage of individual-level exposure and outcome data. METHODS: Multiple linear time-series regression was used to estimate RSV burden in the United Kingdom (UK) between 1995 and 2009 among the total population and adults in terms of general practice (GP) episodes (counted as first consultation ≥28 days following any previous consultation for same diagnosis/diagnostic group), hospitalisations, and deaths for respiratory disease, using data from Public Health England weekly influenza/RSV surveillance, Clinical Practice Research Datalink, Hospital Episode Statistics, and Office of National Statistics. The main outcome considered all ICD-listed respiratory diseases and, for GP episodes, related symptoms. Estimates were adjusted for non-specific seasonal drivers of disease using secular cyclical terms and stratified by age and risk group (according to chronic conditions indicating severe influenza risk as per UK recommendations for influenza vaccination). Trial registration NCT01706302 . Registered 11 October 2012. RESULTS: Among adults aged 18+ years an estimated 487,247 GP episodes, 17,799 hospitalisations, and 8,482 deaths were attributable to RSV per average season. Of these, 175,070 GP episodes (36 %), 14,039 hospitalisations (79 %) and 7,915 deaths (93 %) were in persons aged 65+ years. High- versus low-risk elderly were two-fold more likely to have a RSV-related GP episode or death and four-fold more likely be hospitalised for RSV. In most seasons since 2001, more GP episodes, hospitalisations and deaths were attributable to RSV in adults than to influenza. CONCLUSION: RSV is associated with a substantial disease burden in adults comparable to influenza, with most of the hospitalisation and mortality burden in the elderly. Treatment options and measures to prevent RSV could have a major impact on the burden of RSV respiratory disease in adults, especially the elderly.

Beyond crystal balls: crosscutting solutions in global health to prepare for an unpredictable future.

BACKGROUND: Efforts in global heath need to deal not only with current challenges, but also to anticipate new scenarios, which sometimes unfold at lightning speed. Predictive modeling is frequently used to assist planning, but outcomes depend heavily on a subset of critical assumptions, which are mostly hampered by our limited knowledge about the many factors, mechanisms and relationships that determine the dynamics of disease systems, by a lack of data to parameterize and validate models, and by uncertainties about future scenarios. DISCUSSION: We propose a shift from a focus on the prediction of individual disease patterns to the identification and mitigation of broader fragilities in public health systems. Modeling capabilities should be used to perform "stress tests" on how interrelated fragilities respond when faced with a range of possible or plausible threats of different nature and intensity. This system should be able to reveal crosscutting solutions with the potential to address not only one threat, but multiple areas of vulnerability to future health risks. Actionable knowledge not based on a narrow subset of threats and conditions can better guide policy, build societal resilience and ensure effective prevention in an uncertain world.

Shift in the timing of respiratory syncytial virus circulation in a subtropical megalopolis: implications for immunoprophylaxis.

Respiratory syncytial virus (RSV) is the most common cause of severe respiratory infections worldwide, and an important cause of childhood bronchiolitis, pneumonia, and mortality. Although prevention of RSV infection by immunoprophylaxis with palivizumab has proved effective, a precise understanding of the timing of RSV outbreaks is necessary to ensure that infants are protected when RSV is circulating. In this study a consistent shift in the seasonal patterns of RSV circulation in southeast Brazil (São Paulo) is reported based on the analysis of 15 years of viral surveillance. Surveillance was conducted from 1996 to 2010 and involved the collection of samples from children with symptoms of acute respiratory infection. Putative changes in school terms, in the proportion of RSV genotypes infecting children and in the seasonal dynamics of several climatic parameters during the period were also investigated. The results revealed a progression in the timing of RSV seasons, with a shift in the onset and peak of RSV epidemics from 2007 onwards. Although lower rainfall and temperatures were associated with the onset of outbreaks, there was no evidence of changes in climate, school terms or in the relative proportion of genotypes in the period analyzed. These findings have direct implications for improving the prophylactic use of palivizumab, and stress the importance of fine tuning prophylaxis with recent surveillance data. In the case of São Paulo, palivizumab prophylaxis should be initiated earlier than suggested currently. Similar adjustments may be necessary in other regions.

Productivity of mother pigs is lower, and mortality greater, in countries that still confine them in gestation crates.

Background: For decades, pig farmers have used gestation crates - small metal enclosures about two feet wide - to confine pregnant sows (female breeding pigs). Gestation crates physically restrain sows for most of their life, preventing them from walking or even turning around. Millions of females are still housed in these systems. Growing societal concern about animal welfare has been pressuring the industry for change, with recent legislation in the European Union and California restricting the use of crates. Still, the notion that gestation crates negatively affect sow welfare has been challenged by producers in regions where crates are widely used, who argue that, by facilitating health monitoring and preventing aggression, crates lead to lower sow mortality and higher piglet outputs per sow. We address these claims by comparing sow mortality and performance across countries with different housing systems. Methods: To this end, we use publicly available data from InterPig, a network of pig production economists in 17 countries that provides internationally harmonized methods for meaningful comparisons of national production data. Results: The results show that sow mortality is significantly higher, and annual pig production per sow significantly lower, in those countries where gestation crates are still the norm compared to countries in the European Union, where use of gestation crates is restricted to up to four weeks after insemination. Conclusions: Claims of higher mortality and reduced productivity per sow in crate-free systems are not substantiated by this data. This evidence should be considered in policies affecting the welfare of breeding pigs.

