title: Components of the indirect effect in vaccine trials: identification of contagion and infectiousness effects. Herd protection by a bivalent killed whole-cell oral cholera vaccine in the slums of Kolkata, India. Community-wide effects of permethrin-treated bed nets on child mortality and malaria morbidity in western Kenya. Improving immunisation coverage in rural India: clustered randomised controlled evaluation of immunisation campaigns with and without incentives Effect of scaling up women's groups on birth outcomes in three rural districts in Bangladesh: a cluster-randomised controlled trial Impact of pediatric vaccination with pneumococcal conjugate vaccine on the risk of bacteremic pneumococcal pneumonia in adults. Relationship between neighbourhood-level killed oral cholera vaccine coverage and protective efficacy: evidence for herd immunity. The association between latrine use and trachoma: a secondary cohort analysis from a randomized clinical trial. Effectiveness and spillover of an after-school health promotion program for Hispanic elementary school children. Effectiveness of an oral cholera vaccine in Zanzibar: findings from a mass vaccination campaign and observational cohort study. Toward Causal Inference With Interference Effectiveness of Vi capsular polysaccharide typhoid vaccine among children: a cluster randomized trial in Karachi, Pakistan. Herd immunity in adults against influenza-related illnesses with use of the trivalent-live attenuated influenza vaccine (CAIV-T) in children. Peer effects in learning HIV results. Distance to health services affects local-level vaccine efficacy for pneumococcal conjugate vaccine (PCV) among rural Filipino children Assessing effects of cholera vaccination in the presence of interference. Users identified challenges in applying GRADE to complex interventions and suggested an extension to GRADE. The Minicommunity Design to Assess Indirect Effects of Vaccination Indirect Effect of 7-Valent Pneumococcal Conjugate Vaccine on Pneumococcal Carriage in Newborns in Rural Gambia: A Randomised Controlled Trial Assessment of herd protection against trachoma due to repeated mass antibiotic distributions: a cluster-randomised trial Vaccine Protection of Bangladeshi Infants and Young Children Against Cholera: Implications for Vaccine Deployment and Person-to-Person Transmission Developments in cluster randomized trials and Statistics in Medicine. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials Population effect of 10-valent pneumococcal conjugate vaccine on nasopharyngeal carriage of Streptococcus pneumoniae and non-typeable Haemophilus influenzae in Kilifi, Kenya: findings from cross-sectional carriage studies Promoting Transparency in Social Science Research
abstract: Vaccination of one person may prevent the infection of another either because the vaccine prevents the first from being infected and from infecting the second , or because , even if the first person is infected , the vaccine may render the infection less infectious . We might refer to the first of these mechanisms as a contagion effect and the second as an infectiousness effect . In the simple setting of a r and omized vaccine trial with households of size two , we use counterfactual theory under interference to provide formal definitions of a contagion effect and an unconditional infectiousness effect . Using ideas analogous to mediation analysis , we show that the indirect effect ( the effect of one person 's vaccine on another 's outcome ) can be decomposed into a contagion effect and an unconditional infectiousness effect on the risk difference , risk ratio , odds ratio , and vaccine efficacy scales . We provide identification assumptions for such contagion and unconditional infectiousness effects and describe a simple statistical technique to estimate these effects when they are identified . We also give a sensitivity analysis technique to assess how inferences would change under violations of the identification assumptions . The concepts and results of this paper are illustrated with hypothetical vaccine trial data BACKGROUND We evaluated the herd protection conferred by an oral cholera vaccine using 2 approaches : cluster design and geographic information system ( GIS ) design . METHODS Residents living in 3933 dwellings ( clusters ) in Kolkata , India , were cluster-r and omized to receive either cholera vaccine or oral placebo . Nonpregnant residents aged≥1 year were invited to participate in the trial . Only the first episode of cholera detected for a subject between 14 and 1095 days after a second dose was considered . In the cluster design , indirect protection was assessed by comparing the incidence of cholera among non participants in vaccine clusters vs those in placebo clusters . In the GIS analysis , herd protection was assessed by evaluating association between vaccine coverage among the population residing within 250 m of the household and the occurrence of cholera in that population . RESULTS Among 107 347 eligible residents , 66 990 received 2 doses of either cholera vaccine or placebo . In the cluster design , the 3-year data showed significant total protection ( 66 % protection , 95 % confidence interval [ CI ] , 50%-78 % , P<.01 ) but no evidence of indirect protection . With the GIS approach , the risk of cholera among placebo recipients was inversely related to neighborhood-level vaccine coverage , and the trend was highly significant ( P<.01 ) . This relationship held in multivariable models that also controlled for potentially