Mixed treatment comparison meta-analysis of porcine circovirus type 2 (PCV2) vaccines used in piglets

Preventive Veterinary Medicine 117 (2014) 413–424

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Mixed treatment comparison meta-analysis of porcine circovirus type 2 (PCV2) vaccines used in piglets N. da Silva a , A. Carriquiry a , K. O’Neill b , T. Opriessnig b,c , A.M. O’Connor b,∗ a

Department of Statistics, Iowa State University College of Liberal Arts and Sciences, Ames, IA 50011, United States Department of Veterinary Diagnostics and Production Animal Medicine, Iowa State University College of Veterinary Medicine, 1600 South 16th Street, Ames, IA 50011, United States c The Roslin Institute and The Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, Scotland, UK b

a r t i c l e

i n f o

Article history: Received 21 February 2014 Received in revised form 4 October 2014 Accepted 7 October 2014 Keywords: PCV2 Pigs Mixed treatment comparison meta-analysis Bayesian inference Vaccination

a b s t r a c t Porcine circovirus type 2 (PCV2) vaccination is globally one of the most commonly used intervention strategies in growing pigs since several products became commercially available in 2006. While multiple trials have described the efficacy of individual PCV2 vaccines relative to non-vaccination, few studies provide product-to-product comparisons of efficacy. Given the well-documented efficacy of PCV2 vaccines, information about the comparative efficacy of available vaccines is more relevant to producers and veterinarians than comparison to non-vaccination. The objective of this study was to provide comparative estimates of changes in average daily gain effect associated with the use of the commercially available PCV2 vaccines. PubMed, CAB Abstracts, AGRICOLA, the USA Department of Agriculture Center for Veterinary Biologics database of licenses and provisions, and the proceedings of the Annual Meeting of the American Association of Swine Veterinarians, the Allen D. Leman Swine Conference, the Iowa State University Swine Disease Conference for Swine Practitioners, and the International Pig Veterinary Society Congress were used as the sources of information. Trials of licensed PCV2 vaccines administered according to manufacturers’ specifications to intensively raised piglets with a known herd porcine reproductive and respiratory syndrome virus (PRRSV) status were considered relevant to the meta-analysis. Relevant studies had to report average daily gain (ADG) from weaning to finish and PCV2 infection had to be naturally occurring. © 2014 Elsevier B.V. All rights reserved.

1. Introduction Vaccination against porcine circovirus type 2 (PCV2) is a common method to protect growing pigs against clinical disease manifestations associated with PCV2 infection commonly referred to as porcine circovirus associated disease (PCVAD) (Opriessnig et al., 2007). Four vaccines are

∗ Corresponding author. Tel.: +1 515 294 5012. E-mail address: [email protected] (A.M. O’Connor). http://dx.doi.org/10.1016/j.prevetmed.2014.10.006 0167-5877/© 2014 Elsevier B.V. All rights reserved.

labeled for use in piglets. These vaccines are marketed around the world using various names presented in Table 1. In the USA, the names are FosteraTM PCV (Zoetis Animal Health, New York, NY), a reformulated version of the discontinued Suvaxyn® PCV (Fort Dodge Animal Health, Fort Dodge, IA), Ingelvac® CircoFLEXTM (Boehringer Ingelheim Vetmedica, St. Joseph, MO), Circumvent® PCV (Merck Animal Health, Omaha, NE) and Circovac® (Merial Limited, Duluth, GA). For all these products, available data suggest improved production and health outcomes as compared to non-vaccinated animals. Consequently, PCV2 vaccines are

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Table 1 Vaccine names on different continents. Company

Europe

North America (USA, Canada)

South America (Based on Brazil)

Asia (Based on China)

Australia

BoehringerIngelheim

Ingelvac® CircoFLEXTM

Ingelvac® CircoFLEXTM

Ingelvac® CircoFLEXTM

Ingelvac® CircoFLEXTM

Ingelvac® CircoFLEXTM

Merck/MSD Animal Health

Porcilis® PCV

Circumvent® PCV

Circumvent® PCV

Not determined

Not available

Zoetis

Suvaxyn® PCV

FosteraTM

FosteraTM

Not determined

Not available

Merial

Circovac®

Circovac®

Circovac®

Circovac®

Not available

widely used. Given the efficacy of all the products compared to no vaccination, the comparative efficacy of PCV2 vaccines is of interest to producers and veterinarians, as the choice to be made is likely among vaccines rather than a choice between vaccination and non-vaccination. Ideally, a large number of randomized controlled trials that compare the vaccines would be available to enable both producers and veterinarians to make a scientifically based comparison of vaccines in the same setting. However, to the authors’ knowledge, no trials directly comparing all the vaccines are publicly available. Given this paucity of direct evidence, it can be useful to include information from other comparisons in the evidence network. In this review, we use a mixed treatment comparison meta-analysis (MTC) to use direct and indirect evidence to compare the PCV2 vaccines (Dias et al., 2011a). Therefore primary objective of this meta-analysis was to compare the efficacy of commercially available PCV2 vaccines when used in intensively raised piglets. As a secondary analysis we assessed the effect of using the sample size as a measure of precision in an MTC meta-analysis when information about variation was missing.

reproductive and respiratory syndrome virus (PRRSV) status is known?” Within the PICOS format of the question development, the population (P) of interest was intensively raised piglets in a commercial setting with known PRRSV status. The rationale for the PRRSV eligibility criteria was that a previous meta-analysis of general PCV2 vaccine efficacy (Kristensen et al., 2011) suggested that PRRSV status was a potential source of clinical heterogeneity. The intervention was defined as any PCV2 vaccine administered to piglets. The intervention (I) and comparator (C) were defined as each of the vaccines administered as prescribed by the manufacturer based on the US label for piglets. These protocols reflected some but not all registered protocols as some vaccines also include a protocol for sows. The commercial names for these vaccines used in the US were Circumvent® PCV, Ingelvac® CircoFLEXTM , Suvaxyn® PCV/FosteraTM and Circovac® . Different names may be used in different regions. The outcome of interest was as average daily gain (ADG) from wean to finish. The rationale for this outcome was that it provided a common and important comparison measure of the vaccines. The study designs of interest were trials with naturally occurring PCV2 exposure, i.e., field studies.