Pain-Track: a time-series approach for the description and analysis of the burden of pain.

OBJECTIVE: To present the Pain-Track, a novel framework for the description and analysis of the pain experience based on its temporal evolution, around which intensity and other attributes of pain (texture, anatomy), interventions and clinical symptoms can be registered. This time-series approach can provide valuable insight on the expected evolution of the pain typically associated with different medical conditions and on time-varying (risk) factors associated with the temporal dynamics of pain. RESULTS: We illustrate the use of the framework to explore hypotheses on the temporal profile of the pain associated with an acute injury (bone fracture), and the magnitude of the pain burden it represents. We also show that, by focusing on the critical dimensions of the pain experience (intensity and time), the approach can help map different conditions to a common scale directly relating to the experiences of those who endure them (time in pain), providing the basis for the quantification of the burden of pain inflicted upon individuals or populations. An electronic version for data entry and interpretation is also presented.

Laying hen mortality in different indoor housing systems: a meta-analysis of data from commercial farms in 16 countries.

Societal concern with the welfare of egg laying hens housed in conventional cages is fostering a transition towards cage-free systems in many countries. However, although cage-free facilities enable hens to move freely and express natural behaviours, concerns have also been raised over the possibility that cage-free flocks experience higher mortality, potentially compromising some aspects of their welfare. To investigate this possibility, we conducted a large meta-analysis of laying hen mortality in conventional cages, furnished cages and cage-free aviaries using data from 6040 commercial flocks and 176 million hens from 16 countries. We show that except for conventional cages, mortality gradually drops as experience with each system builds up: since 2000, each year of experience with cage-free aviaries was associated with a 0.35-0.65% average drop in cumulative mortality, with no differences in mortality between caged and cage-free systems in more recent years. As management knowledge evolves and genetics are optimized, new producers transitioning to cage-free housing may experience even faster rates of decline. Our results speak against the notion that mortality is inherently higher in cage-free production and illustrate the importance of considering the degree of maturity of production systems in any investigations of farm animal health, behaviour and welfare.

Means to an end: neotropical parrots manage to pull strings to meet their goals.

Although parrots share with corvids and primates many of the traits believed to be associated with advanced cognitive processing, knowledge of parrot cognition is still limited to a few species, none of which are Neotropical. Here we examine the ability of three Neotropical parrot species (Blue-Fronted Amazons, Hyacinth and Lear's macaws) to spontaneously solve a novel physical problem: the string-pulling test. The ability to pull up a string to obtain out-of-reach food has been often considered a cognitively complex task, as it requires the use of a sequence of actions never previously assembled, along with the ability to continuously monitor string, food and certain body movements. We presented subjects with pulling tasks where we varied the spatial relationship between the strings, the presence of a reward and the physical contact between the string and reward to determine whether (1) string-pulling is goal-oriented in these parrots, (2) whether the string is recognized as a means to obtain the reward and (3) whether subjects can visually determine the continuity between the string and the reward, selecting only those strings for which no physical gaps between string and reward were present. Our results show that some individuals of all species were able to use the string as a means to reach a specific goal, in this case, the retrieval of the food treat. Also, subjects from both macaw species were able to visually determine the presence of physical continuity between the string and reward, making their choices consistently with the recognition that no gaps should be present between the string and the reward. Our findings highlight the potential of this taxonomic group for the understanding of the underpinnings of cognition in evolutionarily distant groups such as birds and primates.

Effect of pneumococcal conjugate vaccine introduction on childhood pneumonia mortality in Brazil: a retrospective observational study.