confounding demographic variables ( hazard ratio , 0.94 [ 95 % CI , .90-.98 ] ; P<.01 ) . CONCLUSIONS Indirect protection was evident in analyses using the GIS approach but not the cluster design approach , likely owing to considerable transmission of cholera between clusters , which would vitiate herd protection in the cluster analyses . CLINICAL TRIALS REGISTRATION NCT00289224 Spatial analyses of the effect of insecticide (permethrin)-treated bed nets ( ITNs ) on nearby households both with and without ITNs was performed in the context of a large-scale , group-r and omized , controlled mortality trial in Asembo , western Kenya . Results illustrate a protective effect of ITNs on compounds lacking ITNs located within 300 meters of compounds with ITNs for child mortality , moderate anemia , high-density parasitemia , and hemoglobin levels . This community effect on nearby compounds without nets is approximately as strong as the effect observed within villages with ITNs . This implies that in areas with intense malaria transmission with high ITN coverage , the primary effect of insecticide-treated nets is via area-wide effects on the mosquito population and not , as commonly supposed , by simple imposition of a physical barrier protecting individuals from biting . The strength of the community effect depended upon the proportion of nearby compounds with treated nets . To maximize their public health impact , high coverage with treated nets is essential Objective To assess the efficacy of modest non-financial incentives on immunisation rates in children aged 1 - 3 and to compare it with the effect of only improving the reliability of the supply of services . Design Clustered r and omised controlled study . Setting Rural Rajasthan , India . Participants 1640 children aged 1 - 3 at end point . Interventions 134 villages were r and omised to one of three groups : a once monthly reliable immunisation camp  ( intervention A ; 379 children from 30 villages ) ; a once monthly reliable immunisation camp with small incentives ( raw lentils and metal plates for completed immunisation ;  intervention B ; 382 children from 30 villages ) , or  control ( no intervention , 860 children in 74 villages ) . Surveys were undertaken in r and omly selected households at baseline and about 18 months after the interventions started ( end point ) . Main outcome measures Proportion of children aged 1 - 3 at the end point who were partially or fully immunised . Results Among children aged 1 - 3 in the end point survey , rates of full immunisation were 39 % ( 148/382 , 95 % confidence interval 30 % to 47 % ) for intervention B villages ( reliable immunisation with incentives ) , 18 % ( 68/379 , 11 % to 23 % ) for intervention A villages ( reliable immunisation without incentives ) , and 6 % ( 50/860 , 3 % to 9 % ) for control villages . The relative risk of complete immunisation for intervention B versus control was 6.7 ( 4.5 to 8.8 ) and for intervention B versus intervention A was 2.2 ( 1.5 to 2.8 ) . Children in areas neighbouring intervention B villages were also more likely to be fully immunised than those from areas neighbouring intervention A villages ( 1.9 , 1.1 to 2.8 ) . The average cost per immunisation was $ 28 ( 1102 rupees , about £ 16 or € 19 ) in intervention A and $ 56 ( 2202 rupees ) in intervention B. Conclusions Improving reliability of services improves immunisation rates , but the effect remains modest . Small incentives have large positive impacts on the uptake of immunisation services in re source poor areas and are more cost effective than purely improving supply . Trial registration IRSCTN87759937 BACKGROUND Two recent trials have shown that women 's groups can reduce neonatal mortality in poor communities . We assessed the effectiveness of a scaled-up development programme with women 's groups to address maternal and neonatal care in three rural districts of Bangladesh . METHODS 18 clusters ( with a mean population of 27 953 [ SD 5953 ] ) in three districts were r and omly assigned to either intervention or control ( nine clusters each ) by use of stratified r and omisation . For each district , cluster names were written on pieces of paper , which were folded and placed in a bottle . The first three cluster names drawn from the bottle were allocated to the intervention group and the remaining three to control . All clusters received health services strengthening and basic training of traditional birth attendants . In intervention clusters , a facilitator convened 18 groups every month to support participatory action and learning for women , and to develop and implement strategies to address maternal and neonatal health problems . Women were eligible to participate if they were aged 15 - 49 years , residing in the project area , and had given birth during the study period ( Feb 1 , 2005 , to Dec 31 , 2007 ) . Neither study investigators nor participants were masked to treatment assignment . In a population of 229 195 people ( intervention clusters only ) , 162 women 's groups provided coverage of one group per 1414 population . The primary outcome was neonatal mortality rate ( NMR ) . Analysis was by intention to treat . This trial is registered as an International St and ard R and omised Controlled Trial , number IS RCT N54792066 . FINDINGS We monitored outcomes for 36 113 births ( intervention clusters , n=17 514 ; control clusters , n=18 599 ) in a population of 503 163 over 3 years . From 2005 to 2007 , there were 570 neonatal deaths in the intervention clusters and 656 in