2. Methods and materials 2.1. Protocol and registration An a priori protocol is not publicly available as mechanisms for registration were not available at the time the review was conducted. The a priori protocol describing the review question and the scope of the review was prepared by KA, AOC, and TO. The protocol was modified after the search and during data extraction. The changes to the eligibility criteria were (1) exclusion of studies that reported group-level allocation, and (2) more explicit criteria for reporting of results into the meta-analysis. The rationale for the change to the eligibility criteria for the meta-analysis, was that the initial eligibility criteria were not explicit enough to realistically identify studies that could be used in the meta-analysis. 2.2. Eligibility criteria for studies in review The review question was “What is the effect of each of commercially available PCV2 vaccines used in piglets on average daily gain from wean to finish in commercial pigs naturally exposed to PCV2 where the porcine

2.3. Information sources A subject librarian specializing in veterinary medicine was consulted for the development of the search string for PubMed (http://www.ncbi.nlm.nih.org/pubmed/), AGRICOLA (EBSCOhost® Research Database, EBSCO® Publishing, Ipswich, MA), and CAB Abstracts (Web of KnowledgeTM , Thomson Reuters, New York, NY). Studies relevant to the review were chronologically self-limited due to the vaccines being only commercially available in since 2006. The final searches of electronic databases were conducted in May 2014. The conference proceedings for the Annual Meeting of the American Association of Swine Veterinarians (AASV), the Allen. Leman Swine Conference, the Iowa State University Swine Disease Conference for Swine Practitioners, and the International Pig Veterinary Society (IPVS) Congress were searched within the Swine Information Library (http://www.aasv.org/library/swineinfo/), from 2006 to May 2014. No language limits were placed on the searches; however, for screening we only assessed abstracts published in English and for data extraction we only used articles published in English.

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2.4. Example search The following search string was used in the PubMed database: (Barrow OR Barrows OR Boar OR Boars OR Feeder OR Finishing OR Gilt OR Gilts OR Hog OR Hogs OR Pig OR Piglet OR Piglets OR Pigs OR Porcine OR Shoats OR Sow OR Sows OR Swine) AND (“Acute Pulmonary Edema” OR “Acute Pulmonary Oedema” OR Circoviridae OR Circovirus OR PCV OR PCV2 OR PCV-2 OR PCVAD OR PCVD OR PMWS OR “Porcine circovirus” OR “Porcine circovirus 2” OR “Porcine circovirus associated disease” OR “Porcine circovirus disease” OR “Porcine circovirus type 2” OR “Porcine circovirus-2” OR “Porcine respiratory disease complex” OR “Postweaning multisystemic wasting disorder” OR “Porcine Postweaning Multisystemic Wasting Syndrome [MeSH]” OR PRDC) AND (Immunisation OR Immunise OR Immunised OR Immunity OR Immunization OR Immunize OR Immunized OR Immunoprophylaxis OR Intervention [tiab] OR Interventions [tiab] OR Vaccinate OR Vaccinated OR Vaccination OR Vaccinations OR Vaccine OR Vaccines). Citations retrieved were managed in a reference managing database (Reference Manager® ver. 11, Thomson Reuters). Duplicates were removed through software detection and manual review. 2.5. Study selection process

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weaning to the finishing period. Further studies were included if the report contained a description of the statistical approach and results that had sufficient information that would enable knowledge of the degrees of freedom and subsequent determination of the SEM of the treatment group mean. These criteria applied to studies that reported the means but with combinations of the following: standard deviation (SD) of the ADG, the sample size at the end of the study period (i.e., loss to follow-up), p-value, and 95% confidence interval (CI) for the mean ADG. When studies reported an approximate p-values the larger pvalue was selected (if p-value < 0.05 then p-value = 0.05 was used). Where possible we attempted to contact the authors of to request required statistical information missing. 2.6. Data collection process For studies that meet all eligibility criteria, data extraction was conducted by different individuals based on expertise. Outcome data were extracted by a student in the ISU statistic graduate program (NDS) and the data verified by discussion with a faculty member in statistics (AC). Intervention information and trial characteristics and clinical sources of heterogeneity were extracted by two microbiology graduate students (KO, PG), specializing in PCV2 research, and working independently. Risk of bias was assessed by a faculty member in epidemiology (AOC).

2.5.1. 1st level of eligibility screening A “study” was a trial which fulfilled the eligibility criteria. There could be multiple “studies” per article. The screening questions were assessed on twenty-eight abstracts by three individuals (AOC, KO and TO) which were modified and discussed until there was 100% agreement. After agreement was reached, screening of the citations was conducted by a single reviewer based on the following questions:

2.7. Data items collected

1 Is the study reported in English? 2 Does the study describe an assessment of one of the commercially available PCV2 vaccines within a field trial with a natural exposure to PCV2? 3 Does the study report both the vaccine and its administration in accordance with the manufacturer specifications? 4 Does the study report ADG from wean to finish? 5 Is the PRRSV status of the herd reported?

2.7.2. Interventions Extracted information about the interventions included the PCV2 vaccine used and the type of control group (saline, no product, adjuvant only). We did not extract the vaccination regime as this was defined in the eligibility criteria, i.e., manufacturers recommendations for piglets.

If needed the full manuscript was obtained for evaluation the questions. Authors of otherwise qualifying studies were contacted via e-mail to identify the PRRSV status. Studies with missing responses were excluded from further consideration. 2.5.2. 2nd level of eligibility screening After the protocol was developed and the first subset of eligible studies identified, a second level of eligibility screening was added: Does the study report information sufficient for inclusion in a meta-analysis? Studies were included if the report directly presented the treatment-group mean ADG and the SEM from the

The data extracted were (1) trial characteristics, (2) intervention, (3) outcome data, and (4) risk of bias. 2.7.1. Trial population characteristics Extracted information about the trial population included the number of animals enrolled, the country of study, and the PRRSV status.

