PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (1337507)

Clipboard (0)
None

Related Articles

1.  Serotype-Specific Changes in Invasive Pneumococcal Disease after Pneumococcal Conjugate Vaccine Introduction: A Pooled Analysis of Multiple Surveillance Sites 
PLoS Medicine  2013;10(9):e1001517.
In a pooled analysis of data collected from invasive pneumococcal disease surveillance databases, Daniel Feikin and colleagues examine serotype replacement after the introduction of 7-valent pneumococcal conjugate vaccine (PCV7) into national immunization programs.
Please see later in the article for the Editors' Summary
Background
Vaccine-serotype (VT) invasive pneumococcal disease (IPD) rates declined substantially following introduction of 7-valent pneumococcal conjugate vaccine (PCV7) into national immunization programs. Increases in non-vaccine-serotype (NVT) IPD rates occurred in some sites, presumably representing serotype replacement. We used a standardized approach to describe serotype-specific IPD changes among multiple sites after PCV7 introduction.
Methods and Findings
Of 32 IPD surveillance datasets received, we identified 21 eligible databases with rate data ≥2 years before and ≥1 year after PCV7 introduction. Expected annual rates of IPD absent PCV7 introduction were estimated by extrapolation using either Poisson regression modeling of pre-PCV7 rates or averaging pre-PCV7 rates. To estimate whether changes in rates had occurred following PCV7 introduction, we calculated site specific rate ratios by dividing observed by expected IPD rates for each post-PCV7 year. We calculated summary rate ratios (RRs) using random effects meta-analysis. For children <5 years old, overall IPD decreased by year 1 post-PCV7 (RR 0·55, 95% CI 0·46–0·65) and remained relatively stable through year 7 (RR 0·49, 95% CI 0·35–0·68). Point estimates for VT IPD decreased annually through year 7 (RR 0·03, 95% CI 0·01–0·10), while NVT IPD increased (year 7 RR 2·81, 95% CI 2·12–3·71). Among adults, decreases in overall IPD also occurred but were smaller and more variable by site than among children. At year 7 after introduction, significant reductions were observed (18–49 year-olds [RR 0·52, 95% CI 0·29–0·91], 50–64 year-olds [RR 0·84, 95% CI 0·77–0·93], and ≥65 year-olds [RR 0·74, 95% CI 0·58–0·95]).
Conclusions
Consistent and significant decreases in both overall and VT IPD in children occurred quickly and were sustained for 7 years after PCV7 introduction, supporting use of PCVs. Increases in NVT IPD occurred in most sites, with variable magnitude. These findings may not represent the experience in low-income countries or the effects after introduction of higher valency PCVs. High-quality, population-based surveillance of serotype-specific IPD rates is needed to monitor vaccine impact as more countries, including low-income countries, introduce PCVs and as higher valency PCVs are used.
Please see later in the article for the Editors' Summary
Editors’ Summary
Background
Pneumococcal disease–a major cause of illness and death in children and adults worldwide–is caused by Streptococcus pneumoniae, a bacterium that often colonizes the nose and throat harmlessly. Unfortunately, S. pneumoniae occasionally spreads into the lungs, bloodstream, or covering of the brain, where it causes pneumonia, septicemia, and meningitis, respectively. These invasive pneumococcal diseases (IPDs) can usually be successfully treated with antibiotics but can be fatal. Consequently, it is better to avoid infection through vaccination. Vaccination primes the immune system to recognize and attack disease-causing organisms (pathogens) rapidly and effectively by exposing it to weakened or dead pathogens or to pathogen molecules that it recognizes as foreign (antigens). Because there are more than 90 S. pneumoniae variants or “serotypes,” each characterized by a different antigenic polysaccharide (complex sugar) coat, vaccines that protect against S. pneumoniae have to include multiple serotypes. Thus, the pneumococcal conjugate vaccine PCV7, which was introduced into the US infant immunization regimen in 2000, contains polysaccharides from the seven S. pneumoniae serotypes mainly responsible for IPD in the US at that time.
Why Was This Study Done?
Vaccination with PCV7 was subsequently introduced in several other high- and middle-income countries, and IPD caused by the serotypes included in the vaccine declined substantially in children and in adults (because of reduced bacterial transmission and herd protection) in the US and virtually all these countries. However, increases in IPD caused by non-vaccine serotypes occurred in some settings, presumably because of “serotype replacement.” PCV7 prevents both IPD caused by the serotypes it contains and carriage of these serotypes. Consequently, after vaccination, previously less common, non-vaccine serotypes can colonize the nose and throat, some of which can cause IPD. In July 2010, a World Health Organization expert consultation on serotype replacement called for a comprehensive analysis of the magnitude and variability of pneumococcal serotype replacement following PCV7 use to help guide the introduction of PCVs in low-income countries, where most pneumococcal deaths occur. In this pooled analysis of data from multiple surveillance sites, the researchers investigate serotype-specific changes in IPD after PCV7 introduction using a standardized approach.
What Did the Researchers Do and Find?
The researchers identified 21 databases that had data about the rate of IPD for at least 2 years before and 1 year after PCV7 introduction. They estimated whether changes in IPD rates had occurred after PCV7 introduction by calculating site-specific rate ratios–the observed IPD rate for each post-PCV7 year divided by the expected IPD rate in the absence of PCV7 extrapolated from the pre-PCV7 rate. Finally, they used a statistical approach (random effects meta-analysis) to estimate summary (pooled) rate ratios. For children under 5 years old, the overall number of observed cases of IPD in the first year after the introduction of PCV7 was about half the expected number; this reduction in IPD continued through year 7 after PCV7 introduction. Notably, the rate of IPD caused by the S. pneumonia serotypes in PCV7 decreased every year, but the rate of IPD caused by non-vaccine serotypes increased annually. By year 7, the number of cases of IPD caused by non-vaccine serotypes was 3-fold higher than expected, but was still smaller than the decrease in vaccine serotypes, thereby leading to the decrease in overall IPD. Finally, smaller decreases in overall IPD also occurred among adults but occurred later than in children 2 years or more after PCV7 introduction.
What Do These Findings Mean?
These findings show that consistent, rapid, and sustained decreases in overall IPD and in IPD caused by serotypes included in PCV7 occurred in children and thus support the use of PCVs. The small increases in IPD caused by non-vaccine serotypes that these findings reveal are likely to be the result of serotype replacement, but changes in antibiotic use and other factors may also be involved. These findings have several important limitations, however. For example, PCV7 is no longer made and extrapolation of these results to newer PCV10 and PCV13 formulations should be done cautiously. On the other hand, many of the serotypes causing serotype replacement after PCV7 are included in these higher valency vaccines. Moreover, because the data analyzed in this study mainly came from high-income countries, these findings may not be generalizable to low-income countries. Nevertheless, based on their analysis, the researchers make recommendations for the collection and analysis of IPD surveillance data that should allow valid interpretations of the effect of PCVs on IPD to be made, an important requisite for making sound policy decisions about vaccination against pneumococcal disease.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001517.
The US Centers for Disease Control and Prevention provides information for patients and health professionals on all aspects of pneumococcal disease and pneumococcal vaccination, including personal stories
Public Health England provides information on pneumococcal disease and on pneumococcal vaccines
The World Health Organization also provides information on pneumococcal vaccines
The not-for-profit Immunization Action Coalition has information on pneumococcal disease, including personal stories
MedlinePlus has links to further information about pneumococcal infections (in English and Spanish)
The International Vaccine Access Center at Johns Hopkins Bloomberg School of Public Health has more information on introduction of pneumococcal conjugate vaccines in low-income countries
doi:10.1371/journal.pmed.1001517
PMCID: PMC3782411  PMID: 24086113
2.  Evaluation of Coseasonality of Influenza and Invasive Pneumococcal Disease: Results from Prospective Surveillance 
PLoS Medicine  2011;8(6):e1001042.
Using a combination of modeling and statistical analyses, David Fisman and colleagues show that influenza likely influences the incidence of invasive pneumococcal disease by enhancing risk of invasion in colonized individuals.
Background
The wintertime co-occurrence of peaks in influenza and invasive pneumococcal disease (IPD) is well documented, but how and whether wintertime peaks caused by these two pathogens are causally related is still uncertain. We aimed to investigate the relationship between influenza infection and IPD in Ontario, Canada, using several complementary methodological tools.
Methods and Findings
We evaluated a total number of 38,501 positive influenza tests in Central Ontario and 6,191 episodes of IPD in the Toronto/Peel area, Ontario, Canada, between 1 January 1995 and 3 October 2009, reported through population-based surveillance. We assessed the relationship between the seasonal wave forms for influenza and IPD using fast Fourier transforms in order to examine the relationship between these two pathogens over yearly timescales. We also used three complementary statistical methods (time-series methods, negative binomial regression, and case-crossover methods) to evaluate the short-term effect of influenza dynamics on pneumococcal risk. Annual periodicity with wintertime peaks could be demonstrated for IPD, whereas periodicity for influenza was less regular. As for long-term effects, phase and amplitude terms of pneumococcal and influenza seasonal sine waves were not correlated and meta-analysis confirmed significant heterogeneity of influenza, but not pneumococcal phase terms. In contrast, influenza was shown to Granger-cause pneumococcal disease. A short-term association between IPD and influenza could be demonstrated for 1-week lags in both case-crossover (odds ratio [95% confidence interval] for one case of IPD per 100 influenza cases  = 1.10 [1.02–1.18]) and negative binomial regression analysis (incidence rate ratio [95% confidence interval] for one case of IPD per 100 influenza cases  = 1.09 [1.05–1.14]).
Conclusions
Our data support the hypothesis that influenza influences bacterial disease incidence by enhancing short-term risk of invasion in colonized individuals. The absence of correlation between seasonal waveforms, on the other hand, suggests that bacterial disease transmission is affected to a lesser extent.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Although some pathogens (disease-causing organisms) cause illness all year round, others are responsible for seasonal peaks of illness. These peaks occur because of a complex interplay of factors such as the loss of immunity to the pathogen over time and seasonal changes in the pathogen's ability to infect new individuals. Thus, in temperate countries in the northern hemisphere, illness caused by influenza viruses (pathogens that infect the nose, throat, and airways) usually peaks between December and March, perhaps because weather conditions during these months favor the survival of influenza virus in the environment and thus increase its chances of being transferred among people. Another illness that peaks during the winter months in temperate regions is pneumonia, a severe lung infection that is often caused by Streptococcus pneumoniae. These bacteria can colonize the back of the throat without causing disease but occasionally spread into the lungs and other organs where they cause potentially fatal invasive pneumococcal disease (IPD).
Why Was This Study Done?
Although the co-occurrence of seasonal peaks of influenza and IPD is well documented, it is unclear whether (or how) these peaks are causally related. For example, do the peaks of influenza and IPD both occur in the winter because influenza enhances person-to-person transmission of S. pneumoniae (hypothesis 1)? Alternatively, do the diseases co-occur because influenza infection increases the risk of IPD in individuals who are already colonized with S. pneumoniae (hypothesis 2)? Healthcare professionals need to know whether there is a causal relationship between influenza and IPD so that they can target vaccination for both diseases to those individuals most at risk of developing the potentially serious complications of these diseases. In this study, the researchers use several mathematical and statistical methods and data on influenza and IPD collected in Ontario, Canada to investigate the relationship between these seasonal illnesses.
What Did the Researchers Do and Find?
Between January 1995 and October 2009, 38,501 positive influenza tests were recorded in Ontario by the Canadian national influenza surveillance network. Over the same time period, the Toronto Invasive Bacterial Diseases Network (a group of hospitals, laboratories, and doctors that undertakes population-based surveillance for serious bacterial infections in the Toronto and Peel Regions of Ontario) recorded 6,191 IPD episodes. The researchers used a mathematical method called fast Fourier transforms that compares the shape of wave forms to look for any relationship between infections with the two pathogens over yearly timescales (a test of hypothesis 1) and three statistical methods to evaluate the short-term effect of influenza dynamics on IPD risk (tests of hypothesis 2). Although they found wintertime peaks for infections with both pathogens, there was no correlation between the seasonal wave forms for influenza and IPD. That is, there was no relationship between the seasonal patterns of the two infections. By contrast, two of the statistical methods used to test hypothesis 2 revealed a short-term association between infections with influenza and with IPD. Moreover, the third statistical method (the Granger causality Wald test, a type of time-series analysis) provided evidence that data collected at intervals on influenza can be used to predict peaks in IPD infections.
What Do These Findings Mean?
These findings support (but do not prove) the hypothesis that influenza influences IPD incidence by enhancing the short-term risk of bacterial invasion in individuals already colonized with S. pneumoniae, possibly by increasing the permeability of the lining of the airways to bacteria. By contrast, the lack of correlation between the seasonal wave forms for the two diseases suggests that person-to-person transfer of S. pneumoniae is affected by influenza infections to a lesser extent. These findings have important implications for disease control policy. First, they suggest that the increased number of influenza infections in pandemic years may not necessarily be accompanied by a marked surge in IPD. Second, because the findings suggest that some cases of IPD may be influenza-attributable, the extension of influenza vaccination to school-age children and young adults (a group of people at particular risk of IPD who are not normally vaccinated against influenza) could reduce the incidence of IPD as well as the incidence of influenza.