the control clusters . Cluster-level mean NMR ( adjusted for stratification and clustering ) was 33.9 deaths per 1000 livebirths in the intervention clusters compared with 36.5 per 1000 in the control clusters ( risk ratio 0.93 , 95 % CI 0.80 - 1.09 ) . INTERPRETATION For participatory women 's groups to have a significant effect on neonatal mortality in rural Bangladesh , detailed attention to programme design and context ual factors , enhanced population coverage , and increased enrolment of newly pregnant women might be needed . FUNDING Women and Children First , the UK Big Lottery Fund , Saving Newborn Lives , and the UK Department for International Development Invasive pneumococcal disease in adults may be declining , reflecting a form of herd protection from a new pediatric pneumococcal conjugate vaccine . Our aim was to determine whether vaccination of children protects adults in the same home from bacteremic pneumococcal pneumonia . We conducted a case-control study with 43 participating hospitals across a five-county region in Pennsylvania . Eligible cases were adults with bacteremic pneumococcal pneumonia identified by the microbiology laboratories at participating hospitals . Controls were healthy adults from the region identified through r and om digit dialing . Cases and controls were interviewed by telephone . We analyzed vaccine protection in those adults who reported living in homes with at least one child < or = 6 years of age . From April 2002 through June 2004 , there was a significant decline in the proportion of adult pneumococcal bacteremia due to any of the seven serotypes in the conjugate vaccine ( p=0.006 ) . Within this time period , 17 % of cases and controls reported living in homes with at least one child < or = 6 years of age . In adjusted analysis , vaccination of the youngest child in the home was associated with an 80 % reduction in the odds of bacteremic pneumococcal pneumonia among adults with children in the home ( OR=0.2 , 95 % CI 0.1 - 0.8 ) . We conclude that introduction of a pneumococcal conjugate vaccine for children has reduced the population rate of adult pneumococcal bacteremia due to vaccine serotypes and is associated with a reduced risk of bacteremic pneumococcal pneumonia for adults with children in the home OBJECTIVES The effectiveness of vaccines in population s must consider both direct and indirect protection . This study reanalyses data from a large individually r and omized oral cholera vaccine trial that was conducted in rural Bangladesh from 1985 to 1990 . A recent analysis of the results of that trial showed that the proportion of people in household clusters who received the vaccine was inversely related to placebo incidence during the first year of surveillance , which was attributed to herd immunity . METHODS In this study we measure the relationship between  neighbourhood-level oral cholera vaccine coverage and protective efficacy ( PE ) during a 2 year follow-up period , controlling for known effect modifiers . We link trial data to a household geographic information system to facilitate the neighbourhood-level analysis . Findings Neighbourhood-level PE can be partially explained by vaccine coverage after adjusting for ecological variables . CONCLUSIONS The inverse relationship between vaccine coverage and efficacy illustrates that people living in high-coverage areas may be indirectly protected from cholera because people living around them are vaccinated Latrine use has been promoted as a component of an integrated strategy for trachoma control . As part of a r and omized trial in Ethiopia , 12 communities received a mass azithromycin distribution followed by a latrine promotion intervention .  A r and om sample of children ages 0 - 9 years in each community was monitored longitudinally for ocular chlamydia . After latrine construction ended , those communities with a higher proportion of households using latrines were more likely to experience a reduction in the prevalence of ocular chlamydia . Specifically , for each 10 % increase in latrine use , there was a 2.0 % decrease ( 95 % confidence interval = 0.2 - 3.9 % decrease ) in the community prevalence of ocular chlamydia over the subsequent year ( P = 0.04 ) OBJECTIVES We evaluated the effectiveness and spillover of an after-school health education and physical activity program among Hispanic elementary school children . METHODS In fall 2008 , students in third through fifth grade s in 6 schools in El Paso , Texas ( n = 901 ) , were r and omized to intervention ( n = 292 participants ) or control ( n = 354 ) classrooms ( 4 unknown ) . Intervention classrooms also contained a spillover group ( n = 251 ) that did not join the after-school program but that completed measurements and surveys . The intervention was a 12-week culturally tailored after-school program meeting twice a week . Four-month outcomes were body mass index , aerobic capacity , and dietary intentions and knowledge . We calculated intervention exposure as the proportion of after-school participants per classroom . RESULTS Intervention exposure predicted lower body mass index ( P = .045 ) , higher aerobic capacity ( P = .012 ) , and greater intentions to eat healthy ( P = .046 ) for the classroom at follow-up . Intervention effectiveness increased with increasing proportions of intervention participants in a classroom . Non participants who had classroom contact with program participants experienced health improvements that could reduce their risk of obesity . CONCLUSIONS Spillover of beneficial