2.7.3. Outcome data The outcome of interest was ADG (g/day) from weaning (approximately three to six weeks of age) to late finishing prior to slaughter (approximately 23–28 weeks of age) for each trial arm. Other outcome data extracted were treatment-group level measures of variation i.e., SD, standard error of the mean (SEM), and p-values. When studies reported results by subgroups (such as sex, genetic designation), the subgroup level data were extracted if each mean and SEM could be obtained using the method above. 2.7.4. Risk of bias assessment Data about the reporting of randomization and blinding were extracted. The type of publication, whether classified as peer reviewed or not, was also extracted. The risk of bias due to failure to report randomization was considered to

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be high, and the risk of bias to due failure to report blinding was considered low. The rationale for assigning a high risk of bias due to failure to either use a randomization methods or report a random allocation methods was that numerous other factors are associated with weight gain in piglets and failure to purposefully control for those factors could result in uneven distribution across groups. The low risk of bias due to failure to report blinding was based on the assessment that the outcome, weight gain, was an objective outcome with a lower risk of bias than other outcomes such as morbidity or body condition score. The frequency of studies with the vaccine manufacturer with either authorship or sponsorship was also reported. 2.8. Summary measures The summary effect measure used in the meta-analysis was the mean difference in ADG from wean to finish. 2.9. Synthesis of results The model used was that described by Dias et al. (2011a), a random effects model used to model multi-treatment trials. Vague priors were employed for parameters db2 , db3 , db4 , db5 ∼ N(0, 1002 ) and a diffuse prior for  ∼ Unif(0, 50). Draws from the joint posterior distribution were obtained using Markov Chain Monte Carlo (MCMC) implemented in JAGS (Plummer, 2003) using the rjagspackage in R (RCore-Team., 2014). The outputs of the meta-analysis were estimates of the difference treatment effects for all possible pairwise comparisons. 2.9.1. Assessing model convergence Convergence was assessed using three independent Markov chains were run with 100,000 iterations after a burn-in of 5000. The Brooks–Gelman–Rubin diagnostic tool (Brooks and Gelman, 1998; Gelman and Rubin, 1992) and history plots were used to evaluate convergence of the three chains. We compared the variation between and within simulated sequences until the two variations were sufficiently similar. We monitored convergence of the iterative simulation by estimating the factor by which the scale of the current distribution for  (scalar estimated) might be reduced if the simulations were continued.  In the limit (Vˆ (|y)/W ) n→ ∞ this reduction is estimated by: Rˆ = (scale reduction factor). 2.9.2. Assessing the consistency assumption To assess the consistency assumption we compared the posterior mean residual deviance of the final MTC model (consistency model) to the posterior mean residual deviance of the inconsistency models (Dias et al., 2011a). Additionally, we compared the 95% credible intervals of db2 , db3 , db4 , and d23 from the consistency and inconsistency models. If the credible intervals overlap this suggest no evidence of inconsistency. We also plotted the posterior mean deviance of the final MTC model against the inconsistency model, with the expectation that if the consistency assumption was reasonable, the points would fall on a line (Dias et al., 2011b).

2.9.3. Assessing model fit and sensitivity analysis To check overall model fit, we used an absolute measure ˆ res , the posterior mean of the residual deviance (the of fit: D deviance for the fitted model minus the deviance for saturated model) as proposed by (Spiegelhalter et al., 2002). We also measured the discrepancy between replicated data from the model and the observed data using as test quantity the 2.5%, 25%, 50%, 75%, and 97.5% quantiles. A test quantity or a discrepancy measure, T(y, ), is a scalar summary of parameters and data that is used as a standard when comparing data to predictive simulations. We assessed sensitivity of the outcome to changing the prior for  that is the variance for trial-specific relative effect of treatment. We compared the posterior predictive distribution using a credible interval for the posterior distribution of  for each model. 2.10. Risk of bias across studies Methods of assessing small study effects with the MTC meta-analysis framework are poorly described. Therefore we used pairwise comparisons of active products to placebo and plotted the SEM against the point estimate of the summary effect. We limited these analyses to comparisons with at least ten pairs (Sterne et al., 2011). 2.11. Additional analyses 2.11.1. Bias due to co-variates We individually assessed the indicators for random allocation (yes, no), blinding of the outcome assessor to the treatment group status (yes, no), and peer review (yes, no). When the p-value for the indicator variable was greater than 0.1, we excluded the variable from the model. 2.11.2. Rankings In addition to obtaining estimates of the different treatment effects for all possible pairwise comparisons, we estimated the relative ranking of each treatment. For each draw from 5000 simulations, we evaluated the relative rankings based on the estimated treatment effect. We then obtained the posterior probability to be in each ranking for each treatment. 2.11.3. Secondary outcome: methods of estimating precision The standard approach for a meta-analysis is a weighted analysis of variance using the inverse variance of the outcome as a weight but very frequently these data were not reported in the papers. In a previous review of PCV2 vaccines, an alternative weighting the variance was used to overcome incomplete reporting of measures of variation (Kristensen et al., 2011). Therefore, we compared the results of the Bayesian model using the standard approach, to a model using the inverse of the sample size multiply by a parameter with a uninformative prior. The rationale for this new parameter in the model was to keep the scale of the precision consistent with terms in the data. We used a biological sensible approach, modifying the previously reported approach, to determine if it might be an acceptable alternative to contacting authors when poor

N. da Silva et al. / Preventive Veterinary Medicine 117 (2014) 413–424 Table 2 Reasons for exclusion of individual levels studies for which the full text was obtained. Author, year

Exclusion description

Bergstrom et al. (2009)

A combined vaccination protocol that included Mycoplasma hyopneumoniae vaccines Study was published in German and funds not available for translation Did not report SEM. Did report SD, however, the sample size was unclear. No response to email questions was received Did not report ADG for desired study period SEM not reported. ADG and SD reported. The study used a complex model and based on the description was not possible to determine with confidence the correct degrees of freedom to calculate the SEM of treatment level ADG. No response to email questions was received. SEM not reported. SEM not reported. ADG and SD reported. The sample size was unclear as the authors reported “approximately 400 pigs assigned to each treatment”. It was not possible to determine with confidence the correct degrees of freedom to calculate the SEM of treatment level ADG. It is not a controlled trial. Poor report not enough information for control. Did not report ADG for desired study period Did not reported ADG for desired study period It is not clear if they report SD or SEM. Did not reported ADG for desired study period It is not clear if they report SD or SEM. There are not data of mortality then we can not get the sample size at the end. There are not model or description about how they test the mean difference between treatments, then we cannot make a proper extraction. SEM, SD, sample size, p value, and model degrees of freedom not reported. Appears to review several studies but no SEM reported.

Bischoff et al. (2009) Criado (2012)

Dan et al. (2012) Edler et al. (2008)

Lopez et al. (2012) Nerem (2010)

Pejsak et al. (2010) Reindl et al. (2010)

Richthofen et al. (2009) Siebel (2010)

Seo et al. (2012)

Weibel et al. (2010)

Wilson et al. (2011)

Wilson et al. (2013)

reporting occurred. The biologically sensible modification 2 of the sample size to a precision measure was n ∗ 1/size where  size ∼ U(0, 1000) and n is the size of the trial arm. This was a post-hoc additional analysis. 3. Results 3.1. Study selection 280 citations were identified by the searches after duplicates were eliminated. The first level of screening identified 32 potentially eligible citations. After the second level of screening 17 publications reporting 20 trials were included. The reasons for exclusion are presented in Table 2.