Additional Information
Please access these Web sites via the online version of this summary at http://www.plosone.org/article/info:doi/10.1371/journal.pone.0015493
A related research article by the same authors evaluating links between respiratory viruses and invasive meningococcal disease can be found in PLoS One (e0015493)
The US Centers for Disease Control and Prevention provides information for patients and health professionals on all aspects of seasonal influenza and pneumococcal disease and pneumococcal vaccination
The UK National Health Service Choices website also provides information for patients about seasonal influenza and pneumococcal infection
MedlinePlus has links to further information about influenza and pneumococcal infections (in English and Spanish)
FluWatch is the Canadian national surveillance system for influenza
More information about the Toronto Invasive Bacterial Network is available
The International Association for Ecology and Health provides information on the physical environment and its influence on health
doi:10.1371/journal.pmed.1001042
PMCID: PMC3110256  PMID: 21687693
3.  Systematic review of methods for individual patient data meta- analysis with binary outcomes 
Background
Meta-analyses (MA) based on individual patient data (IPD) are regarded as the gold standard for meta-analyses and are becoming increasingly common, having several advantages over meta-analyses of summary statistics. These analyses are being undertaken in an increasing diversity of settings, often having a binary outcome. In a previous systematic review of articles published between 1999–2001, the statistical approach was seldom reported in sufficient detail, and the outcome was binary in 32% of the studies considered. Here, we explore statistical methods used for IPD-MA of binary outcomes only, a decade later.
Methods
We selected 56 articles, published in 2011 that presented results from an individual patient data meta-analysis. Of these, 26 considered a binary outcome. Here, we review 26 IPD-MA published during 2011 to consider: the goal of the study and reason for conducting an IPD-MA, whether they obtained all the data they sought, the approach used in their analysis, for instance, a two-stage or a one stage model, and the assumption of fixed or random effects. We also investigated how heterogeneity across studies was described and how studies investigated the effects of covariates.
Results
19 of the 26 IPD-MA used a one-stage approach. 9 IPD-MA used a one-stage random treatment-effect logistic regression model, allowing the treatment effect to vary across studies. Twelve IPD-MA presented some form of statistic to measure heterogeneity across studies, though these were usually calculated using two-stage approach. Subgroup analyses were undertaken in all IPD-MA that aimed to estimate a treatment effect or safety of a treatment,. Sixteen meta-analyses obtained 90% or more of the patients sought.
Conclusion
Evidence from this systematic review shows that the use of binary outcomes in assessing the effects of health care problems has increased, with random effects logistic regression the most common method of analysis. Methods are still often not reported in enough detail. Results also show that heterogeneity of treatment effects is discussed in most applications.
doi:10.1186/1471-2288-14-79
PMCID: PMC4074845  PMID: 24943877
Individual patient data; Meta-analysis; Random effects; Systematic review; Heterogeneity; One-stage
4.  The strengths and limitations of meta-analyses based on aggregate data 
Background
Properly performed systematic reviews and meta-analyses are thought by many to represent among the highest level of evidence addressing important clinical issues. Few would disagree that meta-analyses based on individual patient data (IPD) offer several advantages and represent the standard to which all other systematic reviews should be compared.
Methods
All cancer-related meta-analyses cited in Medline were classified as based on aggregate or individual patient data. A review was then undertaken of all reports comparing the comparative strengths and limitations of meta-analyses using either aggregate or individual patient data.
Results
The majority of published meta-analyses are based on summary or aggregate patient data (APD). Reasons suggested for this include the considerable resources, years of study and often, broad international cooperation required for IPD meta-analyses. Many of the most important features of systematic reviews including formal meta-analyses are addressed by both IPD and APD meta-analyses. The need for defining an explicit and relevant clinical question, exhaustively searching for the totality of evidence, meticulous and unbiased data transfer or extraction, assessment of between study heterogeneity and the use of appropriate statistical methods for estimating summary effect measures are essentially the same for the two approaches.
Conclusion
IPD offers advantages and, when feasible, should be considered the best opportunity to summarize the results of multiple studies. However, the resources, time and cooperation required for such studies will continue to limit their use in many important areas of clinical medicine which can be meaningfully and cost-effectively approached by properly performed APD meta-analyses. APD meta-analyses continue to be the mainstay of systematic reviews utilized by the US Preventive Services Task Force, the Cochrane Collaboration and many professional societies to support clinical practice guidelines.
doi:10.1186/1471-2288-5-14
PMCID: PMC1097735  PMID: 15850485
5.  Hospital at home admission avoidance 
Background
Admission avoidance hospital at home is a service that provides active treatment by health care professionals in the patient’s home for a condition that otherwise would require acute hospital in-patient care, and always for a limited time period. In particular, hospital at home has to offer a specific service to patients in their home requiring health care professionals to take an active part in the patients’ care. If hospital at home were not available then the patient would be admitted to an acute hospital ward. Many countries are adopting this type of care in an attempt to reduce the demand for acute hospital admission.
Objectives
To determine, in the context of a systematic review and meta analysis, the effectiveness and cost of managing patients with admission avoidance hospital at home compared with in-patient hospital care.
Search methods
The following databases were searched through to January 2008: MEDLINE, EMBASE, CINAHL, EconLit and the Cochrane Effective Practice and Organisation of Care Group (EPOC) register. We checked the reference lists of articles identified electronically for evaluations of hospital at home and obtained potentially relevant articles. Unpublished studies were sought by contacting providers and researchers who were known to be involved in this field.
Selection criteria
Randomised controlled trials recruiting patients aged 18 years and over. Studies comparing admission avoidance hospital at home with acute hospital in-patient care. The admission avoidance hospital at home interventions may admit patients directly from the community thereby avoiding physical contact with the hospital, or may admit from the emergency room.
Data collection and analysis
Two authors independently extracted data and assessed study quality. Our statistical analyses sought to include all randomised patients and were done on an intention to treat basis. We requested individual patient data (IPD) from trialists, and relied on published data when we did not receive trial data sets or the IPD did not include the relevant outcomes. When combining outcome data was not possible because of differences in the reporting of outcomes we have presented the data in narrative summary tables.
For the IPD meta-analysis, where at least one event was reported in both study groups in a trial, Cox regression models were used to calculate the log hazard ratio and its standard error for mortality and readmission separately for each data set (where both outcomes were available). We included randomisation group (admission avoidance hospital at home versus control), age (above or below the median), and gender in the models. The calculated log hazard ratios were combined using fixed effects inverse variance meta analysis. If there were no events in one group we used the Peto odds ratio method to calculate a log odds ratio from the sum of the log-rank test ‘O-E’ statistics from a Kaplan Meier survival analysis. Statistical significance throughout was taken at the two-sided 5% level (p<0.05) and data are presented as the estimated effect with 95% confidence intervals. For each comparison using published data for dichotomous outcomes we calculated risk ratios using a fixed effects model to combine data.
Main results
We included 10 RCTs (n=1333), seven of which were eligible for the IPD. Five out of these seven trials contributed to the IPD meta-analysis (n=850/975; 87%). There was a non significant reduction in mortality at three months for the admission avoidance hospital at home group (adjusted HR 0.77, 95% CI 0.54 to 1.09; p=0.15), which reached significance at six months follow-up (adjusted HR 0.62, 95% CI 0.45 to 0.87; p=0.005). A non significant increase in admissions was observed for patients allocated to hospital at home (adjusted HR 1.49, 95% CI 0.96 to 2.33; p=0.08). Few differences were reported for functional ability, quality of life or cognitive ability. Patients reported increased satisfaction with admission avoidance hospital at home. Two trials conducted a full economic analysis, when the costs of informal care were excluded admission avoidance hospital at home was less expensive than admission to an acute hospital ward.
Authors’ conclusions
We performed meta-analyses where there was sufficient similarity among the trials and where common outcomes had been measured. There is no evidence from the analysis to suggest that admission avoidance hospital at home leads to outcomes that differ from inpatient hospital care.
doi:10.1002/14651858.CD007491
PMCID: PMC4033791  PMID: 18843751
Home Care Services [economics; *organization & administration]; Home Care Services, Hospital-Based [economics; *organization & administration]; Hospitalization; Outcome and Process Assessment (Health Care); Randomized Controlled Trials as Topic; Humans
6.  Developing and validating risk prediction models in an individual participant data meta-analysis 
Background
Risk prediction models estimate the risk of developing future outcomes for individuals based on one or more underlying characteristics (predictors). We review how researchers develop and validate risk prediction models within an individual participant data (IPD) meta-analysis, in order to assess the feasibility and conduct of the approach.
Methods
A qualitative review of the aims, methodology, and reporting in 15 articles that developed a risk prediction model using IPD from multiple studies.
Results
The IPD approach offers many opportunities but methodological challenges exist, including: unavailability of requested IPD, missing patient data and predictors, and between-study heterogeneity in methods of measurement, outcome definitions and predictor effects. Most articles develop their model using IPD from all available studies and perform only an internal validation (on the same set of data). Ten of the 15 articles did not allow for any study differences in baseline risk (intercepts), potentially limiting their model’s applicability and performance in some populations. Only two articles used external validation (on different data), including a novel method which develops the model on all but one of the IPD studies, tests performance in the excluded study, and repeats by rotating the omitted study.
Conclusions
An IPD meta-analysis offers unique opportunities for risk prediction research. Researchers can make more of this by allowing separate model intercept terms for each study (population) to improve generalisability, and by using ‘internal-external cross-validation’ to simultaneously develop and validate their model. Methodological challenges can be reduced by prospectively planned collaborations that share IPD for risk prediction.
doi:10.1186/1471-2288-14-3
PMCID: PMC3890557  PMID: 24397587
Meta-analysis; Prognostic factor; Prognosis; Individual participant (patient) data; Review; Reporting
7.  The diagnostic accuracy of the Patient Health Questionnaire-2 (PHQ-2), Patient Health Questionnaire-8 (PHQ-8), and Patient Health Questionnaire-9 (PHQ-9) for detecting major depression: protocol for a systematic review and individual patient data meta-analyses 
Systematic Reviews  2014;3:124.
Background
Major depressive disorder (MDD) may be present in 10%–20% of patients in medical settings. Routine depression screening is sometimes recommended to improve depression management. However, studies of the diagnostic accuracy of depression screening tools have typically used data-driven, exploratory methods to select optimal cutoffs. Often, these studies report results from a small range of cutoff points around whatever cutoff score is most accurate in that given study. When published data are combined in meta-analyses, estimates of accuracy for different cutoff points may be based on data from different studies, rather than data from all studies for each possible cutoff point. As a result, traditional meta-analyses may generate exaggerated estimates of accuracy. Individual patient data (IPD) meta-analyses can address this problem by synthesizing data from all studies for each cutoff score to obtain diagnostic accuracy estimates. The nine-item Patient Health Questionnaire-9 (PHQ-9) and the shorter PHQ-2 and PHQ-8 are commonly recommended for depression screening. Thus, the primary objectives of our IPD meta-analyses are to determine the diagnostic accuracy of the PHQ-9, PHQ-8, and PHQ-2 to detect MDD among adults across all potentially relevant cutoff scores. Secondary analyses involve assessing accuracy accounting for patient factors that may influence accuracy (age, sex, medical comorbidity).
Methods/design
Data sources will include MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, PsycINFO, and Web of Science. We will include studies that included a Diagnostic and Statistical Manual or International Classification of Diseases diagnosis of MDD based on a validated structured or semi-structured clinical interview administered within 2 weeks of the administration of the PHQ. Two reviewers will independently screen titles and abstracts, perform full article review, and extract study data. Disagreements will be resolved by consensus. Risk of bias will be assessed with the Quality Assessment of Diagnostic Accuracy Studies-2 tool. Bivariate random-effects meta-analysis will be conducted for the full range of plausible cutoff values.
Discussion
The proposed IPD meta-analyses will allow us to obtain estimates of the diagnostic accuracy of the PHQ-9, PHQ-8, and PHQ-2.
Systematic review registration
PROSPERO CRD42014010673
doi:10.1186/2046-4053-3-124
PMCID: PMC4218786  PMID: 25348422
Patient health questionnaire; PHQ-9; PHQ-8; PHQ-2; Depression; Screening; Diagnostic test accuracy; Systematic review; Individual patient data meta-analysis
8.  Exercise therapy for chronic low back pain: protocol for an individual participant data meta-analysis 
Systematic Reviews  2012;1:64.
Background
Low back pain (LBP) is one of the leading causes of disability and has a major socioeconomic impact. Despite a large amount of research in the field, there remains uncertainty about the best treatment approach for chronic LBP, and identification of relevant patient subgroups is an important goal. Exercise therapy is a commonly used strategy to treat chronic low back pain and is one of several interventions that evidence suggests is moderately effective.
In parallel with an update of the 2005 Cochrane review, we will undertake an individual participant data (IPD) meta-analysis, which will allow us to standardize analyses across studies and directly derive results, and to examine differential treatment effects across individuals to estimate how patients’ characteristics modify treatment benefit.
Methods/design
We will use standard systematic review methods advocated by the Cochrane Collaboration to identify relevant trials. We will include trials evaluating exercise therapy compared to any or no other interventions in adult non-specific chronic LBP. Our primary outcomes of interest include pain, functional status, and return-to-work/absenteeism. We will assess potential risk of bias for each study meeting selection criteria, using criteria and methods recommended by the Cochrane BRG.