intervention effects to non participants is a valuable public health benefit and should be part of program impact assessment BACKGROUND Zanzibar , in east Africa , has been severely and repeatedly affected by cholera since 1978 . We assessed the effectiveness of oral cholera vaccination in high-risk population s in the archipelago to estimate the indirect ( herd ) protection conferred by the vaccine and direct vaccine effectiveness . METHODS We offered two doses of a killed whole-cell B-subunit cholera vaccine to individuals aged 2 years and older in six rural and urban sites . To estimate vaccine direct protection , we compared the incidence of cholera between recipients and non-recipients using generalised estimating equations with the log link function while controlling for potential confounding variables . To estimate indirect effects , we used a geographic information systems approach and assessed the association between neighbourhood-level vaccine coverage and the risk for cholera in the non-vaccinated residents of that neighbourhood , after controlling for potential confounding variables . This study is registered with Clinical Trials.gov , number NCT00709410 . FINDINGS Of 48,178 individuals eligible to receive the vaccine , 23,921 ( 50 % ) received two doses . Between February , 2009 , and May , 2010 , there was an outbreak of cholera , enabling us to assess vaccine effectiveness . The vaccine conferred 79 % ( 95 % CI 47 - 92 ) direct protection against cholera in participants who received two doses . Indirect ( herd ) protection was shown by a decrease in the risk for cholera of non-vaccinated residents within a household 's neighbourhood as the vaccine coverage in that neighbourhood increased . INTERPRETATION Our findings suggest that the oral cholera vaccine offers both direct and indirect ( herd ) protection in a sub-Saharan African setting . Mass oral cholera immunisation campaigns have the potential to provide not only protection for vaccinated individuals but also for the unvaccinated members of the community and should be strongly considered for wider use . Because this is an internationally-licensed vaccine , we could not undertake a r and omised placebo-controlled trial , but the absence of vaccine effectiveness against non-cholera diarrhoea indicates that the noted protection against cholera could not be explained by bias . FUNDING Bill & Melinda Gates Foundation , Swedish International Development Cooperation Agency , and the South Korean Government A fundamental assumption usually made in causal inference is that of no interference between individuals ( or units ) ; that is , the potential outcomes of one individual are assumed to be unaffected by the treatment assignment of other individuals . However , in many setting s , this assumption obviously does not hold . For example , in the dependent happenings of infectious diseases , whether one person becomes infected depends on who else in the population is vaccinated . In this article , we consider a population of groups of individuals where interference is possible between individuals within the same group . We propose estim and s for direct , indirect , total , and overall causal effects of treatment strategies in this setting . Relations among the estim and s are established ; for example , the total causal effect is shown to equal the sum of direct and indirect causal effects . Using an experimental design with a two-stage r and omization procedure ( first at the group level , then at the individual level within groups ) , unbiased estimators of the proposed estim and s are presented . Variances of the estimators are also developed . The methodology is illustrated in two different setting s where interference is likely : assessing causal effects of housing vouchers and of vaccines BACKGROUND Typhoid fever is endemic in Karachi , with an incidence among children ranging from 170 to 450 per 100,000 child-years .  Vaccination strategies are important for prevention , and the Vi capsular polysaccharide ( ViCPS ) vaccine has been shown to be effective in reducing the burden of typhoid fever . METHODS A cluster r and omized trial was conducted in three low socioeconomic urban squatter settlements in Karachi , Pakistan between 2002 and 2007 . Sub sample s were followed up for assessment of immune response and adverse events after vaccination . RESULTS The study participants were similar in a wide variety of socio-demographic and economic characteristics at baseline . A total of 27,231 individuals of the total target population of 51,965 in 120 clusters either received a ViCPS vaccine ( 13,238 [ 52 % coverage ] ) or the control Hepatitis A vaccine ( 13,993 [ 53 % ] ) . Typhoid fever was diagnosed in 30 ViCPS vaccine recipients and 49 Hepatitis A vaccine recipients with an adjusted total protective effectiveness of 31 % ( 95%CI : -28 % , 63 % ) . The adjusted total vaccine protective effectiveness was -38 % ( 95%CI : -192 % , 35 % ) for children aged 2 - 5 years and 57 % ( 95%CI : 6 % , 81 % ) for children 5 - 16 years old . CONCLUSION The ViCPS vaccine did not confer statistically significant protection to children in the study areas , and there was a decline in antibody response 2 years post-vaccination . However , the ViCPS vaccine showed significant total protection in children 5 - 16 years of age , which is consistent with other studies of ViCPS vaccine conducted in India , Nepal , China and South Africa . These findings suggest that ViCPS vaccination of school-aged children will protect the children of