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3.2. Study characteristics and results of individual studies The interventions used, the ADG (SEM) and the number of animals per trials arm for each study in the meta-analysis are reported in Table 3. 3.3. Risk of bias within studies Table 4 shows the information about the reporting of randomization to group and reporting of blinding of outcome assessment. Fifteen of the 20 trials reported randomization to group. However, as randomization is usually reported at the study level, it is perhaps more appropriate to consider that 12 of 17 publications reported randomization. The prevalence of reporting of blinding was nine of 20 studies. Table 4 also includes information about the source of the study i.e., a peer reviewed journal or another source and PRRS virus status. None of the studies provided an explicit statement of conflicts of interest. The majority of studies had either a vaccine manufacturer as the sponsor and/or authorship (Dunlop et al., 2012; Fachinger et al., 2008; Kixmöller et al., 2008; King et al., 2008; Lising and Megson, 2012; Payne and Cline, 2012; Segalés et al., 2009 Thacker et al., 2008). Several studies did not report how the study was funded (Bergstrom et al., 2009; Ehlorsson et al., 2010; Jacela et al., 2011; Wang et al., 2012). Several studies reported sponsorship that was not obviously associated with vaccine manufacturers (Venegas-Vargas et al., 2011; Horlen et al., 2008). For one study the association with a vaccine manufacturer was unclear (Lyoo et al., 2011). 3.4. Synthesis of results 3.4.1. Results of model As expected, the lowest observed ADG was observed in the unvaccinated groups, which had a mean ADG of 701.82 g (95% credibility interval 648.64, 755.32). The MTC meta-analysis estimate of the expected mean ADG from weaning to slaughter for Circumvent® PCV was 727.5 g/day (95% credibility interval 673.01, 781.83). The MTC metaanalysis estimate of the expected mean ADG from weaning to finishing for Ingelvac® CircoFLEXTM was 727.08 g/day (95% credibility interval 673.13, 780.95). The MTC estimate of the expected mean ADG from weaning to finishing for the Suvaxyn® PCV/FosteraTM PCV products was 718.9 g (95% credibility interval 662.05, 775.55), and for Circovac® the expected mean ADG was 725.35 g (95% credibility interval 665.89, 784.58). The final random effects model expressed as the mean difference in ADG across pairwise comparison of the vaccines is presented in Table 5. Table 5, illustrates that according to the MTC meta-analysis the expected increase in ADG for Circumvent® PCV compared to unvaccinated animals would be 25.68 g/day from weaning to finish with a 95% credible interval from 14.15 g/day to 38.88 g/day. Credible intervals for the expected increase in ADG for Control versus Circumvent® PCV and Control versus Ingelvac® CircoFLEXTM do not include zero. For the comparison between Control and Suvaxyn® PCV/FosteraTM PCV the credible interval does include zero. Similarly the credible

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Table 3 Individual trial arm data (mean ADG (SEM,n)) for trials included in the mixed treatment comparison meta-analysis. Circumvent® PCV

Author, year

Control

Dunlop et al. (2012) Ehlorsson et al. (2010) Fachinger et al. (2008) Heißenberger et al. (2013) Horlen et al. (2008) Jacela et al. (2007) Kixmöller et al. (2008) Lising and Megson (2012) Lyoo et al. (2011) King et al. (2008) Payne and Cline (2012) Potter et al. (2012) Potter et al. (2012) Potter et al. (2012) Potter et al. (2012) Segalés et al. (2009) Thacker et al. (2008) Venegas-Vargas et al. (2011) Venegas-Vargas et al. (2011) Wang et al. (2012)

718 (6.38, 1150) 697 (7.3, 142) 649 (3.06, 694) 484 (4.81, 429) 783 (16.73, 208) 693 (14.2, 436) 619 (3.57, 657) 626 (5.37, 334) 740 (23.69, 18) 689 (4.13, 557) 757 (8.54, 228) 655 (14.70, 57) 741 (15.6, 66) 738 (21.1, 32) 723 (16.1, 51) 618 (4.59, 284) 589 (8.22, 219) 724 (18.1, 39) 580 (10, 59) 565 (9.82, 71)

Ingelvac® CircoFLEXTM

Suvaxyn® PCV/FosteraTM PCV

Circovac®

741 (6.21, 1172) 694 (8.6, 152) 667 (2.84, 714) 509 (4.28, 451) 859 (16.57, 220) 727 (14.1, 452)

810 (14.28, 19) 766 (4.13, 1006) 721 (15.2, 51) 726 (15.4, 61) 755 (21.4, 30) 739 (16.3, 47)

715 (14.1, 452) 650 (3.06, 680) 651 (5.32, 341) 800 (24.46, 16) 712 (4.08, 568) 780 (4.51, 1010)

780 (19.04, 19)

636 (4.27, 309) 612 (8.08, 229) 702 (13.6, 38) 630 (10, 98) 617 (9.75, 71)

Table 4 Individual trial complementary arm data for trials included in the mixed treatment comparison meta-analysis. Author

PRRSV

Ran.

Blnd.

Peer

Dunlop et al. (2012) Ehlorsson et al. (2010) Fachinger et al. (2008) Heißenberger et al. (2013) Horlen et al. (2008) Jacela et al. (2007) Kixmöller et al. (2008) Lising and Megson (2012) Lyoo et al. (2011) King et al. (2008) Payne and Cline (2012) Potter et al. (2012) Potter et al. (2012) Potter et al. (2012) Potter et al. (2012) Segalés et al. (2009) Thacker et al. (2008) Venegas-Vargas et al. (2011) Venegas-Vargas et al. (2011) Wang et al. (2012)

0 0 1 1 0 1 1 0 1 0 1 0 0 0 0 1 1 0 1 1

0 0 1 1 1 1 1 1 1 0 0 1 1 1 1 1 0 1 1 1

0 0 1 1 1 0 1 0 0 0 0 1 1 1 1 1 0 0 0 0

0 0 1 1 1 0 1 0 1 0 0 1 1 1 1 1 0 0 1 0

Note: PRRSV is the porcine reproductive and respiratory syndrome virus and the value 1 if it is positive, Rand. is randomized trial and take value 1 if the study was randomized, Blnd. is blinding and take value 1 if the study was blinding and Peer. is peer reviewed and take value 1 if the study was peer reviewed.