The original individual participant data will be requested from the authors of selected trials having moderate to low risk of bias. We will test original data and compile a master dataset with information about each trial mapped on a pre-specified framework, including reported characteristics of the study sample, exercise therapy characteristics, individual patient characteristics at baseline and all follow-up periods, subgroup and treatment effect modifiers investigated. Our analyses will include descriptive, study-level meta-analysis and meta-regression analyses of the overall treatment effect, and individual-level IPD meta-analyses of treatment effect modification. IPD meta-analyses will be conducted using a one-step approach where the IPD from all studies are modeled simultaneously while accounting for the clustering of participants with studies.
Discussion
We will analyze IPD across a large number of LBP trials. The resulting larger sample size and consistent presentation of data will allow additional analyses to explore patient-level heterogeneity in treatment outcomes and prognosis of chronic LBP.
doi:10.1186/2046-4053-1-64
PMCID: PMC3564764  PMID: 23259855
Low back pain; Exercise therapy; Meta-analysis; Systematic review
9.  Hormonal Contraception and the Risk of HIV Acquisition: An Individual Participant Data Meta-analysis 
PLoS Medicine  2015;12(1):e1001778.
In a meta-analysis of individual participant data, Charles Morrison and colleagues explore the association between hormonal contraception use and risk of HIV infection in sub-Saharan Africa.
Background
Observational studies of a putative association between hormonal contraception (HC) and HIV acquisition have produced conflicting results. We conducted an individual participant data (IPD) meta-analysis of studies from sub-Saharan Africa to compare the incidence of HIV infection in women using combined oral contraceptives (COCs) or the injectable progestins depot-medroxyprogesterone acetate (DMPA) or norethisterone enanthate (NET-EN) with women not using HC.
Methods and Findings
Eligible studies measured HC exposure and incident HIV infection prospectively using standardized measures, enrolled women aged 15–49 y, recorded ≥15 incident HIV infections, and measured prespecified covariates. Our primary analysis estimated the adjusted hazard ratio (aHR) using two-stage random effects meta-analysis, controlling for region, marital status, age, number of sex partners, and condom use. We included 18 studies, including 37,124 women (43,613 woman-years) and 1,830 incident HIV infections. Relative to no HC use, the aHR for HIV acquisition was 1.50 (95% CI 1.24–1.83) for DMPA use, 1.24 (95% CI 0.84–1.82) for NET-EN use, and 1.03 (95% CI 0.88–1.20) for COC use. Between-study heterogeneity was mild (I2 < 50%). DMPA use was associated with increased HIV acquisition compared with COC use (aHR 1.43, 95% CI 1.23–1.67) and NET-EN use (aHR 1.32, 95% CI 1.08–1.61). Effect estimates were attenuated for studies at lower risk of methodological bias (compared with no HC use, aHR for DMPA use 1.22, 95% CI 0.99–1.50; for NET-EN use 0.67, 95% CI 0.47–0.96; and for COC use 0.91, 95% CI 0.73–1.41) compared to those at higher risk of bias (pinteraction = 0.003). Neither age nor herpes simplex virus type 2 infection status modified the HC–HIV relationship.
Conclusions
This IPD meta-analysis found no evidence that COC or NET-EN use increases women’s risk of HIV but adds to the evidence that DMPA may increase HIV risk, underscoring the need for additional safe and effective contraceptive options for women at high HIV risk. A randomized controlled trial would provide more definitive evidence about the effects of hormonal contraception, particularly DMPA, on HIV risk.
Editors’ Summary
Background
AIDS has killed about 36 million people since the first recorded case of the disease in 1981. About 35 million people (including 25 million living in sub-Saharan Africa) are currently infected with HIV, the virus that causes AIDS, and every year, another 2.3 million people become newly infected with HIV. At the beginning of the epidemic, more men than women were infected with HIV. Now, about half of all adults infected with HIV are women. In 2013, almost 60% of all new HIV infections among young people aged 15–24 years occurred among women, and it is estimated that, worldwide, 50 young women are newly infected with HIV every hour. Most women become infected with HIV through unprotected intercourse with an infected male partner—biologically, women are twice as likely to become infected through unprotected intercourse as men. A woman’s risk of becoming infected with HIV can be reduced by abstaining from sex, by having one or a few partners, and by always using condoms.
Why Was This Study Done?
Women and societies both benefit from effective contraception. When contraception is available, women can avoid unintended pregnancies, fewer women and babies die during pregnancy and childbirth, and maternal and infant health improves. However, some (but not all) observational studies (investigations that measure associations between the characteristics of participants and their subsequent development of specific diseases) have reported an association between hormonal contraceptive use and an increased risk of HIV acquisition by women. So, does hormonal contraception increase the risk of HIV acquisition among women or not? Here, to investigate this question, the researchers undertake an individual participant data meta-analysis of studies conducted in sub-Saharan Africa (a region where both HIV infection and unintended pregnancies are common) to compare the incidence of HIV infection (the number of new cases in a population during a given time period) among women using and not using hormonal contraception. Meta-analysis is a statistical method that combines the results of several studies; an individual participant data meta-analysis combines the data recorded for each individual involved in the studies rather than the aggregated results from each study.
What Did the Researchers Do and Find?
The researchers included 18 studies that measured hormonal contraceptive use and incident HIV infection among women aged 15–49 years living in sub-Saharan Africa in their meta-analysis. More than 37,000 women took part in these studies, and 1,830 became newly infected with HIV. Half of the women were not using hormonal contraception, a quarter were using depot-medroxyprogesterone acetate (DMPA; an injectable hormonal contraceptive), and the remainder were using combined oral contraceptives (COCs) or norethisterone enanthate (NET-EN, another injectable contraceptive). After adjustment for other factors likely to influence HIV acquisition (for example, condom use), women using DMPA had a 1.5-fold increased risk of HIV acquisition compared to women not using hormonal contraception. There was a slightly increased risk of HIV acquisition among women using NET-EN compared to women not using hormonal contraception, but this increase was not statistically significant (it may have happened by chance alone). There was no increased risk of HIV acquisition associated with COC use. DMPA use was associated with a 1.43-fold and 1.32-fold increased risk of HIV acquisition compared with COC and NET-EN use, respectively. Finally, neither age nor herpes simplex virus 2 infection status modified the effect of hormonal contraceptive use on HIV acquisition.
What Do These Findings Mean?
The findings of this individual patient data meta-analysis provide no evidence that COC or NET-EN use increases a woman’s risk of acquiring HIV, but add to the evidence suggesting that DMPA use increases the risk of HIV acquisition. These findings are likely to be more accurate than those of previous meta-analyses that used aggregated data but are likely to be limited by the quality, design, and representativeness of the studies included in the analysis. These findings nevertheless highlight the need to develop additional safe and effective contraceptive options for women at risk of HIV, particularly those living in sub-Saharan Africa, where although contraceptive use is generally low, DMPA is the most widely used hormonal contraceptive. In addition, these findings highlight the need to initiate randomized controlled trials to provide more definitive evidence of the effects of hormonal contraception, particularly DMPA, on HIV risk.
Additional Information.
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001778.
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS, and summaries of recent research findings on HIV care and treatment, including personal stories about living with HIV/AIDS and a news report on this meta-analysis
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including detailed information on women, HIV, and AIDS, and on HIV and AIDS in South Africa (in English and Spanish); personal stories of women living with HIV are available
The World Health Organization provides information on all aspects of HIV/AIDS (in several languages); information about a 2012 WHO technical consultation about hormonal contraception and HIV
The 2013 UNAIDS World AIDS Day report provides up-to-date information about the AIDS epidemic and efforts to halt it; UNAIDS also provides information about HIV and hormonal contraception
doi:10.1371/journal.pmed.1001778
PMCID: PMC4303292  PMID: 25612136
10.  Protocol for a systematic review and individual patient data meta-analysis of prognostic factors of foot ulceration in people with diabetes: the international research collaboration for the prediction of diabetic foot ulcerations (PODUS) 
Background
Diabetes–related lower limb amputations are associated with considerable morbidity and mortality and are usually preceded by foot ulceration. The available systematic reviews of aggregate data are compromised because the primary studies report both adjusted and unadjusted estimates. As adjusted meta-analyses of aggregate data can be challenging, the best way to standardise the analytical approach is to conduct a meta-analysis based on individual patient data (IPD).
There are however many challenges and fundamental methodological omissions are common; protocols are rare and the assessment of the risk of bias arising from the conduct of individual studies is frequently not performed, largely because of the absence of widely agreed criteria for assessing the risk of bias in this type of review. In this protocol we propose key methodological approaches to underpin our IPD systematic review of prognostic factors of foot ulceration in diabetes.
Review questions;
1. What are the most highly prognostic factors for foot ulceration (i.e. symptoms, signs, diagnostic tests) in people with diabetes?
2. Can the data from each study be adjusted for a consistent set of adjustment factors?
3. Does the model accuracy change when patient populations are stratified according to demographic and/or clinical characteristics?
Methods
MEDLINE and EMBASE databases from their inception until early 2012 were searched and the corresponding authors of all eligible primary studies invited to contribute their raw data. We developed relevant quality assurance items likely to identify occasions when study validity may have been compromised from several sources. A confidentiality agreement, arrangements for communication and reporting as well as ethical and governance considerations are explained.
We have agreement from the corresponding authors of all studies which meet the eligibility criteria and they collectively possess data from more than 17000 patients. We propose, as a provisional analysis plan, to use a multi-level mixed model, using “study” as one of the levels. Such a model can also allow for the within-patient clustering that occurs if a patient contributes data from both feet, although to aid interpretation, we prefer to use patients rather than feet as the unit of analysis. We intend to only attempt this analysis if the results of the investigation of heterogeneity do not rule it out and the model diagnostics are acceptable.
Discussion
This review is central to the development of a global evidence-based strategy for the risk assessment of the foot in patients with diabetes, ensuring future recommendations are valid and can reliably inform international clinical guidelines.
doi:10.1186/1471-2288-13-22
PMCID: PMC3599337  PMID: 23414550
11.  Efficacy of Pneumococcal Nontypable Haemophilus influenzae Protein D Conjugate Vaccine (PHiD-CV) in Young Latin American Children: A Double-Blind Randomized Controlled Trial 
PLoS Medicine  2014;11(6):e1001657.
In a double-blind randomized controlled trial, Xavier Saez-Llorens and colleagues examine the vaccine efficacy of PHiD-CV against community-acquired pneumonia in young children in Panama, Argentina, and Columbia.
Please see later in the article for the Editors' Summary
Background
The relationship between pneumococcal conjugate vaccine–induced antibody responses and protection against community-acquired pneumonia (CAP) and acute otitis media (AOM) is unclear. This study assessed the impact of the ten-valent pneumococcal nontypable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) on these end points. The primary objective was to demonstrate vaccine efficacy (VE) in a per-protocol analysis against likely bacterial CAP (B-CAP: radiologically confirmed CAP with alveolar consolidation/pleural effusion on chest X-ray, or non-alveolar infiltrates and C-reactive protein ≥ 40 µg/ml); other protocol-specified outcomes were also assessed.
Methods and Findings
This phase III double-blind randomized controlled study was conducted between 28 June 2007 and 28 July 2011 in Argentine, Panamanian, and Colombian populations with good access to health care. Approximately 24,000 infants received PHiD-CV or hepatitis control vaccine (hepatitis B for primary vaccination, hepatitis A at booster) at 2, 4, 6, and 15–18 mo of age. Interim analysis of the primary end point was planned when 535 first B-CAP episodes, occurring ≥2 wk after dose 3, were identified in the per-protocol cohort. After a mean follow-up of 23 mo (PHiD-CV, n = 10,295; control, n = 10,201), per-protocol VE was 22.0% (95% CI: 7.7, 34.2; one-sided p = 0.002) against B-CAP (conclusive for primary objective) and 25.7% (95% CI: 8.4%, 39.6%) against World Health Organization–defined consolidated CAP. Intent-to-treat VE was 18.2% (95% CI: 5.5%, 29.1%) against B-CAP and 23.4% (95% CI: 8.8%, 35.7%) against consolidated CAP. End-of-study per-protocol analyses were performed after a mean follow-up of 28–30 mo for CAP and invasive pneumococcal disease (IPD) (PHiD-CV, n = 10,211; control, n = 10,140) and AOM (n = 3,010 and 2,979, respectively). Per-protocol VE was 16.1% (95% CI: −1.1%, 30.4%; one-sided p = 0.032) against clinically confirmed AOM, 67.1% (95% CI: 17.0%, 86.9%) against vaccine serotype clinically confirmed AOM, 100% (95% CI: 74.3%, 100%) against vaccine serotype IPD, and 65.0% (95% CI: 11.1%, 86.2%) against any IPD. Results were consistent between intent-to-treat and per-protocol analyses. Serious adverse events were reported for 21.5% (95% CI: 20.7%, 22.2%) and 22.6% (95% CI: 21.9%, 23.4%) of PHiD-CV and control recipients, respectively. There were 19 deaths (n = 11,798; 0.16%) in the PHiD-CV group and 26 deaths (n = 11,799; 0.22%) in the control group. A significant study limitation was the lower than expected number of captured AOM cases.
Conclusions
Efficacy was demonstrated against a broad range of pneumococcal diseases commonly encountered in young children in clinical practice.