urban , typhoid endemic areas against typhoid fever Highest attack rates for influenza occur in children . Immunization of schoolchildren with inactivated influenza vaccine in Michigan and Japan was associated with decreased morbidity and mortality , respectively , in older community contacts . An open-labeled , non-r and omized , community-based trial in children with the cold adapted influenza vaccine , trivalent ( CAIV-T )  was initiated to determine the coverage necessary to reduce spread of influenza in the community . Age-specific baseline rates of medically attended acute respiratory illness ( MAARI ) for Scott and White Health Plan ( SWHP ) members at intervention ( Temple and Belton ) and comparison communities ( Waco , Bryan , and College Station ) were obtained in 1997 - 1998 . During three subsequent vaccination years , 4298 , 5251 and 5150 children received one dose per season of CAIV-T.  Vaccinees represented 20 - 25 % of the age-eligible children .  Age-specific MAARI rates were compared for SWHP members in the intervention and comparison sites during the influenza outbreaks . Baseline age-specific MAARI rates per 100 persons for the influenza season were comparable between the intervention and comparison communities . In the subsequent three influenza seasons , the age groups 35 - 44 , 45 - 54 , 55 - 65 and > 64 years experienced reductions in MAARI rates in the intervention communities . In adults > or = 35 years of age , significant reductions in MAARI of 0.08 ( 95 % CI : 0.04 , 0.13 ) , 0.18 ( 95 % CI : 0.14 , 0.22 ) and 0.15 ( 95 % CI : 0.12 , 0.19 ) , were observed in the influenza seasons for vaccination years 1 , 2 and 3 , respectively . No consistent reduction in MAARI rates was detected in the younger age groups . Vaccination of approximately 20 - 25 % of children , 1.5 - 18 years of age in the intervention communities result ed in an indirect protection of 8 - 18 % against MAARI in adults > or = 35 years of age How do neighbors positively or negatively influence individuals living in rural Malawi to learn their HIV results ? Using data of location of homes and distance to neighbors , we measure the social network effects of neighbors ' learning their HIV results on individuals own learning . Using the fact that  neighbors  were r and omly offered monetary incentives of varying amounts to learn their HIV results , we find positive effects of neighbors attending clinics on others living nearby : a 10 percentage point increase of the percentage of neighbors ( approximately 2.4 individuals ) learning their HIV results increases the probability of learning HIV results by 1.1 percentage points . The strongest network effects are among closest neighbors ; we find no effect among religious social networks . We also find a negative interaction between direct cash incentives and peers : the effect of peers doubles among those who were not offered any individual financial incentive to learn their HIV results Significance Although pneumococcal conjugate vaccines ( PCVs ) are widely available in industrialized nations , the cost of these vaccines and the strategy of universal vaccination of infants , as endorsed by the World Health Organization , are daunting obstacles to the adoption of these vaccines in developing countries . Using spatial epidemiological methods to examine the spatial variation in vaccine efficacy ( VE ) in an 11-valent PCV trial in Bohol , Philippines , we suggest an alternative strategy to universal vaccination . Our main finding suggests that areas with poor access to healthcare have the highest VE . An alternative vaccination strategy could target vaccination to areas where children are most likely to benefit , rather than focus on nationwide immunization . Pneumococcal conjugate vaccines ( PCVs ) have demonstrated efficacy against childhood pneumococcal disease in several regions globally . We demonstrate how spatial epidemiological analysis of a PCV trial can assist in developing vaccination strategies that target specific geographic sub population s at greater risk for pneumococcal pneumonia . We conducted a secondary analysis of a r and omized , placebo-controlled , double-blind vaccine trial that examined the efficacy of an 11-valent PCV among children less than 2 y of age in Bohol , Philippines . Trial data were linked to the residential location of each participant using a geographic information system . We use spatial interpolation methods to create smoothed surface maps of vaccination rates and local-level vaccine efficacy across the study area . We then measure the relationship between distance to the main study hospital and local-level vaccine efficacy , controlling for ecological factors , using spatial autoregressive models with spatial autoregressive disturbances . We find a significant amount of spatial variation in vaccination rates across the study area . For the primary study endpoint vaccine efficacy increased with distance from the main study hospital from −14 % for children living less than 1.5 km from Bohol Regional Hospital ( BRH ) to 55 % for children living greater than 8.5 km from BRH . Spatial regression models indicated that after adjustment for ecological factors , distance to the main study hospital was positively related to vaccine efficacy , increasing at a rate of 4.5 % per kilometer distance . Because areas with poor access to care have significantly higher VE , targeted vaccination of children in these areas might allow for a more effective implementation of global programs Interference occurs when the