Table 5 Posterior mean, standard deviation (SD), median and 95% credible interval (CrI) for the random effects model for the treatment effects of Circumvent® PCV, Ingelvac® CircoFLEXTM , Suvaxyn® PCV/FosteraTM PCV and Circovac® (d12 , d13 , d14 and d15 ) relative to Unvaccinated. Consistency model

d12 d13 d14 d15 d23 d24 d25 d34 d35 d45 ˇ1 ˛  ˆ res D Pd DIC

Mean

SD

Median

CrI

25.68 25.26 17.08 23.53 −0.42 −8.6 −2.15 −8.18 −1.74 6.44 −62.65 701.82 10.11

6.28 4.68 9.67 12.84 7.2 10.78 14.37 10.55 13.68 16.09 35.41 27.25 5.06

25.38 25.19 17.03 23.6 −0.05 −8.21 −1.52 −8.2 −1.58 6.62 −62.06 701.88 9.66 65.5 27.4 363.4

(14.15, 38.88) (15.98, 34.97) (−2.15, 36.56) (−2.74, 49.33) (−15.65, 12.91) (−30.96, 11.78) (−32.65, 24.93) (−29.33, 12.92) (−29.96, 25.61) (−26.43, 38.58) (−131.44, 11.56) (648.64, 755.32) (1.44, 21.3)

Note: dij is the mean treatment j effect relative to treatment i, ˇ1 is the effect of PRRSV status on the mean ADG, ˛ is the overall mean for the ˆ res is the posteADG,  is the standard deviation of the treatment effect, D rior mean of the posterior deviance, pD is used to estimate the effective number of parameters, DIC is the Deviance Information Criterion. Where vaccine 1 is the Control, 2 is Circumvent® PCV, 3 is Ingelvac® CircoFLEXTM , 4 is Suvaxyn® PCV/FosteraTM PCV and 5 is Circovac® .

interval between Control and Circovac® includes zero. The direction of the point estimate of the PRRSV indicator was as expected i.e., negative (ˇprrsv = -62.65 g ADG ( -131.44, 11.56)).

observed in both forest plots were associated with smaller studies. However, more negative effects were also associated with smaller studies.

3.5. Risk of bias across studies

3.6. Results of model checking procedures

The plots designed to evaluated small study effects (Fig. 1), do not suggest a tendency for smaller studies to report more positive differences in the average daily gain compared to the placebo groups. The larger positive effects

3.6.1. Consistency, fit and sensitivity The final random effect model attained the convergence criteria after 100,000 simulations. Table 6 shows the results from the consistency model and the

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30 30

20

SE

SE

25

20

15 10 10 −25 0 25 50 75 Mean difference ADG, Control vs Circumvent size.a

250

500

750

1000

0 20 40 Mean difference ADG, Control vs Ingelvac

1250

size.b

500

1000

1500

60

2000

Fig. 1. Funnel plot, the right panel shows on the x-axis the mean difference ADG for Control vs Ingelvac and on y-axis the SE for the effect, on the left panel shows on the x-axis the mean difference ADG for Control vs Circumvent and on y-axis the SE for the effect. Table 6 Results of consistency and inconsistency models for main model (using precision based on SEM) and additional model (using precision based on sample size). Parameter

MTC model using SEM

MTC model using sample size

Consistency

d12 d13 d14 d23  ˆ res D Pd DIC

Inconsistency

Mean

sd

25.7 25.3 17.1 −0.4 10.11

6.3 (14.2, 38.9) 4.7 (16, 35) 9.7 (−2.1, 36.6) 7.2 (−15.7, 12.9) 5.06 (1.44, 21.3) 65.5 27.4 363.4

CrI 95%

Consistency

Inconsistency

Mean

sd

CrI 95%

Mean

sd

CrI 95%

Mean

sd

23.8 24.1 21.8 0.1 9.38

6.9 (11.1, 38.2) 4.6 (14.6, 33.4) 10 (2.7, 42.8) 99.9 (−195.4, 196.6) 5.06 (0.99, 20.97) 61.5 25.3 330.3

27.36 26.3 18.7 −1.1 7.4

7.2 5.5 11.2 8.2 5.3

(13.6, 42.1) (15.2, 37.2) (−3.6, 41.1) (−18.2, 14.5) (0.3, 19.7)

26.6 24.9 22.2 0.2 8.2

8.7 5.8 12.1 99.9 5.6

43 21.1 374.1

CrI 95% (10.3, 44.4) (13, 36.1) (−1.5, 46.6) (−195.6, 196.2) (0.4, 21.2) 40.9 24.3 350.1

ˆ res is the posterior mean of the posterior Note: dij is the mean treatment j effect relative to treatment i,  is the standard deviation of the treatment effect, D deviance, pD is used to estimate the effective number of parameters, DIC is the Deviance Information Criterion Where vaccine 1 is the Control, 2 is Circumvent® PCV, 3 is Ingelvac® CircoFLEXTM , 4 is Suvaxyn® PCV/FrosteraTM PCV and 5 is Circovac® .

Table 7 Main results for sensitivity analysis for model using SEM as measure of precision. Three alternative specifications for . Parameter

 ∼ U(0, 50) Mean

d12 d13 d14 d15 d23 d24 d25 d34 d35 d45 ˛ ˆ res D Pd DIC

25.68 25.26 17.08 23.53 −0.42 −8.6 −2.15 −8.18 −1.74 6.44 701.82

 2 ∼ Inv-Gamma(10−3 , 10−3 )

 ∼ U(0, 200) CrI 95% (14.15,38.88) (15.98,34.97) (−2.15,36.56) (−2.74,49.33) (−15.65,12.91) (−30.96,11.78) (−32.65,24.93) (−29.33,12.92) (−29.96,25.61) (−26.43,38.58) (648.64,755.32) 65.5 27.4 363.4

Mean 26.01 25.4 17.13 23.63 −0.61 −8.88 −2.38 −8.27 −1.77 6.5 650

CrI 95% (14.37,39.11) (16.15,35.09) (−2.15,36.49) (−2.8,49.33) (−15.75,12.83) (−31.3,11.45) (−32.77,24.71) (−29.43,12.71) (−29.97,25.37) (−26.22,38.49) (649.98,650.02) 65.7 32.3 380.8

Mean 23.88 25.11 16.74 23.73 1.23 −7.14 −0.15 −8.38 −1.38 6.99 650

CrI 95% (13.99,36.16) (18.04,32.7) (1.48,32.6) (3.71,43.34) (−12.1,12.2) (−26.46,9.78) (−24.99,20.37) (−25.37,8.46) (−23.05,19.22) (−18.74,31.81) (649.98,650.02) 70.9 21.4 359.8

ˆ res is the posterior mean of the posterior deviance, pD is Note: dij is the mean treatment j effect relative to treatment i, ˛ is the overall mean for the ADG, D used to estimate the effective number of parameters, DIC is the Deviance Information Criterion. Where vaccine 1 is the Control, 2 is Circumvent® PCV, 3 is Ingelvac® CircoFLEXTM , 4 is Suvaxyn® PCV/FosteraTM PCV and 5 is Circovac® .