Trial registration
www.ClinicalTrials.gov NCT00466947
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Pneumococcal diseases are illnesses caused by Streptococcus pneumoniae bacteria, pathogens (disease-causing organisms) that are transmitted through contact with infected respiratory secretions. S. pneumoniae causes mucosal diseases–infections of the lining of the body cavities that are connected to the outside world–such as community-acquired pneumonia (CAP; lung infection) and acute otitis media (AOM; middle-ear infection). It also causes invasive pneumococcal diseases (IPDs) such as septicemia and meningitis (infections of the bloodstream and the covering of the brain, respectively). Although pneumococcal diseases can sometimes be treated with antibiotics, CAP and IPDs are leading global causes of childhood deaths, particularly in developing countries. It is best therefore to avoid S. pneumoniae infections through vaccination. Vaccination primes the immune system to recognize and attack pathogens rapidly and effectively by exposing it to weakened or dead pathogens or to pathogen molecules that it recognizes as foreign (antigens). Because there are more than 90 S. pneumoniae variants (“serotypes”), each characterized by a different antigenic polysaccharide (complex sugar) coat, S. pneumoniae vaccines have to include antigens from multiple serotypes. For example, the PHiD-CV vaccine contains polysaccharides from ten S. pneumoniae serotypes.
Why Was This Study Done?
Although in most countries PHiD-CV has been licensed for protection against IPD and pneumococcal AOM, at the time of study, it was not known how well it protected against CAP and overall AOM, which are important public health problems. In this double-blind randomized controlled trial (the Clinical Otitis Media and Pneumonia Study; COMPAS), the researchers investigate the efficacy of PHiD-CV against CAP and AOM and assess other clinical end points, such as IPD, in Latin American infants. Double-blind randomized controlled trials compare the effects of interventions by assigning study participants to different interventions randomly and measuring predefined outcomes without the study participants or researchers knowing who has received which intervention until the trial is completed. Vaccine efficacy is the reduction in the incidence of a disease (the number of new cases that occur in a population in a given time) among trial participants who receive the vaccine compared to the incidence among participants who do not receive the vaccine.
What Did the Researchers Do and Find?
The researchers enrolled around 24,000 infants living in urban areas of Argentina, Panama, and Colombia. Half the infants were given PHiD-CV at 2, 4, and 6 months of age and a booster dose at age 15–18 months. The remaining infants were given a hepatitis control vaccine at the same intervals. The trial's primary end point was likely bacterial CAP (B-CAP) –radiologically confirmed CAP, with the airspaces (alveoli) in the lungs filled with liquid instead of gas (alveolar consolidation) or with non-alveolar infiltrates and raised blood levels of C-reactive protein (a marker of inflammation). In a planned interim analysis, which was undertaken after an average follow-up of 23 months, the vaccine efficacy in the per-protocol cohort (the group of participants who actually received their assigned intervention) was 22% against B-CAP. Intent-to-treat vaccine efficacy in the interim analysis (which considered all the trial participants regardless of whether they received their assigned intervention) was 18.2%. At the end of the study (average follow up 30 months), the vaccine efficacy against B-CAP was 18.2% and 16.7% in the per-protocol and intent-to-treat cohorts, respectively. Per-protocol vaccine efficacies against clinically confirmed AOM and vaccine serotype AOM were 16.1% and 67.1%, respectively. Against any IPD and against vaccine serotype IPD, the respective vaccine efficacies were 65% and 100%. Finally, about one-fifth of children who received PHiD-CV and a similar proportion who received the control vaccine experienced a serious adverse event (for example, gastroenteritis); 19 children who received PHiD-CV died compared to 26 children who received the control vaccine.
What Do These Findings Mean?
These findings indicate that in Latin America, a region with an intermediate burden of pneumococcal disease, PHiD-CV is efficacious against a broad range of pneumococcal diseases that often affect young children. The accuracy of these findings may be limited by the withdrawal of 14% of participants from the trial because of adverse media coverage and by the low number of reported cases of AOM. Moreover, because most study participants lived in urban areas, these findings may not be generalizable to rural settings. Despite these and other study limitations, these findings provide new information about the magnitude of the effect of PHiD-CV vaccination against CAP and AOM, two mucosal pneumococcal diseases of global public health importance.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001657.
The US Centers for Disease Control and Prevention provides information for patients and health professionals on all aspects of pneumococcal disease and pneumococcal vaccination, including personal stories
Public Health England provides information on pneumococcal disease and on pneumococcal vaccines
The not-for-profit Immunization Action Coalition has information on pneumococcal disease, including personal stories
The GAVI Alliance provides information about pneumococcal disease and the importance of vaccination
MedlinePlus has links to further information about pneumococcal infections, including pneumonia and otitis media (in English and Spanish)
More information about COMPAS is available
The European Medicines Agency provides information about PHiD-CV (Synflorix)
doi:10.1371/journal.pmed.1001657
PMCID: PMC4043495  PMID: 24892763
12.  Systematic Evaluation of Serotypes Causing Invasive Pneumococcal Disease among Children Under Five: The Pneumococcal Global Serotype Project 
PLoS Medicine  2010;7(10):e1000348.
Hope Johnson and colleagues calculate the global and regional burden of serotype-specific pneumococcal disease in children under the age of five.
Background
Approximately 800,000 children die each year due to pneumococcal disease and >90% of these deaths occur in developing countries where few children have access to life-saving serotype-based vaccines. Understanding the serotype epidemiology of invasive pneumococcal disease (IPD) among children is necessary for vaccine development and introduction policies. The aim of this study was to systematically estimate the global and regional distributions of serotypes causing IPD in children <5 years of age.
Methods and Findings
We systematically reviewed studies with IPD serotype data among children <5 years of age from the published literature and unpublished data provided by researchers. Studies conducted prior to pneumococcal conjugate vaccine (PCV) introduction, from 1980 to 2007, with ≥12 months of surveillance, and reporting ≥20 serotyped isolates were included. Serotype-specific proportions were pooled in a random effects meta-analysis and combined with PD incidence and mortality estimates to infer global and regional serotype-specific PD burden. Of 1,292, studies reviewed, 169 were included comprising 60,090 isolates from 70 countries. Globally and regionally, six to 11 serotypes accounted for ≥70% of IPD. Seven serotypes (1, 5, 6A, 6B, 14, 19F, 23F) were the most common globally; and based on year 2000 incidence and mortality estimates these seven serotypes accounted for >300,000 deaths in Africa and 200,000 deaths in Asia. Serotypes included in both the 10- and 13-valent PCVs accounted for 10 million cases and 600,000 deaths worldwide.
Conclusions
A limited number of serotypes cause most IPD worldwide. The serotypes included in existing PCV formulations account for 49%–88% of deaths in Africa and Asia where PD morbidity and mortality are the highest, but few children have access to these life-saving vaccines.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Despite all the international attention on Millennium Development Goal (MDG) 4—to reduce deaths in children under 5 years by two thirds by 2015—pneumonia, sepsis, and meningitis together comprise >25% of the 10 million deaths occurring annually in children <5 years of age. Streptococcus pneumoniae is a leading bacterial cause of these diseases and the World Health Organization estimates that approximately 800,000 children die each year of invasive pneumococcal disease. Three pneumococcal conjugate vaccines are currently available and protect against the serotypes most commonly causing invasive pneumococcal disease in young children in North America. However, few countries with the highest burden of invasive pneumococcal disease have introduced the vaccines into their national immunization programs. Not only is it important to introduce a vaccine, but also to use a vaccine covering the appropriate serotypes prevalent in a susceptible region.
Why Was This Study Done?
Over the past few years, data on serotyping in many high burden countries has become available. The authors conducted this study (a systematic review and meta-analysis) to quantify the serotypes causing invasive pneumococcal disease in children <5 years of age in order to estimate the global and regional serotype distribution and serotype-specific disease burden. This information can then be used to estimate the potential public health impact of pneumococcal conjugate vaccine formulations and help to inform decision making for both pneumococcal vaccine development and the introduction of a vaccine into a specific region.
What Did the Researchers Do and Find?
Using published studies and unpublished data provided by researchers, the researchers systematically reviewed studies that included data on invasive pneumococcal disease serotype among children <5 years of age. The researchers then used statistical tools to pool the serotype-specific proportions and combined this information with pneumococcal disease incidence and mortality estimates to calculate the global and regional burden of serotype-specific pneumococcal disease.
The researchers reviewed 1,292 studies and included 169 suitable studies in their analysis, which included information on 60,090 isolates from 70 countries. The researchers produced regional estimates of the serotypes that caused invasive pneumococcal disease among under five-year-olds in different regions: six serotypes were identified as causing most invasive pneumococcal disease in North America; nine serotypes were identified in Africa; and 11 serotypes were identified in Asia. The researchers also found that seven serotypes (1, 5, 6A, 6B, 14, 19F, and 23F) were the most common globally and that these seven serotypes accounted for 58%–66% of invasive pneumococcal disease in every region. On the basis of incidence and mortality estimates of invasive pneumococcal disease for the year 2000 (before pneumococcal conjugate vaccines were introduced), the researchers found that these serotypes represented >300,000 deaths in Africa and 200,000 deaths in Asia.
What Do These Findings Mean?
This study shows that a limited number of serotypes cause most invasive pneumococcal disease worldwide. This finding contradicts the conventional supposition that the most common serotypes causing invasive pneumococcal disease vary greatly across geographic regions. Crucially, the findings of this study also show that the serotypes currently included in existing pneumococcal conjugate formulations account for 49%–74% of deaths in Africa and Asia where the morbidity and mortality of pneumococcal disease are the highest and where most children do not have access to current pneumococcal conjugate vaccines. Although the authors do not provide country-level estimates of serotype distribution, country-specific vaccine impact estimates can be made using country-level pneumococcal disease burden numbers combined with the regional serotype estimates provided in this study. This means that national policy makers can assess the potential impact of serotypes included in different conjugate vaccines, which should contribute to their decision-making process. In addition, manufacturers can now work from a consensus set of serotype coverage estimates to plan and design future serotype-based vaccine formulations to target the pneumococcal disease burden.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000348
The World Health Organization provides information about pneumococcus
The PneumoACTION provides information about pneumonia and pneumococcal disease
The Global Alliance for Vaccination and Immunisation has information on all aspects of vaccination and immunization
The US Centers for Disease Control provides information about pneumococcal conjugate vaccination
The Word Pneumonia Day coalition provides information about pneumonia
doi:10.1371/journal.pmed.1000348
PMCID: PMC2950132  PMID: 20957191
13.  Association of Non-alcoholic Fatty Liver Disease with Chronic Kidney Disease: A Systematic Review and Meta-analysis 
PLoS Medicine  2014;11(7):e1001680.
In a systematic review and meta-analysis, Giovanni Musso and colleagues examine the association between non-alcoholic fatty liver disease and chronic kidney disease.
Please see later in the article for the Editors' Summary
Background
Chronic kidney disease (CKD) is a frequent, under-recognized condition and a risk factor for renal failure and cardiovascular disease. Increasing evidence connects non-alcoholic fatty liver disease (NAFLD) to CKD. We conducted a meta-analysis to determine whether the presence and severity of NAFLD are associated with the presence and severity of CKD.
Methods and Findings
English and non-English articles from international online databases from 1980 through January 31, 2014 were searched. Observational studies assessing NAFLD by histology, imaging, or biochemistry and defining CKD as either estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 or proteinuria were included. Two reviewers extracted studies independently and in duplicate. Individual participant data (IPD) were solicited from all selected studies. Studies providing IPD were combined with studies providing only aggregate data with the two-stage method. Main outcomes were pooled using random-effects models. Sensitivity and subgroup analyses were used to explore sources of heterogeneity and the effect of potential confounders. The influences of age, whole-body/abdominal obesity, homeostasis model of insulin resistance (HOMA-IR), and duration of follow-up on effect estimates were assessed by meta-regression. Thirty-three studies (63,902 participants, 16 population-based and 17 hospital-based, 20 cross-sectional, and 13 longitudinal) were included. For 20 studies (61% of included studies, 11 cross-sectional and nine longitudinal, 29,282 participants), we obtained IPD. NAFLD was associated with an increased risk of prevalent (odds ratio [OR] 2.12, 95% CI 1.69–2.66) and incident (hazard ratio [HR] 1.79, 95% CI 1.65–1.95) CKD. Non-alcoholic steatohepatitis (NASH) was associated with a higher prevalence (OR 2.53, 95% CI 1.58–4.05) and incidence (HR 2.12, 95% CI 1.42–3.17) of CKD than simple steatosis. Advanced fibrosis was associated with a higher prevalence (OR 5.20, 95% CI 3.14–8.61) and incidence (HR 3.29, 95% CI 2.30–4.71) of CKD than non-advanced fibrosis. In all analyses, the magnitude and direction of effects remained unaffected by diabetes status, after adjustment for other risk factors, and in other subgroup and meta-regression analyses. In cross-sectional and longitudinal studies, the severity of NAFLD was positively associated with CKD stages. Limitations of analysis are the relatively small size of studies utilizing liver histology and the suboptimal sensitivity of ultrasound and biochemistry for NAFLD detection in population-based studies.