treatment of one person affects the outcome of another . For example , in infectious diseases , whether one individual is vaccinated may affect whether another individual becomes infected or develops disease . Quantifying such indirect ( or spillover ) effects of vaccination could have important public health or policy implication s. In this article we use recently developed inverse-probability weighted ( IPW ) estimators of treatment effects in the presence of interference to analyze an individually-r and omized , placebo-controlled trial of cholera vaccination that targeted 121,982 individuals in Matlab , Bangladesh . Because these IPW estimators have not been employed previously , a simulation study was also conducted to assess the empirical behavior of the estimators in setting s similar to the cholera vaccine trial . Simulation study results demonstrate the IPW estimators can yield unbiased estimates of the direct , indirect , total , and overall effects of vaccination when there is interference provided the untestable no unmeasured confounders assumption holds and the group-level propensity score model is correctly specified . Application of the IPW estimators to the cholera vaccine trial indicates the presence of interference . For example , the IPW estimates suggest on average 5.29 fewer cases of cholera per 1000 person-years ( 95 % confidence interval 2.61 , 7.96 ) will occur among unvaccinated individuals within neighborhoods with 60 % vaccine coverage compared to neighborhoods with 32 % coverage . Our analysis also demonstrates how not accounting for interference can render misleading conclusions about the public health utility of vaccination OBJECTIVES To explore user perspectives on applying the Grading of Recommendations Assessment , Development and Evaluation ( GRADE ) to systematic review s of complex interventions . STUDY DESIGN AND SETTING Thirty-three authors of recent ( 2013 onward ) systematic review s were contacted regarding their perspectives on using  GRADE from three Cochrane review groups : Cochrane Developmental , Psychosocial , and Learning Problems Group ; Cochrane Public Health Group ; and Cochrane Depression , Anxiety , and Neurosis Group . Framework Analysis was applied to the data to identify the challenges in applying GRADE and suggestions for its extension , that is , adaptation . These two themes were cross-compared between the groups of answers from " simple " vs. " complex " intervention review authors to identify the specific perspectives on using GRADE in review s of complex interventions . RESULTS Specific challenges were identified in applying GRADE to review s of complex interventions . These were related to the assessment of nonr and omized studies and performance bias in GRADE . Authors perceived these challenges to contribute to frequent downgrading of the " best evidence possible " for complex interventions . Meanwhile , GRADE was found to lack an analytic approach to enable adequate evidence synthesis and assessment of intervention implementation elements . CONCLUSION Users suggest that the GRADE guidance be extended to address-specific considerations for complex interventions Abstract We propose the minicommunity design to estimate indirect effects of vaccination . Establishing indirect effects of vaccination in unvaccinated sub population s could have important implication s for global vaccine policies . In the minicommunity design , the household or other small transmission unit serves as the cluster in which to estimate indirect effects of vaccination , similar to studies in larger communities to estimate indirect , total , and overall effects . Examples from the literature include studies in small transmission units to estimate indirect effects of pertussis , pneumococcal , influenza , and cholera vaccines . We characterize the minicommunity design by several method ologic considerations , including the assignment mechanism , ascertainment , the role of transmission outside the transmission unit , and the relation of the size of the transmission unit to number of people vaccinated . The minicommunity study for indirect effects is contrasted with studies to estimate vaccine effects on infectiousness and protective effects under conditions of household exposure within small transmission units . The minicommunity design can be easily implemented in individually r and omized studies by enrolling and following-up members of households of the r and omized individuals . The methodology for the minicommunity design for estimating indirect effects of vaccination deserves much future research Background Gambian infants frequently acquire Streptococcus pneumoniae soon after birth . We investigated the indirect effect of 7-valent pneumococcal conjugate vaccine ( PCV-7 ) on pneumococcal acquisition in newborn Gambian babies . Methods Twenty-one villages were r and omised to receive PCV-7 to all subjects ( 11 vaccinated villages ) or to infants aged 2–30 months ( 10 control villages ) . Other control villagers received Meningococcal C conjugate vaccine . From 328 babies born during the trial , nasopharyngeal swabs were collected after birth , then weekly until 8 weeks of age when they received their first dose of PCV-7 .  