BACKGROUND: Understanding the real-world effect of pneumococcal conjugate vaccines (PCVs) on pneumonia mortality is crucial because of the expectation that increased PCV use will substantially reduce the burden of pneumonia deaths in children younger than 5 years. However, few post-vaccine introduction studies have estimated the benefits of PCV use on childhood mortality and results have been inconsistent. Therefore, we set out to assess the effect of introduction of ten-valent pneumococcal conjugate vaccine (PCV10) on pneumonia mortality in children in Brazil. METHODS: In this retrospective observational study, we used publicly available mortality data of children aged 3-59 months in Brazil. We separated data by age group (3-11 months, 3-23 months, and 3-59 months) and stratified data by three different socioeconomic factors of Brazilian municipalities (in 2010): Human Development Index, proportion of children living in extreme poverty, and proportion of mothers with no primary education. We first examined long-term trends in childhood pneumonia mortality in Brazil (from 1980 to 2014). We then assessed the effect of PCV10-introduced in Brazil in 2010-both nationally and in municipalities stratified by socioeconomic status, with a synthetic control approach as our primary analytical method. FINDINGS: Between 1980 and 2010, a period during which Brazil's Human Development Index rose substantially, national pneumonia mortality in children younger than 5 years decreased from about 150 to 15 deaths per 100 000 children younger than 5 years. Despite rapid uptake of PCV10 after its introduction in 2010, we observed a further vaccine-associated decline of about 10% in national childhood pneumonia mortality with our primary analytical method, with a high degree of uncertainty in the estimates. We observed larger reductions in municipal childhood pneumonia mortality in all three age groups (3-11 months, 3-23 months, and 3-59 months) in municipalities with a high percentage of extreme childhood poverty and mothers with no primary education, with the largest decrease observed in children aged 3-23 months in municipalities with low maternal education (24%, 95% credible interval 7-35). INTERPRETATION: The large reduction observed from 1980 to 2010 in national pneumonia mortality in children younger than 5 years underscores that improvements in nutrition, hygiene, education, and health care have an important role in reducing pneumonia mortality. Although the PCV-associated reduction in childhood pneumonia mortality at the national level was modest, we found that PCV led to larger reductions in low-income municipalities. Similarly, large benefits might occur when PCVs are introduced in other low-income settings. FUNDING: Bill & Melinda Gates Foundation and National Institute of Allergy and Infectious Diseases.

Cognition in an ever-changing world: climatic variability is associated with brain size in Neotropical parrots.

Research on the conditions favoring the evolution of complex cognition and its underlying neural structures has increasingly stressed the role of environmental variability. These studies suggest that the ability to learn, behave flexibly and innovate would be favored under unpredictable variations in the availability of resources, as it would enable organisms to adjust to novel conditions. Despite the growing number of studies based on the idea that larger-brained organisms would be better prepared to cope with environmental challenges, direct testing of the association between brain size and environmental variability per se remains scant. Here we focus on Neotropical parrots as our model group and test the hypothesis that if relatively larger brains were favored in climatically variable environments, larger-brained species should currently tolerate a higher degree of environmental uncertainty. Although we show that there are also other factors underlying the dynamics of brain size variation in this group, our results support the hypothesis that proportionally larger-brained species are more tolerant to climatic variability, both on a temporal and spatial scale. Additionally, they suggest that the differences in relative brain size among Neotropical parrots represent multiple, recent events in the evolutionary history of the group, and are particularly tied to an increased dependence on more open and climatically unstable habitats. As this is the first study to present evidence of the link between brain size and climatic variability in birds, our findings provide a step towards understanding the potential benefits underlying variation in brain size and the maintenance of highly enlarged brains in this and other groups.

We could learn much more from 1918 pandemic-the (mis)fortune of research relying on original death certificates.

PURPOSE: The analysis of historical death certificates has enormous potential for understanding how the health of populations was shaped by diseases and epidemics and by the implementation of specific interventions. In Brazil, the systematic archiving of mortality records was initiated only in 1944-hence the analysis of death registers before this time requires searching for these documents in public archives, notaries, parishes, and especially ancient cemeteries, which are often the only remaining source of information about these deaths. This article describes an effort to locate original death certificates in Brazil and document their organization, accessibility, and preservation. METHODS: To this end, we conducted an exploratory study in 19 of the 27 Brazilian states, focusing on the period surrounding the 1918 influenza pandemic (1913-1921). We included 55 cemeteries, 22 civil archives, and one military archive. RESULTS: Apart from few exceptions, the results show the absence of a curatorial policy for the organization, access or even physical preservation of this material, frequently leading to unavailability, deterioration, and ultimately its complete loss. CONCLUSIONS: This study indicates the need to promote the preservation of a historical heritage that is a key to understanding historical epidemiological patterns and human responses to global health threats.

State-dependent decisions cause apparent violations of rationality in animal choice.

Normative models of choice in economics and biology usually expect preferences to be consistent across contexts, or "rational" in economic language. Following a large body of literature reporting economically irrational behaviour in humans, breaches of rationality by animals have also been recently described. If proven systematic, these findings would challenge long-standing biological approaches to behavioural theorising, and suggest that cognitive processes similar to those claimed to cause irrationality in humans can also hinder optimality approaches to modelling animal preferences. Critical differences between human and animal experiments have not, however, been sufficiently acknowledged. While humans can be instructed conceptually about the choice problem, animals need to be trained by repeated exposure to all contingencies. This exposure often leads to differences in state between treatments, hence changing choices while preserving rationality. We report experiments with European starlings demonstrating that apparent breaches of rationality can result from state-dependence. We show that adding an inferior alternative to a choice set (a "decoy") affects choices, an effect previously interpreted as indicating irrationality. However, these effects appear and disappear depending on whether state differences between choice contexts are present or not. These results open the possibility that some expressions of maladaptive behaviour are due to oversights in the migration of ideas between economics and biology, and suggest that key differences between human and nonhuman research must be recognised if ideas are to safely travel between these fields.