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Inconsistency Model

20

15

10

5 5

10

15

20

Consistency Model Fig. 2. Plot of individual data points posterior mean deviance contributions for the consistency model and the inconsistency model along with the line of equality. Table 8 Probability ranking for order of average daily gain. 1 = highest average daily gain, 5 = means lowest average daily gain. Treatment

Control Circumvent® PCV Ingelvac® CircoFLEXTM Suvaxyn® PCV/FosteraTM Circovac®

Rankings model using SEM

Rankings model using sample size

5

4

3

2

1

5

4

3

2

1

0.93 0 0 0.04 0.03

0.07 0.1 0.07 0.51 0.24

0 0.27 0.26 0.24 0.22

0 0.33 0.39 0.12 0.16

0 0.29 0.28 0.09 0.34

0.87 0 0 0.05 0.08

0.13 0.06 0.09 0.46 0.27

0.01 0.24 0.3 0.24 0.2

0 0.38 0.39 0.12 0.13

0 0.32 0.28 0.09 0.33

inconsistency model. There is no evidence of inconsistency. The plot of posterior mean deviance in Fig. 2 also suggests the consistency assumption is reasonable. The total residual deviance for the consistency model was 65.5 which was close to the total number of data points as expected. Not all results of the sensitivity analysis are reported, however Table 7 shows the results of the sensitivity analysis for some of the parameters of interest. The three alternatives presented for the standard deviation  are;  ∼ Uniform(0, 50),  ∼ Uniform(0, 200) and  2 ∼ Inv-Gamma(10−3 , 10−3 ). The preferred and used model was the one with the smaller residuals deviance.

3.7. Additional analyses 3.7.1. Bias due to co-variates The mean estimates for indicator variables for randomization, blinding, and peer review were quite close to zero suggesting little effect on the outcome, especially when compared to the distribution for the PPRSV

ˆ random = −9.52(95% CrI(−72.87, 62.15)), indicator: ˇ ˆ blinding = −1.06(95% CrI(−69.26, 73.20), ˇ ˆ peer = −4(95% ˇ CrI(−80.43, 60.06)). 3.7.2. Rankings We have calculated rankings of vaccines efficacy based on treatment effect from the MTC model. In Table 8 we presented the posterior probability distribution of the rank for each vaccine, where the rank 5 indicates the worst and rank 1 indicates the best i.e. the treatment with the highest ADG. The unvaccinated group had the highest probability of the lowest ADG (i.e. rank 5) (0.93). While Circovac® had the highest (0.34) probability to be ranked first it also had a high probability of being 4th (0.24). This reflects uncertainty about this product. Circumvent® PCV and Ingelvac® CircoFLEXTM had a very similar probabilities and where most consistently ranked within the top two ranks i.e. around 62–67% of being in the top two ranks. While Circovac® had a lower probability of being in the top 2 ranked products, approximately 50%. Finally, Suvaxyn®

N. da Silva et al. / Preventive Veterinary Medicine 117 (2014) 413–424 Table 9 Pairwise probability for treatment arms in mixed treatment comparison of PCV2 vaccines. Treatments ®

Probability TM

®

TM

Ingelvac CircoFLEX vs Suvaxyn PCV/Fostera Circumvent® PCV vs Suvaxyn® PCV/FosteraTM Ingelvac® CircoFLEXTM vs Circovac® Circumvent® PCV vs Circovac® Circumvent® PCV vs Ingelvac® CircoFLEXTM Suvaxyn® PCV/FosteraTM vs Circovac®

0.8 0.78 0.56 0.54 0.49 0.32

Table 10 Mean ranking for treatment arms in mixed treatment comparison of PCV2 vaccines. Treatment ®

TM

Ingelvac CircoFLEX Circumvent® PCV Circovac® Suvaxyn® PCV/FosteraTM Control

Mean ranking

SD of rank

3.87 3.82 3.54 2.7 1.08

0.9 0.97 1.27 1.02 0.27

PCV/FosteraTM has a highest probability of being ranked 4th with respect to ADG (Table 8). The pairwise comparison of products by ranking are provided in Table 9. The mean rankings are provided in Table 10. Circumvent® PCV and Ingelvac® have the highest and very similar average rankings. The standard deviation of Circovac® illustrates the uncertainty associated with this product which is discussed further below. 3.7.3. Secondary outcome: methods of estimating precision The results of the secondary analysis model which used information about the sample size as precision are reported in Table 6. This approach provided very similar results to those obtained from the main model. The DIC was lower for the model that used the empirical data, however, the difference was very small. 4. Discussion 4.1. Summary of evidence The objective of this MTC meta-analysis was to utilize publicly available data on commercial PCV2 vaccines used in piglets to provide a product-to-product comparison of impact on ADG. The results of the meta-analysis suggest that all products were associated with increased ADG compared to no vaccine. For example, the comparison of Circumvent® PCV to the control group suggested a 95% credibility interval for the mean ADG from 14 g/day to 38 g/day. The Ingelvac® CircoFLEXTM product had a very similar range. The mean and median for the Suvaxyn® PCV/FosteraTM product was positive though around 8 g/day lower, suggesting that the studies from Suvaxyn® PCV/FosteraTM did not document as substantial ADG as Circumvent® PCV and Ingelvac® . The range of the 95% credibility interval for the mean ADG for Suvaxyn® PCV/FosteraTM included negative values and values as high as those associated with the two other products. The mean for Cicrocvac® is positive around 23.5 and the range of the 95% credible interval includes negative values. The