Pneumococcal carriage and acquisition rates were compared between the study arms and with a baseline study . Results 57.4 % of 2245 swabs were positive for S. pneumoniae . Overall carriage was similar in both arms . In vaccinated villages fewer infants carried pneumococci of vaccine serotypes ( VT ) ( 16.9 % [ 31/184 ] vs. 37.5 % [ 54/144 ] , p<0.001 ) and more carried pneumococci of non-vaccine serotypes ( NVT ) ( 80.9 % [ 149/184 ] vs. 75.7 % [ 109/144 ] , p = 0.246 ) . Infants from vaccinated villages had a significantly lower acquisition rate of VT ( HR 0.39 [ 0.26–0.58 ] , p<0.001 ) and increased acquisition of NVT ( HR 1.16 [ 0.87–1.56 ] , p = 0.312 ) . VT carriage ( 51.6 % vs. 37.5 % , p = 031 in control and 46.1 % vs. 16.8 % , p<0.001 in vaccinated villages ) and acquisition rates ( HR 0.68 [ 0.50–0.92 ] , p = 0.013 in control villages and HR 0.31 [ 0.19–0.50 ] , p<.001 in vaccinated villages ) were significantly lower in both study arms than in the baseline study . NVT carriage ( 63.2 % vs. 75.7 % , p = 0.037 in control and 67.2 % vs. 75.3 % , p = 0.005 in vaccinated villages ) and acquisition rates ( HR 1.48 [ 1.06–2.06 ] , p = 0.022 ) and ( HR 1.52 [ 1.11–2.10 ] , p = 0.010 respectively ) were significantly higher . Conclusion PCV-7 significantly reduced carriage of VT pneumococci in unvaccinated infants . This indirect effect likely originated from both the child and adult vaccinated population s. Increased carriage of NVT pneumococci needs ongoing monitoring . Trial Registration IS RCT N Register BACKGROUND Trachoma-control programmes distribute oral azithromycin to treat the ocular strains of chlamydia that cause the disease and to control infection . Theoretically , elimination of infection is feasible if untreated individuals receive an indirect protective effect from living in repeatedly treated communities , which is similar to herd protection in vaccine programmes . We assessed indirect protection against trachoma with mass azithromycin distributions . METHODS In a cluster r and omised trial , 24 subkebeles ( government-defined units ) in Amhara , Ethiopia , were r and omised , with use of a simple r and om sample , to distribution four times per year of single-dose oral azithromycin to children aged 1 - 10 years ( 12 subkebeles , 4764 children ) , or to delayed treatment until  after the  study ( control ; 12 subkebeles , 6014 children ) . We compared the prevalence of  ocular chlamydial infection  in untreated individuals 11 years and older between baseline and 12 months in the treated subkebeles , and at 12 months between the treated and control subkebeles . Health-care and laboratory personnel were blinded to study group . Analysis was intention to treat . The study is registered with clinical trials.gov , number NCT00322972 . FINDINGS At 12 months , 637 children aged 1 - 10 years and 561 adults and children aged 11 years and older were analysed in the children-treated group , and 618 and 550 , respectively , in the control group . The mean prevalence of infection in children decreased from 48.4 % ( 95 % CI 42.9 - 53.9 ) to 3.6 % ( 0.8 - 6.4 ) after four mass treatments . At 12 months , the mean prevalence of infection in the untreated age group ( > /=11 years ) was 47 % ( 95 % CI 33 - 57 ) less than baseline ( p=0.002 ) , and 35 % ( 95 % CI 1 - 57 ) less than that in untreated communities ( p=0.04 ) . INTERPRETATION Frequent treatment of children , who are a core group for transmission of trachoma , could eventually eliminate infection from the entire community . Herd protection is offered by repeated mass antibiotic treatments , providing a strategy for elimination of a bacterial disease when an effective vaccine is unavailable . FUNDING National Institutes of Health Background : Killed oral cholera vaccines are internationally licensed for older children and adults , but not for infants and young children . We investigated whether mass immunization of older children and adults can confer herd protection to children too young to be vaccinated . Methods : We analyzed the first year of surveillance of an individually r and omized , placebo-controlled trial of killed oral cholera vaccines in 89,596 older Bangladeshi children and adult women .  Vaccine herd protection of children less than 2 years of age , who were too young to participate in the trial , was evaluated by determining whether the incidence of cholera during the first year of follow-up of this age group was lower in residential clusters with higher levels of vaccine coverage than in clusters with lower levels of vaccine coverage . Results : Vaccine coverage of the targeted population ranged from 4 % to 65 % in different clusters . The incidence ( cases per 1000 ) of cholera among children less than 2 years of age ranged from 18.9 in clusters in the lowest quintile of vaccine coverage to 8.6 in clusters in the highest quintile ( P = 0.004 for the inverse association between vaccine coverage and risk of cholera ) Vaccine coverage of adult women ( relative risk of cholera = 0.95 for each percent increase in vaccine coverage ; 95 % confidence interval : 0.92–0.99 ; P < 0.01 ) , but not of older children , was independently associated with a lower risk of cholera in children less than 2 years of age . Conclusions : Vaccination of older age groups was associated with protection of children too young to be vaccinated . The pronounced herd protection of young children associated with vaccination of adult women suggests that adult women may play a prominent role in the transmission of cholera to young children in this setting The design and analysis of cluster r and omized trials has been a recurrent theme in Statistics in Medicine since the early volumes . In celebration of 25 years of Statistics in Medicine , this paper review s recent developments , particularly those that featured in the journal . Issues in