Height and Prostate Cancer Risk: A Large Nested Case-Control Study (ProtecT) and Meta-analysis

A growing body of evidence indicates that greater height—a marker of diet and health throughout the growing years (1)—is positively associated with prostate cancer risk. Many cohort and case-control studies published thus far show an increase in risk of up to 20% to 40% for the top compared with the bottom height quantiles, suggesting the possibility of a long-term influence of childhood nutrition on carcinogenesis (2). Many studies are based on very small numbers, overall findings are inconsistent, and few studies assess the components of height (leg and trunk length) in relation to prostate cancer. Examining the relationship of cancer with leg and trunk length may indicate sensitive periods during childhood growth when risk factors or biological mechanisms underlying height-cancer associations operate (3). It has been shown that prepubertal growth is due more to an increase in leg length rather than trunk length (4), and leg length is sensitive to maternal smoking in pregnancy (5), socioeconomic conditions, nutrition (in particular milk intake; ref. 6), and energy intake in prepubertal children (7). Trunk length reflects factors influencing pubertal growth (7, 8) and is affected by “shrinkage” in late adult life due to compression of the spine (9).

The most plausible biological mechanism for the association of height with prostate cancer is that involving insulin-like growth factor-I (IGF-I) levels in childhood, of which height is a marker (10). In turn, IGF-I levels in adulthood are positively associated with prostate cancer (11).

We investigated the relationship of height and its components to prostate cancer in a case-control study nested within the intensive population-based prostate-specific antigen (PSA) testing phase of the Prostate Testing for Cancer and Treatment (ProtecT) study (12).

In addition, we placed our results in the context of the available evidence by systematically reviewing the published literature on the association between height and prostate cancer and meta-analyzing dose-response estimates derived from retrieved studies. Two previous reviews have been published on this topic (3, 13), but only one included a meta-analysis and was not specifically focused on height as it was part of a broader study on body size and composition (13). Compared with previous studies, our analysis explored in greater detail sources of heterogeneity, including publication bias and the influence of PSA testing on effect estimates (14, 15). We performed additional analysis in the ProtecT study and the meta-analysis by distinguishing between clinical subgroups (defined by grade and/or stage), where possible, to explore whether height could have differing effects on prostate cancer initiation versus progression.

Prostate Cancer Detection. ProtecT is an ongoing randomized controlled trial, evaluating the effectiveness of treatment for clinically localized prostate cancer (12). Men aged 50 to 69 years registered with 400 general practices located around nine U.K. cities are invited to a prostate check clinic where PSA testing is carried out. Men with an increased PSA (≥3 ng/mL) are invited for digital rectal examination, repeat PSA test, and transrectal ultrasound-guided biopsy (10 cores).

Men with a normal biopsy are offered repeat biopsy if the PSA is persistently increased or if there is a high index of clinical suspicion (chiefly evidence of high-grade prostatic intraepithelial neoplasia or suspicious features on initial biopsy). Histologic material obtained at biopsy is reviewed by specialized pathologists and given a Gleason score; tumors with a Gleason score ≥7 were considered high grade. Clinical staging used the tumor-node-metastasis staging system (16). Cases with stages T1-T2 and NXM0 were classified as localized cancers; those with T3-T4 were classified as advanced prostate cancers.

Case-Control Selection. This study is nested within the ProtecT PSA-tested cohort. Cases were men aged 50 to 69 years with histologically confirmed prostate cancer, detected among the 59,217 men who attended for PSA testing and had their PSA result recorded between November 2001 and November 2006. Prostate cancers diagnosed over 2 years after the initial PSA test were excluded from this analysis to distinguish “PSA-detected” from possible “incident” cancers. During this period, 6,329 men (11%) had increased PSA levels; of these, 2,022 (32%) had histologically confirmed prostate cancer.

All participants in the ProtecT cohort who had no evidence of prostate cancer were eligible for selection as controls. These included all men with a PSA below 3.0 ng/mL and any men with a PSA above this threshold who were biopsy negative. Cases were frequency matched to up to six controls by age of attendance at the check clinic (5-year age bands) and the general practice from which they were recruited. As the clinics were held and completed in each general practice in turn, matching for general practice automatically matched for the calendar date of recruitment.