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variability associated with the estimates for Circovac® are high compared to the other products. This may be a function of several factors. First, there is only one study that contributes to the estimate of this effect. The estimate was 509–484 g i.e. a 23.5 g difference. However, the baseline level of average daily gain is one of the lowest observed across the entire body of work. As a proportion of gain the Circovac® might be considered to have very high gains therefore the point estimate is very high, which is why it sometimes ranks highly. However, as there is only one study, the variation is also high, meaning it can also have low ranking. Further, the metric we used, and is standard for continuous variables such as weight gain, was the mean difference. Therefore when an absolute measure of effect size is used to compare products Circovac® shows a high gain with uncertainty. In a significance testing framework with an alpha of 5%, the inclusion of zero in the 95% credible interval would be interpreted as not statistical significant. Using a significance testing framework, this would suggest that we would not reject the null hypothesis that either Circovac® or Suvaxyn® PCV/FosteraTM are different from no vaccine. For the other products, in a significance testing framework we would conclude that Circumvent® PCV and Ingelvac® CircoFLEXTM are different from no vaccine. However, we believe a more appropriate interpretation is that evidence suggests a lower ADG for Suvaxyn® PCV/FosteraTM with greater uncertainty about that conclusion. This uncertainty is likely a product of the smaller number of field trials for this product. We would propose that the amount of information available about the performance of Circovac® is so small as to be insufficient to make any comparison with other products. However, we propose the one study does provide evidence that it is likely superior to no vaccine. One approach to try to convey this uncertainty about the comparisons is to employ ranking information. If rankings are used as a way to differentiate the vaccines, these data would suggest that the vaccines Circumvent® and Ingelvac® are probably equivalent based on ADG. This is illustrated by two aspects of the rankings. In Table 8 we see that Circumvent® and Ingelvac® both have about a 70% probability of being the best and 2nd best products. In Table 9 the pairwise comparison of which is best is very close to 50% suggesting a 50/50 chance that one is better than the other i.e. roughly equivalent. Note we have not conducted a formal statistical testing of equivalence here as we are unaware of approaches to formally testing equivalence in the MTC analysis context. Our use of the term equivalence here is interpretive rather than statistical. The similar average rankings in Table 10 also reflect this. For the other products the rankings are perhaps more difficult to interpret and reflect the uncertainty. Because Circovac® has such wide variation is has a high probability of being the best but also a high probability of being the 3rd and 4th best. This illustrates uncertainty. For the product Suvaxyn® PCV/FosteraTM , the rankings are generally lower than the other three products. It should be note that the rankings do not include other outcomes which may be important, such as mortality. It is possible that products that ranking highly for average daily gain are not the same products that rank highly for mortality. Table 10 which shows the average

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rankings perhaps best captures the comparative information about the rankings. In two products Circumvent® and Ingelvac® are the 1 and 2 ranked products. From other ways of presenting rankings and the estimates of mean difference we propose these products are very similar. The Circovac® product has a lower average ranking than the other two products and this reflects its uncertainty about this product. The Suvaxyn® PCV/FosteraTM product has the lowest ranking, though it is likely superior to no vaccine. With respect to the risk of bias within the individual studies this body for work compares very favorably relative to others in swine. The proportion of studies reporting reported randomization is higher than previously reported. Brace et al. (2010) reported that only thirty of eightynine abstracts about vaccine studies from the American Association of Swine Veterinarians Conference reported randomization (33%). The risk of bias due to failure to blind was considered low because it the outcome is objectively measured. However, the prevalence of reporting of blinding still compares very favorably to other reports (two of eighty-nine) (Brace et al., 2010). Complete reporting of these design features was more likely in peer reviewed journals. As this paper contains more peer-reviewed articles and Brace et al. (2010) only assessed conference abstracts it is perhaps not surprising that important design features are better reported. With respect to risk of bias across the studies and the influence of those biases on the estimate, the influence of randomization, blinding and source of publication on the parameter estimates was apparently minimal as all indicator estimates were near zero. Small study effects are often evaluated as a proxy for publication bias. We could only evaluate this indirectly for two products. One advantage of the MTC is that if small study biases do exist for all products compared to placebo then all studies will be penalized when the indirect information is incorporated. There was little evidence of publication bias, although there was evidence that small studies did report the extreme ranges of ADG both positive and negative. While there are other meta-analyses pertaining to PCV2, they are limited to experimental studies (Tomas et al., 2008), pairwise comparison (Holck et al., 2010; Diaz and Edler, 2010; Coll et al., 2010), or focus on general PCV2 vaccine efficacy with no comparison between products (Kristensen et al., 2011). Ideally, randomized controlled trials that compare all products would be publicly available to enable comparison of the products. Furthermore, information would be available from non-inferiority trials to suggest which products could be considered equivalent. In lieu of such studies, utilization of MTC meta-analysis allows for the combination of data from multiple studies while maintaining the randomization and individuality of each data set (Dias et al., 2011a). This is, to the authors’ knowledge, the first MTC meta-analysis of PCV2 vaccines. These observations within a MTC meta-analysis are important because they allow for comprehensive decision making on the producer’s end. Primarily with this study, if the vaccines are not different with respect to ADG, then producers and veterinarians may give greater weight to other factors that motivate vaccine choice such as impact on mortality, morbidity, cost, and ease of use.

From a methodological point of view, we were not the first to notice incomplete reporting of measures of variation for continuous outcomes. The favorable comparison of the two methods of estimating precision in the model suggests that an approach to coping with incomplete reporting of variance measures for continuous outcomes may be to rely upon scaled measures of precision based on the sample size. The rationale for this additional analysis was that we noticed, as others have, that for continuous data measures of variation were poorly reported in this body of work (Kristensen et al., 2011). We wanted to evaluate the impact of using the sample size as the measure of variation compared to contacting authors which was a long and often fruitless process. The results of the two models were very similar. Of course, we would not suggest that adoption of the method we evaluated is preferable to authors reporting the data in a manner consistent with current recommendations. Clearly authors have an obligation to comprehensively report studies and include measure of variation (Lang and Altman, 2013). The robustness of this method in other situations also remains to be explored and is beyond the scope of this project. 4.2. Limitations 4.2.1. Study level Within the narrowly defined study population of intensively raised pigs in modern commercial systems, we made the assumption that baseline ADG was sufficiently consistent (within a random distribution) to enable reporting of absolute treatment effect. This is a perhaps a strong assumption that warrants testing in future reviews and provides further rationale for limiting the review studies in intensely raised swine which are more likely to meet this assumption. The study by Heißenberger et al. (2013) may be an example of this issue. Alternative summary measures could have included the ratio of ADG, however, this is rarely used or understood in production settings. Further, we had to make some assumptions about the measures of variation because of the incomplete nature of the reporting. As had been mentioned previously on numerous occasions, there is substantial value in improving the quality of reporting in veterinary science. We had a large number of conference proceedings in our body of work. Conference proceedings are usually not reported as well as peer reviewed studies. We choose to include conference proceedings because in swine production, it seems, publication in peer reviewed literature is a low priority. Prior data suggests that for swine vaccine trials fewer than 10% of conferences proceedings are followed up with peer reviewed publications (Brace et al., 2010). It is unclear why this is the case, however we speculate that many conferences proceedings are presented by biological companies which place a lower value on peer review publication. This body for work did have a high number of company sponsored studies, but other avenues for funding such studies are almost nonexistent. 4.2.2. Outcome level We chose to use ADG from weaning to finishing as the outcome of interest. This was a common outcome, but not the only measure reported in the studies. This outcome