design such as sample size calculations , matched paired design s , cohort versus cross-sectional design s , and practical design problems are covered . Developments in analysis include modification of robust methods to cope with small numbers of clusters , generalized estimation equations , population averaged and cluster specific models . Finally , issues on presenting data , some other clustering issues and the general problem of evaluating complex interventions are briefly mentioned The CONSORT statement is used worldwide to improve the reporting of r and omised controlled trials . Kenneth Schulz and colleagues describe the latest version , CONSORT 2010 , which up date s the reporting guideline based on new method ological evidence and accumulating experience . To encourage dissemination of the CONSORT 2010 Statement , this article is freely accessible on bmj.com and will also be published in the Lancet , Obstetrics and Gynecology , PLoS Medicine , Annals of Internal Medicine , Open Medicine , Journal of Clinical Epidemiology , BMC Medicine , and Trials Summary Background The effect of 7-valent pneumococcal conjugate vaccine ( PCV ) in developed countries was enhanced by indirect protection of unvaccinated individuals , mediated by reduced nasopharyngeal carriage of vaccine-serotype pneumococci . The potential indirect protection of 10-valent PCV ( PCV10 ) in a developing country setting is unknown . We sought to estimate the effectiveness of introduction of PCV10 in Kenya against carriage of vaccine serotypes and its effect on other bacteria . Methods PCV10 was introduced into the infant vaccination programme in Kenya in January , 2011 , accompanied by a catch-up campaign in Kilifi County for children aged younger than 5 years . We did annual cross-sectional carriage studies among an age-stratified , r and om population sample in the 2 years before and 2 years after PCV10 introduction . A nasopharyngeal rayon swab specimen was collected from each participant and was processed in accordance with WHO recommendations . Prevalence ratios of carriage before and after introduction of PCV10 were calculated by log-binomial regression . Findings About 500 individuals were enrolled each year ( total n=2031 ) . Among children younger than 5 years , the baseline ( 2009–10 ) carriage prevalence was 34 % for vaccine-serotype Streptococcus pneumoniae , 41 % for non-vaccine-serotype Streptococcus pneumoniae , and 54 % for non-typeable Haemophilus influenzae . After PCV10 introduction ( 2011–12 ) , these percentages were 13 % , 57 % , and 40 % , respectively . Adjusted prevalence ratios were 0·36 ( 95 % CI 0·26–0·51 ) , 1·37 ( 1·13–1·65 ) , and 0·62 ( 0·52–0·75 ) , respectively . Among individuals aged 5 years or older , the adjusted prevalence ratios for vaccine-serotype and non-vaccine-serotype S pneumoniae carriage were 0·34 ( 95 % CI 0·18–0·62 ) and 1·13 ( 0·92–1·38 ) , respectively . There was no change in prevalence ratio for Staphylococcus aureus ( adjusted prevalence ratio for those < 5 years old 1·02 , 95 % CI 0·52–1·99 , and for those ≥5 years old 0·90 , 0·60–1·35 ) . Interpretation After programmatic use of PCV10 in Kilifi , carriage of vaccine serotypes was reduced by two-thirds both in children younger than 5 years and in older individuals . These findings suggest that PCV10 introduction in Africa will have substantial indirect effects on invasive pneumococcal disease . Funding GAVI Alliance and Wellcome Trust Social scientists should adopt higher transparency st and ards to improve the quality and credibility of research . There is growing appreciation for the advantages of experimentation in the social sciences . Policy-relevant cl aims that in the past were backed by theoretical arguments and inconclusive correlations are now being investigated using more credible methods . Changes have been particularly pronounced in development economics , where hundreds of r and omized trials have been carried out over the last decade . When experimentation is difficult or impossible , research ers are using quasi-experimental design s. Governments and advocacy groups display a growing appetite for evidence -based policy-making . In 2005 , Mexico established an independent government agency to rigorously evaluate social programs , and in 2012 , the U.S. Office of Management and Budget advised federal agencies to present evidence from r and omized program evaluations in budget requests ( 1 , 2 )
target: We identified three primary mechanisms of spillovers : reduced disease transmission , social proximity and substitution of re sources within households .
  We found the strongest evidence for spillovers through reduced disease transmission , particularly vaccines and mass drug administration .
  In general , the proportion of a population receiving an intervention was associated with improved health .
  We found evidence of publication bias for certain spillover estimates but not for total or direct effects .
  Conclusions We found the strongest evidence for spillovers from vaccines and mass drug administration to control infectious disease .
  There was little high quality evidence of spillovers for other interventions
background: Background Many interventions delivered to improve health may benefit not only direct recipients but also people in close physical or social proximity .
  Our objective was to review all published literature about the spillover effects of interventions on health outcomes in low-middle income countries and to identify methods used in estimating these effects .