Conclusion
The presence and severity of NAFLD are associated with an increased risk and severity of CKD.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Chronic kidney disease (CKD)—the gradual loss of kidney function—is becoming increasingly common. In the US, for example, more than 10% of the adult population (about 26 million people) and more than 25% of individuals older than 65 years have CKD. Throughout life, the kidneys perform the essential task of filtering waste products (from the normal breakdown of tissues and from food) and excess water from the blood to make urine. CKD gradually destroys the kidneys' filtration units, the rate of blood filtration decreases, and dangerous amounts of waste products build up in the blood. Symptoms of CKD, which rarely occur until the disease is very advanced, include tiredness, swollen feet, and frequent urination, particularly at night. There is no cure for CKD, but progression of the disease can be slowed by controlling high blood pressure and diabetes (two risk factors for CKD), and by adopting a healthy lifestyle. The same interventions also reduce the chances of CKD developing in the first place.
Why Was This Study Done?
CKD is associated with an increased risk of end-stage renal (kidney) disease and of cardiovascular disease. These life-threatening complications are potentially preventable through early identification and treatment of CKD. Because early recognition of CKD has the potential to reduce its health-related burden, the search is on for new modifiable risk factors for CKD. One possible new risk factor is non-alcoholic fatty liver disease (NAFLD), which, like CKD is becoming increasingly common. Healthy livers contain little or no fat but, in the US, 30% of the general adult population and up to 70% of patients who are obese or have diabetes have some degree of NAFLD, which ranges in severity from simple fatty liver (steatosis), through non-alcoholic steatohepatitis (NASH), to NASH with fibrosis (scarring of the liver) and finally cirrhosis (extensive scarring). In this systematic review and meta-analysis, the researchers investigate whether NAFLD is a risk factor for CKD by looking for an association between the two conditions. A systematic review identifies all the research on a given topic using predefined criteria, meta-analysis uses statistical methods to combine the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 33 studies that assessed NAFLD and CKD in nearly 64,000 participants, including 20 cross-sectional studies in which participants were assessed for NAFLD and CKD at a single time point and 13 longitudinal studies in which participants were assessed for NAFLD and then followed up to see whether they subsequently developed CKD. Meta-analysis of the data from the cross-sectional studies indicated that NAFLD was associated with a 2-fold increased risk of prevalent (pre-existing) CKD (an odds ratio [OR]of 2.12; an OR indicates the chance that an outcome will occur given a particular exposure, compared to the chance of the outcome occurring in the absence of that exposure). Meta-analysis of data from the longitudinal studies indicated that NAFLD was associated with a nearly 2-fold increased risk of incident (new) CKD (a hazard ratio [HR] of 1.79; an HR indicates often a particular event happens in one group compared to how often it happens in another group, over time). NASH was associated with a higher prevalence and incidence of CKD than simple steatosis. Similarly, advanced fibrosis was associated with a higher prevalence and incidence of CKD than non-advanced fibrosis.
What Do These Findings Mean?
These findings suggest that NAFLD is associated with an increased prevalence and incidence of CKD and that increased severity of liver disease is associated with an increased risk and severity of CKD. Because these associations persist after allowing for established risk factors for CKD, these findings identify NAFLD as an independent CKD risk factor. Certain aspects of the studies included in this meta-analysis (for example, only a few studies used biopsies to diagnose NAFLD; most used less sensitive tests that may have misclassified some individuals with NAFLD as normal) and the methods used in the meta-analysis may limit the accuracy of these findings. Nevertheless, these findings suggest that individuals with NAFLD should be screened for CKD even in the absence of other risk factors for the disease, and that better treatment of NAFLD may help to prevent CKD.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001680.
The US National Kidney and Urologic Diseases Information Clearinghouse provides information about all aspects of kidney disease; the US National Digestive Diseases Information Clearinghouse provides information about non-alcoholic liver disease
The US National Kidney Disease Education Program provides resources to help improve the understanding, detection, and management of kidney disease (in English and Spanish)
The UK National Health Service Choices website provides information for patients on chronic kidney disease, including some personal stories, and information on non-alcoholic fatty liver disease
The US National Kidney Foundation, a not-for-profit organization, provides information about chronic kidney disease (in English and Spanish)
The not-for-profit UK National Kidney Federation provides support and information for patients with kidney disease and for their carers
The British Liver Trust, a not-for-profit organization, provides information about non-alcoholic fatty liver disease, including a patient story
doi:10.1371/journal.pmed.1001680
PMCID: PMC4106719  PMID: 25050550
14.  Sharing Individual Participant Data from Clinical Trials: An Opinion Survey Regarding the Establishment of a Central Repository 
PLoS ONE  2014;9(5):e97886.
Background
Calls have been made for increased access to individual participant data (IPD) from clinical trials, to ensure that complete evidence is available. However, despite the obvious benefits, progress towards this is frustratingly slow. In the meantime, many systematic reviews have already collected IPD from clinical trials. We propose that a central repository for these IPD should be established to ensure that these datasets are safeguarded and made available for use by others, building on the strengths and advantages of the collaborative groups that have been brought together in developing the datasets.
Objective
Evaluate the level of support, and identify major issues, for establishing a central repository of IPD.
Design
On-line survey with email reminders.
Participants
71 reviewers affiliated with the Cochrane Collaboration's IPD Meta-analysis Methods Group were invited to participate.
Results
30 (42%) invitees responded: 28 (93%) had been involved in an IPD review and 24 (80%) had been involved in a randomised trial. 25 (83%) agreed that a central repository was a good idea and 25 (83%) agreed that they would provide their IPD for central storage. Several benefits of a central repository were noted: safeguarding and standardisation of data, increased efficiency of IPD meta-analyses, knowledge advancement, and facilitating future clinical, and methodological research. The main concerns were gaining permission from trial data owners, uncertainty about the purpose of the repository, potential resource implications, and increased workload for IPD reviewers. Restricted access requiring approval, data security, anonymisation of data, and oversight committees were highlighted as issues under governance of the repository.
Conclusion
There is support in this community of IPD reviewers, many of whom are also involved in clinical trials, for storing IPD in a central repository. Results from this survey are informing further work on developing a repository of IPD which is currently underway by our group.
doi:10.1371/journal.pone.0097886
PMCID: PMC4038514  PMID: 24874700
15.  Individual patient data meta-analysis of diagnostic and prognostic studies in obstetrics, gynaecology and reproductive medicine 
Background
In clinical practice a diagnosis is based on a combination of clinical history, physical examination and additional diagnostic tests. At present, studies on diagnostic research often report the accuracy of tests without taking into account the information already known from history and examination. Due to this lack of information, together with variations in design and quality of studies, conventional meta-analyses based on these studies will not show the accuracy of the tests in real practice. By using individual patient data (IPD) to perform meta-analyses, the accuracy of tests can be assessed in relation to other patient characteristics and allows the development or evaluation of diagnostic algorithms for individual patients.
In this study we will examine these potential benefits in four clinical diagnostic problems in the field of gynaecology, obstetrics and reproductive medicine.
Methods/design
Based on earlier systematic reviews for each of the four clinical problems, studies are considered for inclusion. The first authors of the included studies will be invited to participate and share their original data. After assessment of validity and completeness the acquired datasets are merged. Based on these data, a series of analyses will be performed, including a systematic comparison of the results of the IPD meta-analysis with those of a conventional meta-analysis, development of multivariable models for clinical history alone and for the combination of history, physical examination and relevant diagnostic tests and development of clinical prediction rules for the individual patients. These will be made accessible for clinicians.
Discussion
The use of IPD meta-analysis will allow evaluating accuracy of diagnostic tests in relation to other relevant information. Ultimately, this could increase the efficiency of the diagnostic work-up, e.g. by reducing the need for invasive tests and/or improving the accuracy of the diagnostic workup. This study will assess whether these benefits of IPD meta-analysis over conventional meta-analysis can be exploited and will provide a framework for future IPD meta-analyses in diagnostic and prognostic research.
doi:10.1186/1471-2288-9-22
PMCID: PMC2667527  PMID: 19327146
16.  Repeat prenatal corticosteroid prior to preterm birth: a systematic review and individual participant data meta-analysis for the PRECISE study group (prenatal repeat corticosteroid international IPD study group: assessing the effects using the best level of evidence) - study protocol 
Systematic Reviews  2012;1:12.
Background
The aim of this individual participant data (IPD) meta-analysis is to assess whether the effects of repeat prenatal corticosteroid treatment given to women at risk of preterm birth to benefit their babies are modified in a clinically meaningful way by factors related to the women or the trial protocol.
Methods/Design
The Prenatal Repeat Corticosteroid International IPD Study Group: assessing the effects using the best level of Evidence (PRECISE) Group will conduct an IPD meta-analysis. The PRECISE International Collaborative Group was formed in 2010 and data collection commenced in 2011. Eleven trials with up to 5,000 women and 6,000 infants are eligible for the PRECISE IPD meta-analysis. The primary study outcomes for the infants will be serious neonatal outcome (defined by the PRECISE International IPD Study Group as one of death (foetal, neonatal or infant); severe respiratory disease; severe intraventricular haemorrhage (grade 3 and 4); chronic lung disease; necrotising enterocolitis; serious retinopathy of prematurity; and cystic periventricular leukomalacia); use of respiratory support (defined as mechanical ventilation or continuous positive airways pressure or other respiratory support); and birth weight (Z-scores). For the children, the primary study outcomes will be death or any neurological disability (however defined by trialists at childhood follow up and may include developmental delay or intellectual impairment (developmental quotient or intelligence quotient more than one standard deviation below the mean), cerebral palsy (abnormality of tone with motor dysfunction), blindness (for example, corrected visual acuity worse than 6/60 in the better eye) or deafness (for example, hearing loss requiring amplification or worse)). For the women, the primary outcome will be maternal sepsis (defined as chorioamnionitis; pyrexia after trial entry requiring the use of antibiotics; puerperal sepsis; intrapartum fever requiring the use of antibiotics; or postnatal pyrexia).
Discussion
Data analyses are expected to commence in 2011 with results publicly available in 2012.
doi:10.1186/2046-4053-1-12
PMCID: PMC3351733  PMID: 22588009
17.  Reporting and Methods in Clinical Prediction Research: A Systematic Review 
PLoS Medicine  2012;9(5):e1001221.
Walter Bouwmeester and colleagues investigated the reporting and methods of prediction studies in 2008, in six high-impact general medical journals, and found that the majority of prediction studies do not follow current methodological recommendations.
Background
We investigated the reporting and methods of prediction studies, focusing on aims, designs, participant selection, outcomes, predictors, statistical power, statistical methods, and predictive performance measures.
Methods and Findings
We used a full hand search to identify all prediction studies published in 2008 in six high impact general medical journals. We developed a comprehensive item list to systematically score conduct and reporting of the studies, based on recent recommendations for prediction research. Two reviewers independently scored the studies. We retrieved 71 papers for full text review: 51 were predictor finding studies, 14 were prediction model development studies, three addressed an external validation of a previously developed model, and three reported on a model's impact on participant outcome. Study design was unclear in 15% of studies, and a prospective cohort was used in most studies (60%). Descriptions of the participants and definitions of predictor and outcome were generally good. Despite many recommendations against doing so, continuous predictors were often dichotomized (32% of studies). The number of events per predictor as a measure of statistical power could not be determined in 67% of the studies; of the remainder, 53% had fewer than the commonly recommended value of ten events per predictor. Methods for a priori selection of candidate predictors were described in most studies (68%). A substantial number of studies relied on a p-value cut-off of p<0.05 to select predictors in the multivariable analyses (29%). Predictive model performance measures, i.e., calibration and discrimination, were reported in 12% and 27% of studies, respectively.
Conclusions
The majority of prediction studies in high impact journals do not follow current methodological recommendations, limiting their reliability and applicability.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
There are often times in our lives when we would like to be able to predict the future. Is the stock market going to go up, for example, or will it rain tomorrow? Being able predict future health is also important, both to patients and to physicians, and there is an increasing body of published clinical “prediction research.” Diagnostic prediction research investigates the ability of variables or test results to predict the presence or absence of a specific diagnosis. So, for example, one recent study compared the ability of two imaging techniques to diagnose pulmonary embolism (a blood clot in the lungs). Prognostic prediction research investigates the ability of various markers to predict future outcomes such as the risk of a heart attack. Both types of prediction research can investigate the predictive properties of patient characteristics, single variables, tests, or markers, or combinations of variables, tests, or markers (multivariable studies). Both types of prediction research can include also studies that build multivariable prediction models to guide patient management (model development), or that test the performance of models (validation), or that quantify the effect of using a prediction model on patient and physician behaviors and outcomes (impact assessment).
Why Was This Study Done?
With the increase in prediction research, there is an increased interest in the methodology of this type of research because poorly done or poorly reported prediction research is likely to have limited reliability and applicability and will, therefore, be of little use in patient management. In this systematic review, the researchers investigate the reporting and methods of prediction studies by examining the aims, design, participant selection, definition and measurement of outcomes and candidate predictors, statistical power and analyses, and performance measures included in multivariable prediction research articles published in 2008 in several general medical journals. In a systematic review, researchers identify all the studies undertaken on a given topic using a predefined set of criteria and systematically analyze the reported methods and results of these studies.
What Did the Researchers Do and Find?