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measure period was chosen after discussions with swine production faculty at Iowa State University. Other options were wean to grow or grow to finish. Of course, the length of wean to finish is not precise and differs slightly between studies. We do not consider this to be a concern, as the differences likely occur within each vaccine rather than separated by vaccine. We also did not assess mortality or morbidity. This may be of interest and could be the subject of a review, however, our goal was to assess a production outcome. Certainly, if we had chosen to study mortality or morbidity, the issues of reporting variation would have been less of a concern. 4.2.3. Review limitations The use of indirect evidence to obtain evidence of comparison of interest is not novel, although the application to a production outcome in swine is novel. The major concern with the MTC model is the assessment of consistency assumption. Our conclusion is that the assumption appears valid in this application. Similarly, we have assessed and reported sources of bias across the studies. We have reported our conclusions but the data are available for others to assess the validity of our conclusions. 4.3. Conclusions In summary, this analysis suggests that all PCV2 vaccines are likely associated with increased ADG from wean to finish in swine. The Suvaxyn® PCV/FosteraTM product was associated with the lowest estimate of ADG and a greatest uncertainty. Circovac® shows a high gain with large uncertainty. The data suggested few differences between the Circumvent® PCV and Ingelvac® CircoFLEXTM products with respect to ADG from wean to finish. Authorship Primary author N. da Silva had chief responsibility for outcome result extraction and statistical analysis. Contributing authors are listed in alphabetical order. K. O’Neil conducted the search, screening for relevant abstracts and data extraction of population and intervention information. A. Carriquiry had an advisory role for statistical analysis and interpretation of model results. T. Opriessnig had an advisory role for vaccine information and interpretation of model results. Senior/supervisory author: A. O’Connor had primary responsibility for designing and coordinating the approach to the review question, including interpretation. All authors contributed to discussion and conclusion. All authors acknowledge that they met the following ICMJE standards for authorship (http://www.icmje.org/roles a.html). 1. Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; AND 2. Drafting the work or revising it critically for important intellectual content; AND 3. Final approval of the version to be published; AND 4. Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or

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integrity of any part of the work are appropriately investigated and resolved. Disclosure The authors affirm that this manuscript is an honest, accurate, and transparent account of the review being reported; no important aspects of the review have been omitted; and any discrepancies from the review as planned have been documented and explained. Funding No external funding was provided for this study. Conflicts of interest T. Opriessnig has received funding for vaccine research from Boehringer Ingelheim Vetmedica, Inc., Pfizer Animal Health/Zoetis, and Fort Dodge Animal Health. Rest of the authors has no conflicts of interest to declare. Acknowledgments Thank you to Dr. Dinkelman for guidance designing the search and P. Gerber for assistance in conducting the search. References Bergstrom, J., Potter, M., Tokach, M., Henry, S., Dritz, S., Nelssen, J., Goodband, R., DeRouchey, J., 2009. Effects of porcine circovirus type 2 and Mycoplasma hyopneumoniae vaccination strategy, birth weight, and gender on postweaning performance of growing-finishing pigs reared in a commercial environment. In: KSU Swine Day 2009 Report of Progress 1020, Manhattan, KS, November 2009, pp. 8–20. Bischoff, R., Jedidia, S.B., Rocker, B., Kamphake, M., et al., 2009. Longitudinal study on the efficacy of Ingelvac® CircoFLEXTM against Porcine Respiratory Disease Complex (PRDC). Praktische Tierarzt 90 (1), 58–63. Brace, S., Taylor, D., OConnor, A.M., 2010. The quality of reporting and publication status of vaccines trials presented at veterinary conferences from 1988 to 2003. Vaccine 28 (32), 5306–5314. Brooks, S.P., Gelman, A., 1998. General methods for monitoring convergence of iterative simulations. J. Comput. Graph. Stat. 7 (4), 434–455. Coll, T., Villalba, D., Maass, P., 2010. Meta-analysis of globally published results on the efficacy of Ingelvac® CircoFLEXTM vaccination. In: Proceedings of Allen D. Leman Swine Conference, St. Paul, MN, September, p. 167. Criado, J.L., 2012. Vaccinating Iberian pigs against PCV2 and Mycoplasma hyopneumoniae: the payback at the slaughterhouse. In: Proceedings of 22nd IPVS Congress, Jeju, Korea, June 10–13, p. 873. Dan, T.T., Toan, N.T., Diem, N.T.H., Hung, V.K., Dung, V.N., Duy, N.B., Duy, D.T., Nam, N.T.T., Ninh, N.T.P., Ngoc, L.H., 2012. Efficiency of twodose vaccine versus one-dose vaccine against PCV2 in Vietnam. In: Proceedings of 22nd IPVS Congress, Jeju, Korea, June 10–13, p. 899. Dias, S., Welton, N.J., Sutton, A.J., Ades, A.E., 2011a. NICE DSU Technical Support Document 2: A Generalised Linear Modelling Framework for Pairwise and Network Meta-Analysis of Randomised Controlled Trials. National Institute for Health and Clinical Excellence, London, UK. Dias, S., Welton, N.J., Sutton, A.J., Caldwell, D.M., Guobing, Lu, Ades, A.E., 2011b. NICE DSU Technical Support Document 4: Inconsistency in Networks of Evidence Based on Randomised Controlled Trials. National Institute for Health and Clinical Excellence, London, UK. Diaz, E., Edler, R., 2010. Effect of one or two dose vaccination regimens on PCV2 viremia and ADG in 5 different US studies. In: Proceedings of Allen D. Leman Swine Conference, St. Paul, MN, September 18, p. 166. Dunlop, R.H., Pollock, G., Marr, P., Lising, R.T., 2012. Control of PCVAD in a 2,000 sow farrow-finish Australian herd. In: Proceedings of 22nd IPVS Congress, Jeju, Korea, June 10–13, p. 898. Edler, R., Wilt, V., Diaz, E., Cline, G., 2008. Efficacy of PCV2 vaccination of pigs, dams, or both on pig performance. In: Proceedings of Allen D. Leman Swine Conference, St. Paul, MN, September 22, p. 10.

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