The researchers identified all the multivariable prediction studies meeting their predefined criteria that were published in 2008 in six high impact general medical journals by browsing through all the issues of the journals (a hand search). They then scored the methods and reporting of each study using a comprehensive item list based on recent recommendations for the conduct of prediction research (for example, the reporting recommendations for tumor marker prognostic studies—the REMARK guidelines). Of 71 retrieved studies, 51 were predictor finding studies, 14 were prediction model development studies, three externally validated an existing model, and three reported on a model's impact on participant outcome. Study design, participant selection, definitions of outcomes and predictors, and predictor selection were generally well reported, but other methodological and reporting aspects of the studies were suboptimal. For example, despite many recommendations, continuous predictors were often dichotomized. That is, rather than using the measured value of a variable in a prediction model (for example, blood pressure in a cardiovascular disease prediction model), measurements were frequently assigned to two broad categories. Similarly, many of the studies failed to adequately estimate the sample size needed to minimize bias in predictor effects, and few of the model development papers quantified and validated the proposed model's predictive performance.
What Do These Findings Mean?
These findings indicate that, in 2008, most of the prediction research published in high impact general medical journals failed to follow current guidelines for the conduct and reporting of clinical prediction studies. Because the studies examined here were published in high impact medical journals, they are likely to be representative of the higher quality studies published in 2008. However, reporting standards may have improved since 2008, and the conduct of prediction research may actually be better than this analysis suggests because the length restrictions that are often applied to journal articles may account for some of reporting omissions. Nevertheless, despite some encouraging findings, the researchers conclude that the poor reporting and poor methods they found in many published prediction studies is a cause for concern and is likely to limit the reliability and applicability of this type of clinical research.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001221.
The EQUATOR Network is an international initiative that seeks to improve the reliability and value of medical research literature by promoting transparent and accurate reporting of research studies; its website includes information on a wide range of reporting guidelines including the REMARK recommendations (in English and Spanish)
A video of a presentation by Doug Altman, one of the researchers of this study, on improving the reporting standards of the medical evidence base, is available
The Cochrane Prognosis Methods Group provides additional information on the methodology of prognostic research
doi:10.1371/journal.pmed.1001221
PMCID: PMC3358324  PMID: 22629234
18.  Repetitive Transcranial Magnetic Stimulation for the Treatment of Major Depressive Disorder 
Executive Summary
Objective
This review was conducted to assess the effectiveness of repetitive transcranial magnetic stimulation (rTMS) in the treatment of major depressive disorder (MDD).
The Technology
rTMS is a noninvasive way to stimulate nerve cells in areas of the brain. During rTMS, an electrical current passes through a wire coil placed over the scalp. The current induces a magnetic field that produces an electrical field in the brain that then causes nerve cells to depolarize, resulting in the stimulation or disruption of brain activity.
Researchers have investigated rTMS as an option to treat MDD, as an add-on to drug therapy, and, in particular, as an alternative to electroconvulsive therapy (ECT) for patients with treatment-resistant depression.
The advantages of rTMS over ECT for patients with severe refractory depression are that general anesthesia is not needed, it is an outpatient procedure, it requires less energy, the simulation is specific and targeted, and convulsion is not required. The advantages of rTMS as an add-on treatment to drug therapy may include hastening of the clinical response when used with antidepressant drugs.
Review Strategy
The Medical Advisory Secretariat used its standard search strategy to locate international health technology assessments and English-language journal articles published from January 1996 to March 2004.
Summary of Findings
Some early meta-analyses suggested rTMS might be effective for the treatment of MDD (for treatment-resistant MDD and as an add-on treatment to drug therapy for patients not specifically defined as treatment resistant). There were, however, several crucial methodological limitations in the included studies that were not critically assessed. These are discussed below.
Recent meta-analyses (including 2 international health technology assessments) have done evidence-based critical analyses of studies that have assessed rTMS for MDD. The 2 most recent health technology assessments (from the Oxford Cochrane Collaboration and the Norwegian Centre for Health Technology Assessment) concluded that there is no evidence that rTMS is effective for the treatment of MDD, either as compared with a placebo for patients with treatment-resistant or nontreatment-resistant MDD, or as an alternative to ECT for patients with treatment-resistant MDD. This mainly due to the poor quality of the studies.
The major methodological limitations were identified in older meta-analyses, recent health technology assessments, and the most recently published trials (Level 2–4 evidence) on the effectiveness of rTMS for MDD are discussed below.
Small sample size was a limitation acknowledged by many of the authors. There was also a lack of a priori sample size calculation or justification.
Biased randomization may have been a problem. Generally, the published reports lacked detailed information on the method of allocation concealment used. This is important because it is impossible to determine if there was a possible influence (direct or indirect) in the allocation of the patients to different treatment groups.
The trials were single blind, evaluated by external blinded assessors, rather than double blind. Double blinding is more robust, because neither the participants nor the investigators know which participants are receiving the active treatment and which are getting a placebo. Those administering rTMS, however, cannot be blinded to whether they are administering the active treatment or a placebo.
There was patient variability among the studies. In some studies, the authors said that patients were “medication resistant,” but the definitions of resistant, if provided, were inconsistent or unclear. For example, some described “medication resistant” as failing at least one trial of drugs during the current depressive episode. Furthermore, it was unclear if the term “medication resistant” referred to antidepressants only or to combinations of antidepressants and other drug augmentation strategies (such as neuroleptics, benzodiazepine, carbamazepine, and lithium). Also variable was the type of depression (i.e., unipolar and/or bipolar), if patients were inpatients or outpatients, if they had psychotic symptoms or no psychotic symptoms, and the chronicity of depression.
Dropouts or withdrawals were a concern. Some studies reported that patients dropped out, but provided no further details. Intent-to-treat analysis was not done in any of the trials. This is important, because ignoring patients who drop out of a trial can bias the results, usually in favour of the treatment. This is because patients who withdraw from trials are less likely to have had the treatment, more likely to have missed their interim checkups, and more likely to have experienced adverse effects when taking the treatment, compared with patients who do not withdraw. (1)
Measurement of treatment outcomes using scales or inventories makes interpreting results and drawing conclusions difficult. The most common scale, the Hamilton Depression Rating Scale (HDRS) is based on a semistructured interview. Some authors (2) reported that rating scales based on semistructured interviews are more susceptible to observation bias than are self-administered questionnaires such as the Beck Depression Inventory (BDI). Martin et al. (3) argued that the lack of consistency in effect as determined by the 2 scales (a positive result after 2 weeks of treatment as measured by the HDRS and a negative result for the BDI) makes definitive conclusions about the nature of the change in mood of patients impossible. It was suggested that because of difficulties interpreting results from psychometric scales, (4) and the subjective or unstable character of MDD, other, more objective, outcome measures such as readmission to hospital, time to hospital discharge, time to adjunctive treatment, and time off work should be used to assess rTMS for the treatment of depression.
A placebo effect could have influenced the results. Many studies reported response rates for patients who received placebo treatment. For example, Klein et al. (5) reported a control group response rate as high as 25%. Patients receiving placebo rTMS may receive a small dose of magnetic energy that may alter their depression.
Short-term studies were the most common. Patients received rTMS treatment for 1 to 2 weeks. Most studies followed-up patients for 2 to 4 weeks post-treatment. Dannon et al. (6) followed-up patients who responded to a course of ECT or rTMS for up to 6 months; however, the assessment procedure was not blinded, the medication regimen during follow-up was not controlled, and initial baseline data for the patient groups were not reported. The long-term effectiveness of rTMS for the treatment of depression is unknown, as is the long-term use, if any, of maintenance therapy. The cost-effectiveness of rTMS for the treatment of depression is also unknown. A lack of long-term studies makes cost-effectiveness analysis difficult.
The complexity of possible combinations for administering rTMS makes comparing like with like difficult. Wasserman and Lisanby (7) have said that the method for precisely targeting the stimulation in this area is unreliable. It is unknown if the left dorsolateral prefrontal cortex is the optimal location for treatment. Further, differences in rTMS administration include number of trains per session, duration of each train, and motor threshold.
Clinical versus statistical significance. Several meta-analyses and studies have found that the degree of therapeutic change associated with rTMS across studies is relatively modest; that is, results may be statistically, but not necessarily clinically, significant. (8-11). Conventionally, a 50% reduction in the HDRS scores is commonly accepted as a clinically important reduction in depression. Although some studies have observed a statistically significant reduction in the depression rating, many have not shows the clinically significant reduction of 50% on the HDRS. (11-13) Therefore, few patients in these studies would meet the standard criteria for response. (9)
Clinical/methodological diversity and statistical heterogeneity. In the Norwegian health technology assessment, Aarre et al. (14) said that a formal meta-analysis was not feasible because the designs of the studies varied too much, particularly in how rTMS was administered and in the characteristics of the patients. They noted that the quality of the study designs was poor. The 12 studies that comprised the assessment had small samples, and highly variable inclusion criteria and study designs. The patients’ previous histories, diagnoses, treatment histories, and treatment settings were often insufficiently characterized. Furthermore, many studies reported that patients had treatment-resistant MDD, yet did not listclear criteria for the designation. Without this information, Aarre and colleagues suggested that the interpretation of the results is difficult and the generalizability of results is questionable. They concluded that rTMS cannot be recommended as a standard treatment for depression: “More, larger and more carefully designed studies are needed to demonstrate convincingly a clinically relevant effect of rTMS.”
In the Cochrane Collaboration systematic review, Martin et al. (3;15) said that the complexity of possible combinations for administering rTMS makes comparison of like versus like difficult. A statistical test for heterogeneity (chi-square test) examines if the observed treatment effects are more different from each other than one would expect due to random error (or chance) alone. (16) However, this statistical test must be interpreted with caution because it has low power in the (common) situation of a meta-analysis when the trials have small sample sizes or are few. This means that while a statistically significant result may indicate a problem with heterogeneity, a nonsignificant result must not be taken as evidence of no heterogeneity.
Despite not finding statistically significant heterogeneity, Martin et al. reported that the overall mean baseline depression values for the severity of depression were higher in the treatment group than in the placebo group. (3;15) Although these differences were not significant at the level of each study, they may have introduced potential bias into the meta-analysis of pooled data by accentuating the tendency for regression to the mean of the more extreme values. Individual patient data from all the studies were not available; therefore, an appropriate adjustment according to baseline severity was not possible. Martin et al. concluded that the findings from the systematic review and meta-analysis provided insufficient evidence to suggest that rTMS is effective in the treatment of depression. Moreover, there were several confounding factors (e.g., definition of treatment resistance) in the studies, thus the authors concluded, “The rTMS technique needs more high quality trials to show its effectiveness for therapeutic use.”
Conclusion
Due to several serious methodological limitations in the studies that have examined the effectiveness of rTMS in patients with MDD, it is not possible to conclude that rTMS either is or is not effective as a treatment for MDD (in treatment-resistant depression or in nontreatment-resistant depression).
PMCID: PMC3387754  PMID: 23074457
19.  Pneumococcal Serotypes and Mortality following Invasive Pneumococcal Disease: A Population-Based Cohort Study 
PLoS Medicine  2009;6(5):e1000081.
Analyzing population-based data collected over 30 years in more than 18,000 patients with invasive pneumococcal infection, Zitta Harboe and colleagues find specific pneumococcal serotypes to be associated with increased mortality.
Background
Pneumococcal disease is a leading cause of morbidity and mortality worldwide. The aim of this study was to investigate the association between specific pneumococcal serotypes and mortality from invasive pneumococcal disease (IPD).
Methods and Findings
In a nationwide population-based cohort study of IPD in Denmark during 1977–2007, 30-d mortality associated with pneumococcal serotypes was examined by multivariate logistic regression analysis after controlling for potential confounders. A total of 18,858 IPD patients were included. Overall 30-d mortality was 18%, and 3% in children younger than age 5 y. Age, male sex, meningitis, high comorbidity level, alcoholism, and early decade of diagnosis were significantly associated with mortality. Among individuals aged 5 y and older, serotypes 31, 11A, 35F, 17F, 3, 16F, 19F, 15B, and 10A were associated with highly increased mortality as compared with serotype 1 (all: adjusted odds ratio ≥3, p<0.001). In children younger than 5 y, associations between serotypes and mortality were different than in adults but statistical precision was limited because of low overall childhood-related mortality.
Conclusions
Specific pneumococcal serotypes strongly and independently affect IPD associated mortality.
Editors' Summary
Background
Pneumococcal diseases—illnesses caused by Streptococcus pneumoniae bacteria—are leading causes of illness and death around the world. S. pneumoniae is transmitted through contact with infected respiratory secretions and usually causes noninvasive diseases such as ear infections and bronchitis. Sometimes, however, the bacteria invade the lungs (where they cause pneumonia), the bloodstream (where they cause bacteremia), or the covering of the brain (where they cause meningitis). These invasive pneumococcal diseases (IPDs) are often fatal. One million children die annually from pneumococcal disease, many of them in developing countries. In the developed world, however, IPDs mainly affect elderly people and patients with chronic conditions such as diabetes and alcoholism. Although pneumococcal diseases can sometimes be treated successfully with antibiotics, many patients die or develop long-term complications. Consequently, vaccination with “pneumococcal polysaccharide vaccine” (PPV) is recommended for everyone over 65 years old and for people between 2 and 65 years old who are at high risk of developing IPD; vaccination with “pneumococcal conjugate vaccine” (PCV) is recommended for children younger than 2 years old who are at high risk of IPDs.
Why Was This Study Done?
S. pneumoniae is not a single organism. There are actually more than 90 S. pneumoniae variants or “serotypes.” These variants are coated with different polysaccharides (complex sugar molecules) that are, in part, responsible for the deleterious effects of S. pneumonia infections. The same molecules also trigger the human immune response that kills the bacteria. Consequently, pneumococcal vaccines contain polysaccharide mixtures isolated from the S. pneumoniae serotypes responsible for most pneumococcal disease. But are these serotypes also responsible for most of the deaths caused by IPD? Until now, the few studies that have investigated the association between S. pneumoniae serotypes and death from IPD have yielded conflicting results. Here, therefore, the researchers undertook a large population-based study to discover whether there is an association between specific pneumococcal serotypes and death following IPD.
What Did the Researchers Do and Find?
The researchers linked data on the serotype of S. pneumoniae isolates sent to the Danish National Neisseria and Streptococcus Reference Center between 1977 and 2007 with clinical data from national medical databases. After allowing for other factors that might affect a person's likelihood of dying from IPD (for example, age and other illnesses), the researchers used multivariate logistic regression analysis (a statistical approach) to look for associations between S. pneumoniae serotypes and death within 30 days of admission to hospital for pneumococcal bacteremia or meningitis. Overall, 18% of the nearly 19,000 people included in this analysis died within 30 days of hospital admission; among the children younger than 5 years included in the study, the death rate was 3%. Among patients 5 years old or older, nine S. pneumoniae serotypes were associated with a more than 3-fold higher death rate (mostly from bacteremia) than serotype 1, the most common serotype isolated during the study. Interestingly, in young children, a different set of serotypes seemed to be associated with death. However, because so few children died from IPD, this result is statistically uncertain. The researchers' results also show that age, gender, having meningitis, having other illnesses, and alcoholism all affected a patient's chances of dying from IPD.
What Do These Findings Mean?
These findings show that specific pneumococcal serotypes strongly affect the likelihood that a person aged 5 years or over will die within 30 days of admission to hospital with IPD. Importantly, unlike previous studies, this study was large and comprehensive—the Danish surveillance center covers more than 90% of the Danish population—and the researchers carefully took other factors into account that might have affected a patient's chances of dying from IPD. Thus, these new insights into which pneumococcal serotypes are most deadly could help in the design of new pneumococcal vaccines, at least for people aged 5 years or older. For younger children, however, the results are not as informative and a similar study now needs to be done in developing countries, where more young people die from IPD.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000081.
The US Centers for Disease Control and Prevention provides information for patients and health professionals on all aspects of pneumococcal disease and pneumococcal vaccination
The US National Foundation for Infectious Diseases has a fact sheet on pneumococcal disease
The UK Health Protection Agency also provides background information on pneumococcal disease
The GAVI's Pneumococcal Vaccines Accelerated Development and Introduction Plan focuses on pneumococcal vaccines for children
doi:10.1371/journal.pmed.1000081
PMCID: PMC2680036  PMID: 19468297
20.  Hospital at home early discharge 
Background
‘Early discharge hospital at home’ is a service that provides active treatment by health care professionals in the patient’s home for a condition that otherwise would require acute hospital in-patient care. If hospital at home were not available then the patient would remain in an acute hospital ward.
Objectives
To determine, in the context of a systematic review and meta-analysis, the effectiveness and cost of managing patients with early discharge hospital at home compared with in-patient hospital care.
Search methods
We searched the Cochrane Effective Practice and Organisation of Care (EPOC) Group Register , MEDLINE (1950 to 2008), EMBASE (1980 to 2008), CINAHL (1982 to 2008) and EconLit through to January 2008. We checked the reference lists of articles identified for potentially relevant articles.
Selection criteria
Randomised controlled trials recruiting patients aged 18 years and over. Studies comparing early discharge hospital at home with acute hospital in-patient care. Evaluations of obstetric, paediatric and mental health hospital at home schemes are excluded from this review.
Data collection and analysis
Two authors independently extracted data and assessed study quality. Our statistical analyses were done on an intention-to-treat basis. We requested individual patient data (IPD) from trialists, and relied on published data when we did not receive trial data sets or the IPD did not include the relevant outcomes. For the IPD meta-analysis, where at least one event was reported in both study groups in a trial, Cox regression models were used to calculate the log hazard ratio and its standard error for mortality and readmission separately for each data set. The calculated log hazard ratios were combined using fixed-effect inverse variance meta-analysis.
Main results
Twenty-six trials were included in this review [n = 3967]; 21 were eligible for the IPD meta-analysis and 13 of the 21 trials contributed data [1899/2872; 66%]. For patients recovering from a stroke and elderly patients with a mix of conditions there was insufficient evidence of a difference in mortality between groups (adjusted HR 0.79, 95% CI 0.32 to 1.91; N = 494; and adjusted HR 1.06, 95% CI 0.69 to 1.61; N = 978). Readmission rates were significantly increased for elderly patients with a mix of conditions allocated to hospital at home (adjusted HR 1.57; 95% CI 1.10 to 2.24; N = 705). For patients recovering from a stroke and elderly patients with a mix of conditions respectively, significantly fewer people allocated to hospital at home were in residential care at follow-up (RR 0.63; 95% CI 0.40 to 0.98; N = 4 trials; RR 0.69, 95% CI 0.48 to 0.99; N =3 trials). Patients reported increased satisfaction with early discharge hospital at home. There was insufficient evidence of a difference for readmission between groups in trials recruiting patients recovering from surgery. Evidence on cost savings was mixed.
Authors’ conclusions
Despite increasing interest in the potential of early discharge hospital at home services as a cheaper alternative to in-patient care, this review provides insufficient objective evidence of economic benefit or improved health outcomes.
doi:10.1002/14651858.CD000356.pub3
PMCID: PMC4175532  PMID: 19160179
*Hospitalization [economics]; Home Care Services, Hospital-Based [economics; *standards]; Patient Care [economics; standards]; Patient Discharge; Randomized Controlled Trials as Topic; Adult; Humans
21.  Investigation of continuous effect modifiers in a meta-analysis on higher versus lower PEEP in patients requiring mechanical ventilation - protocol of the ICEM study 
Systematic Reviews  2014;3:46.
Background
Categorizing an inherently continuous predictor in prognostic analyses raises several critical methodological issues: dependence of the statistical significance on the number and position of the chosen cut-point(s), loss of statistical power, and faulty interpretation of the results if a non-linear association is incorrectly assumed to be linear. This also applies to a therapeutic context where investigators of randomized clinical trials (RCTs) are interested in interactions between treatment assignment and one or more continuous predictors.
Methods/Design
Our goal is to apply the multivariable fractional polynomial interaction (MFPI) approach to investigate interactions between continuous patient baseline variables and the allocated treatment in an individual patient data meta-analysis of three RCTs (N = 2,299) from the intensive care field. For each study, MFPI will provide a continuous treatment effect function. Functions from each of the three studies will be averaged by a novel meta-analysis approach for functions. We will plot treatment effect functions separately for each study and also the averaged function. The averaged function with a related confidence interval will provide a suitable basis to assess whether a continuous patient characteristic modifies the treatment comparison and may be relevant for clinical decision-making. The compared interventions will be a higher or lower positive end-expiratory pressure (PEEP) ventilation strategy in patients requiring mechanical ventilation. The continuous baseline variables body mass index, PaO2/FiO2, respiratory compliance, and oxygenation index will be the investigated potential effect modifiers. Clinical outcomes for this analysis will be in-hospital mortality, time to death, time to unassisted breathing, and pneumothorax.
Discussion
This project will be the first meta-analysis to combine continuous treatment effect functions derived by the MFPI procedure separately in each of several RCTs. Such an approach requires individual patient data (IPD). They are available from an earlier IPD meta-analysis using different methods for analysis. This new analysis strategy allows assessing whether treatment effects interact with continuous baseline patient characteristics and avoids categorization-based subgroup analyses. These interaction analyses of the present study will be exploratory in nature. However, they may help to foster future research using the MFPI approach to improve interaction analyses of continuous predictors in RCTs and IPD meta-analyses. This study is registered in PROSPERO (CRD42012003129).
doi:10.1186/2046-4053-3-46
PMCID: PMC4035853  PMID: 24887172
Fractional polynomials; Interaction analysis; MFPI; Continuous predictors; Individual patient data meta-analysis; Acute respiratory distress syndrome
22.  Clinical features and outcomes of serotype 19A invasive pneumococcal disease in Calgary, Alberta 
The recent introduction of the seven-valent pneumococcal conjugate vaccine has led to changes in the proportion of disease caused by different serotypes. The serotypes targeted by the vaccine have been reduced, and Streptococcus pneumonia serotype 19A is now the most commonly isolated serotype causing invasive pneumococcal disease. This serotype has been associated with antibiotic resistance. The authors of this article conducted a review of cases of invasive pneumococcal disease diagnosed between 2000 and 2010 in Calgary, Alberta, to examine the disease course of serotype 19A invasive pneumococcal disease compared with other serotypes.
BACKGROUND:
Streptoccocus pneumoniae serotype 19A (ST19A) became an important cause of invasive pneumococcal disease (IPD) after the introduction of the conjugate vaccine.
OBJECTIVE:
To examine the severity and outcome of ST19A IPD compared with non-ST19A IPD.
METHODS:
The Calgary Area Streptococcus pneumoniae Epidemiology Research (CASPER) study collects clinical and laboratory data on all IPD cases in Calgary, Alberta. Analysis was performed on data from 2000 to 2010 comparing ST19A and non-ST19A IPD cases. Adjusted linear and logistic regression models were used to examine outcomes of duration of appropriate intravenous antibiotic therapy and intensive care unit admission, respectively.
RESULTS:
ST19A tended to cause disease in younger patients. ST19A isolates were more often multidrug resistant (19% versus 0.3%; P<0.001). Adjusted logistic regression showed no difference in intensive care unit admission between ST19A and non-ST19A IPD cases (OR 1.4 [95% CI 0.8 to 2.7]). An adjusted linear regression model showed patients <18 years of age with a diagnosis of bacteremia and no risk factors infected with ST19A were, on average, treated with antibiotics 1.4 times (95% CI 1.1 to 1.9) as long as patients with non-19A IPD and the same baseline characteristics.
DISCUSSION:
ST19A IPD was associated with an increase in average time on antibiotics. Although many of the infecting strains of ST19A were within the threshold for susceptibility, they may be sufficiently resilient to require a longer duration of antibiotic therapy or higher dose to clear the infection.
CONCLUSIONS:
ST19A is more common in younger individuals, is more antibiotic resistant and may require longer average treatment duration.
PMCID: PMC4028678  PMID: 24855484
Antibiotic resistance; Meningitis; Mortality; Serotype 19A; Streptococcus pneumoniae
23.  Effect of Water, Sanitation, and Hygiene on the Prevention of Trachoma: A Systematic Review and Meta-Analysis 
PLoS Medicine  2014;11(2):e1001605.
Matthew Freeman and colleagues identified 86 individual studies that reported a measure of the effect of water, sanitation, and hygiene on trachoma and conducted 15 meta-analyses for specific exposure-outcome pairs.
Please see later in the article for the Editors' Summary
Background
Trachoma is the world's leading cause of infectious blindness. The World Health Organization (WHO) has endorsed the SAFE strategy in order to eliminate blindness due to trachoma by 2020 through “surgery,” “antibiotics,” “facial cleanliness,” and “environmental improvement.” While the S and A components have been widely implemented, evidence and specific targets are lacking for the F and E components, of which water, sanitation, and hygiene (WASH) are critical elements. Data on the impact of WASH on trachoma are needed to support policy and program recommendations. Our objective was to systematically review the literature and conduct meta-analyses where possible to report the effects of WASH conditions on trachoma and identify research gaps.
Methods and Findings
We systematically searched PubMed, Embase, ISI Web of Knowledge, MedCarib, Lilacs, REPIDISCA, DESASTRES, and African Index Medicus databases through October 27, 2013 with no restrictions on language or year of publication. Studies were eligible for inclusion if they reported a measure of the effect of WASH on trachoma, either active disease indicated by observed signs of trachomatous inflammation or Chlamydia trachomatis infection diagnosed using PCR. We identified 86 studies that reported a measure of the effect of WASH on trachoma. To evaluate study quality, we developed a set of criteria derived from the GRADE methodology. Publication bias was assessed using funnel plots. If three or more studies reported measures of effect for a comparable WASH exposure and trachoma outcome, we conducted a random-effects meta-analysis. We conducted 15 meta-analyses for specific exposure-outcome pairs. Access to sanitation was associated with lower trachoma as measured by the presence of trachomatous inflammation-follicular or trachomatous inflammation-intense (TF/TI) (odds ratio [OR] 0.85, 95% CI 0.75–0.95) and C. trachomatis infection (OR 0.67, 95% CI 0.55–0.78). Having a clean face was significantly associated with reduced odds of TF/TI (OR 0.42, 95% CI 0.32–0.52), as were facial cleanliness indicators lack of ocular discharge (OR 0.42, 95% CI 0.23–0.61) and lack of nasal discharge (OR 0.62, 95% CI 0.52–0.72). Facial cleanliness indicators were also associated with reduced odds of C. trachomatis infection: lack of ocular discharge (OR 0.40, 95% CI 0.31–0.49) and lack of nasal discharge (OR 0.56, 95% CI 0.37–0.76). Other hygiene factors found to be significantly associated with reduced TF/TI included face washing at least once daily (OR 0.76, 95% CI 0.57–0.96), face washing at least twice daily (OR 0.85, 95% CI 0.80–0.90), soap use (OR 0.76, 95% CI 0.59–0.93), towel use (OR 0.65, 95% CI 0.53–0.78), and daily bathing practices (OR 0.76, 95% CI 0.53–0.99). Living within 1 km of a water source was not found to be significantly associated with TF/TI or C. trachomatis infection, and the use of sanitation facilities was not found to be significantly associated with TF/TI.
Conclusions
We found strong evidence to support F and E components of the SAFE strategy. Though limitations included moderate to high heterogenity, low study quality, and the lack of standard definitions, these findings support the importance of WASH in trachoma elimination strategies and the need for the development of standardized approaches to measuring WASH in trachoma control programs.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Trachoma is a bacterial eye infection, which if left untreated may lead to irreversible blindness. Repeated infections over many years cause scarring on the eyelid, making the eyelashes turn inward. This causes pain and damage to the cornea at the front of the eye, which eventually leads to loss of vision. The disease is most common in rural areas in low-income countries, specifically sub-Saharan Africa. It spreads easily through contact with the discharge from an infected eye or nose, by hands, or by flies landing on the face. Women and children are more often affected than men. Trachoma is the world's leading cause of preventable blindness. A global alliance, led by The World Health Organization, is aiming to eliminate trachoma by 2020 by adopting the SAFE strategy. There are four components of this strategy. Two relate to treating the disease—“surgery” and “antibiotics.” The other two components relate to long-term prevention by promoting “facial” cleanliness and “environmental” changes (for example improving access to water and sanitation or reducing the breeding grounds for flies).
Why Was This Study Done?
The SAFE approach has been very successful in reducing the number of people with trachoma from 84 million in 2003 to 21.4 million in 2012. However, it is widely recognized that efforts need to be scaled up to reach the 2020 goal. Furthermore, if current improvements are to be sustained, then more attention needs to be given to the “F” and “E” elements and effective prevention. This study aimed to identify the most effective ways to improve hygiene, sanitation, and access to water for better trachoma control, and to find better ways of monitoring progress. The overall goal was to summarize the evidence in order to devise strategic and cost-effective approaches to trachoma prevention.
What Did the Researchers Do and Find?
The researchers conducted a systematic review, which involved first identifying and then assessing the quality of all of the research published on this topic. They then carried out a statistical analysis of the combined data from these studies, with the aim of drawing more robust conclusions (a meta-analysis). The analysis involved 15 different water, sanitation, and hygiene exposures (either hardware or practices, as determined by what was available in the literature) to determine which had the biggest impact on reducing the levels of trachoma. Most of the data came from studies carried out in Africa. The findings suggested that 11 of these exposures made a significant difference to the risk of infection or clinical symptoms of the disease. Improving personal hygiene had the greatest impact. Effective measures included face washing once or twice a day, using soap, using a towel, and daily bathing. Similarly, access to a sanitation facility, rather than open ground, also had a positive impact. The researchers also analyzed the data relating to water access. However, the studies so far have not yet measured this in a way that addresses the issues relevant to trachoma infection. Most studies have looked at whether the distance from a water source has an impact (and it seems it does not), whereas it may be more important to assess whether people have access to clean water or to enough water to wash. Many of these analyses require additional research to further clarify the impact of individual water, sanitation, and hygiene exposure on disease.
What Do These Findings Mean?
Overall, the results support that notion that water, sanitation, and hygiene are important components of an integrated strategy to control trachoma. Based on the research available to date, the two most effective ways are face washing and having access to a household-level sanitation facility, typically a simple pit latrine. The findings also point to ways in which current policy could be improved. Firstly, public health guidance should be placing greater emphasis on keeping the face clean. Current advice tends to focus on washing with clean water, but use of soap appears more effective. There are also opportunities for organizations to collaborate in this area. For example, organizations focusing on the prevention of diarrhea in children, which promote handwashing, could at the same time campaign for face washing to reduce transmission of trachoma. The second policy area to target is access to good quality sanitation. Such policy initiatives need to be better resourced in countries where trachoma is a problem. For example, although sub-Saharan Africa has the world's highest burden of trachoma, more than 50% of households there still do not have access to any sanitation facility.
There were a number of limitations to this study, which may affect the strength of the conclusions. The researchers found that many studies on this topic were observational, meaning that they did not assess an intervention and employ a control group, thus they are of limited rigor for assessing the impact of a water, sanitation, and hygiene intervention on trachoma. There was also a lot of variation in the way that different studies had defined and measured improvements to water, sanitation, and hygiene access. This made it difficult to make comparisons. Standard methods and indicators need to be developed for this purpose. The study also highlighted gaps in the research. More work is required to determine precisely what is needed in terms of access to water to reduce the incidence of trachoma. Similarly, in terms of improving sanitation, it is still unclear whether ensuring every household has a simple, onsite facility would be more effective than providing clean communal facilities. The potential role of schools in promoting relevant public health measures also needs investigation.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001605.
WHO provides information on trachoma (in several languages)
The US Centers for Disease Control and Prevention provide information on trachoma
International Trachoma Initiative is dedicated to the goal of elimination of blinding trachoma
The Carter Center: Trachoma Control Program has a Trachoma Health Education Materials Library
WASHNTD has an online manual resource for NTDs for WASH policy and programming
doi:10.1371/journal.pmed.1001605
PMCID: PMC3934994  PMID: 24586120
24.  Effect of Pneumococcal Conjugate Vaccination on Serotype-Specific Carriage and Invasive Disease in England: A Cross-Sectional Study 
PLoS Medicine  2011;8(4):e1001017.
A cross sectional study by Stefan Flasche and coworkers document the serotype replacement of Streptococcus pneumoniae that has occurred in England since the introduction of PCV7 vaccination.
Background
We investigated the effect of the 7-valent pneumococcal conjugate vaccine (PCV7) programme in England on serotype-specific carriage and invasive disease to help understand its role in serotype replacement and predict the impact of higher valency vaccines.
Methods and Findings
Nasopharyngeal swabs were taken from children <5 y old and family members (n = 400) 2 y after introduction of PCV7 into routine immunization programs. Proportions carrying Streptococcus pneumoniae and serotype distribution among carried isolates were compared with a similar population prior to PCV7 introduction. Serotype-specific case∶carrier ratios (CCRs) were estimated using national data on invasive disease. In vaccinated children and their contacts vaccine-type (VT) carriage decreased, but was offset by an increase in non-VT carriage, with no significant overall change in carriage prevalence, odds ratio 1.06 (95% confidence interval 0.76–1.49). The lower CCRs of the replacing serotypes resulted in a net reduction in invasive disease in children. The additional serotypes covered by higher valency vaccines had low carriage but high disease prevalence. Serotype 11C emerged as predominant in carriage but caused no invasive disease whereas 8, 12F, and 22F emerged in disease but had very low carriage prevalence.
Conclusion
Because the additional serotypes included in PCV10/13 have high CCRs but low carriage prevalence, vaccinating against them is likely to significantly reduce invasive disease with less risk of serotype replacement. However, a few serotypes with high CCRs could mitigate the benefits of higher valency vaccines. Assessment of the effect of PCV on carriage as well as invasive disease should be part of enhanced surveillance activities for PCVs.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Pneumococcal diseases—major causes of illness and death in children and adults worldwide—are caused by Streptococcus pneumoniae, a bacterium that often colonizes the nasopharynx (the area of the throat behind the nose). Carriage of S. pneumoniae bacteria does not necessarily cause disease. However, these bacteria can cause local, noninvasive diseases such as ear infections and sinusitis and, more rarely, they can spread into the lungs, the bloodstream, or the covering of the brain, where they cause pneumonia, septicemia, and meningitis, respectively. Although these invasive pneumococcal diseases (IPDs) can be successfully treated if administered early, they can be fatal. Consequently, it is better to protect people against IPDs through vaccination than risk infection. Vaccination primes the immune system to recognize and attack disease-causing organisms (pathogens) rapidly and effectively by exposing it to weakened or dead pathogens or to pathogen molecules (antigens) that it recognizes as foreign.
Why Was This Study Done?
There are more than 90 S. pneumoniae variants or “serotypes” characterized by different polysaccharide (complex sugar) coats, which trigger the immune response against S. pneumoniae and determine each serotype's propensity to cause IPD. The pneumococcal conjugate vaccine PCV7 contains polysaccharides (linked to a protein carrier) from the seven serotypes mainly responsible for IPD in the US in 2000 when routine childhood PCV7 vaccination was introduced in that country. PCV7 prevents both IPD caused by the serotypes it contains and carriage of these serotypes, which means that, after vaccination, previously uncommon, nonvaccine serotypes can colonize the nasopharynx. If these serotypes have a high invasiveness potential, then “serotype replacement” could reduce the benefits of vaccination. In this cross-sectional study (a study that investigates the relationship between a disease and an intervention in a population at one time point), the researchers investigate the effect of the UK PCV7 vaccination program (which began in 2006) on serotype-specific carriage and IPD in England to understand the role of PCV7 in serotype replacement and to predict the likely impact of vaccines containing additional serotypes (higher valency vaccines).
What Did the Researchers Do and Find?
The researchers examined nasopharyngeal swabs taken from PCV7-vaccinated children and their families for S. pneumoniae, determined the serotype of any bacteria they found, and compared the proportion of people carrying S. pneumoniae (carrier prevalence) and the distribution of serotypes in this study population and in a similar population that was studied in 2000/2001, before the PCV vaccination program began. Overall, there was no statistically significant change in carrier prevalence, but carriage of vaccine serotypes decreased in vaccinated children and their contacts whereas carriage of nonvaccine serotypes increased. The serotype-specific case-to-carrier ratios (CCRs; a measure of serotype invasiveness that was estimated using national IPD data) of the replacing serotypes were generally lower than those of the original serotypes, which resulted in a net reduction in IPD in children. Moreover, before PCV7 vaccination began, PCV7-included serotypes were responsible for similar proportions of pneumococcal carriage and disease; afterwards, the additional serotypes present in the higher valency vaccines PVC10 and PVC13 were responsible for a higher proportion of disease than carriage. Finally, three serotypes not present in the higher valency vaccines with outstandingly high CCRs (high invasiveness potential) are identified.
What Do These Findings Mean?
These findings document the serotype replacement of S. pneumoniae that has occurred in England since the introduction of PCV7 vaccination and highlight the importance of assessing the effects of pneumococcal vaccines on carriage as well as on IPDs. Because the additional serotypes included in PCV10 and PCV13 have high CCRs but low carriage prevalence and because most of the potential replacement serotypes have low CCRs, these findings suggest that the introduction of higher valency vaccines should further reduce the occurrence of invasive disease with limited risk of additional serotype replacement. However, the emergence of a few serotypes that have high CCRs but are not included in PCV10 and PCV13 might mitigate the benefits of higher valency vaccines. In other words, although the recent introduction of PCV13 into UK vaccination schedules is likely to have an incremental benefit on the reduction of IPD compared to PCV7, this benefit might be offset by increases in the carriage of some high CCR serotypes. These serotypes should be considered for inclusion in future vaccines.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001017.
The US Centers for Disease Control and Prevention provides information for patients and health professionals on all aspects of pneumococcal disease and pneumococcal vaccination
The US National Foundation for Infectious Diseases has a fact sheet on pneumococcal diseases
The UK Health Protection Agency provides information on pneumococcal disease and on pneumococcal vaccines
The World Health Organization also provides information on pneumococcal vaccines
MedlinePlus has links to further information about pneumococcal infections (in English and Spanish)
doi:10.1371/journal.pmed.1001017
PMCID: PMC3071372  PMID: 21483718
25.  Individual Participant Data Meta-Analysis for a Binary Outcome: One-Stage or Two-Stage? 
PLoS ONE  2013;8(4):e60650.
Background
A fundamental aspect of epidemiological studies concerns the estimation of factor-outcome associations to identify risk factors, prognostic factors and potential causal factors. Because reliable estimates for these associations are important, there is a growing interest in methods for combining the results from multiple studies in individual participant data meta-analyses (IPD-MA). When there is substantial heterogeneity across studies, various random-effects meta-analysis models are possible that employ a one-stage or two-stage method. These are generally thought to produce similar results, but empirical comparisons are few.
Objective
We describe and compare several one- and two-stage random-effects IPD-MA methods for estimating factor-outcome associations from multiple risk-factor or predictor finding studies with a binary outcome. One-stage methods use the IPD of each study and meta-analyse using the exact binomial distribution, whereas two-stage methods reduce evidence to the aggregated level (e.g. odds ratios) and then meta-analyse assuming approximate normality. We compare the methods in an empirical dataset for unadjusted and adjusted risk-factor estimates.
Results
Though often similar, on occasion the one-stage and two-stage methods provide different parameter estimates and different conclusions. For example, the effect of erythema and its statistical significance was different for a one-stage (OR = 1.35, ) and univariate two-stage (OR = 1.55, ). Estimation issues can also arise: two-stage models suffer unstable estimates when zero cell counts occur and one-stage models do not always converge.
Conclusion
When planning an IPD-MA, the choice and implementation (e.g. univariate or multivariate) of a one-stage or two-stage method should be prespecified in the protocol as occasionally they lead to different conclusions about which factors are associated with outcome. Though both approaches can suffer from estimation challenges, we recommend employing the one-stage method, as it uses a more exact statistical approach and accounts for parameter correlation.
doi:10.1371/journal.pone.0060650
PMCID: PMC3621872  PMID: 23585842

Results 1-25 (1337507)