All study participants gave fully informed consent for the use of their data for research purposes. The study received ethical approval from Trent MREC.

Exposure Assessment. All participants were asked to complete a health and lifestyle questionnaire after the check clinic but before their PSA result was available. The questionnaire included the following questions on height and leg length: “How tall are you?” (feet and inches) and “What is your inside leg measurement? (If you do not know, please examine a pair of your trousers)” (inches). All measures were converted to centimeters, and trunk length was calculated as total height minus leg length (estimated from inside leg measurement). Self-reported data on current weight, lifestyle, diet, comorbidities, occupation, ethnicity, and early-life factors (including birth weight and number of siblings) were also obtained from the questionnaires.

Overall 1,419 (70% of the total) men with histologically confirmed prostate cancer [1,230 (87%) localized cancers] and 8,343 controls returned the questionnaire and completed the sections on height and leg length. Sixty-two cases and 353 controls were excluded because of implausible values; thus, the analysis was based on 1,357 (67% of the total) cases (1,180 localized) and 7,990 controls.

Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for the association of height, leg, and trunk length with PSA-detected prostate cancer. As the men were stratum-matched in broad 5-year age bands (5 years), and the risk of prostate cancer increases steeply with age, age as a continuous variable was also entered in all models. ORs were compared across quartiles of height measures, using cutoffs derived from the distribution of controls and the lowest quartile as the reference group. Estimates of dose-response effects were then derived, per 10 cm increase in height and 5 cm increase in leg or trunk length, and per SD increase for all exposures, by fitting models with the exposures as continuous variables. Wald tests were used to test for linear trend across the height distribution. Additional models for leg length were adjusted for trunk length and vice versa, to account for total height and investigate whether the biologically relevant measurement is disproportion or absolute length of the leg or trunk (17). Genetic susceptibility, as indexed by family history of prostate cancer, and early life factors correlated with adult height were adjusted for in multivariable models. These factors included self-reported birth weight, number of siblings, and occupational socioeconomic class (dichotomized as manual and nonmanual, according to their main occupation throughout life). Number of siblings and socioeconomic class may index some of the putative risk factors for prostate cancer that height is a marker for, rather than confound the height-cancer association, so the fully adjusted multivariable models were interpreted with caution.

To investigate whether associations of height with prostate cancer differed for sporadic compared with familial tumors, age, or ethnic groups—which have very different baseline rates of incident and fatal disease—we tested for interactions using likelihood ratio tests.

Associations of cancer risk with height measures were assessed separately by stage, using multinomial logistic regression adjusted for the matching factors, with the outcome variable grouped into three categories: controls, localized cases (stage T1 or T2; NXM0), and advanced cases (stage T3 or T4). Similarly, low-grade (Gleason sum <7) and high-grade (Gleason sum ≥7) cases were compared with controls in multinomial regression models. Heterogeneity in associations of height with localized compared with advanced stage or low-grade compared with high-grade cancers were tested using Wald tests.

A different probability of detecting prostate cancer in taller men compared with shorter men could bias the estimates of height-prostate cancer association. To evaluate the likelihood of this particular detection bias, the mean percentage variation of PSA levels across quartiles of height among controls was estimated by fitting linear regression models to logged PSA values, adjusting for age, center, and date of PSA testing.

Stata 10.1 was used for all statistical analyses (Stata Corp.).

This review was undertaken as part of a systematic review on the associations of food, nutrition, and physical activity with prostate cancer, funded by the World Cancer Research Fund (18). The review protocol is publicly available (19) and details on searches, inclusion criteria, data extraction procedures, and statistical analysis are available in the Supplementary Methods.

We fitted to the data both fixed-effect and random-effects models; we gave preference to the random-effects meta-analysis, which accounts for between-study heterogeneity.

Study Quality. No set of quality criteria on the design and analysis of observational studies is available. It is generally agreed that cohort studies provide higher quality/more robust evidence than case-control studies. Therefore, results from prospective studies (including cohort, case-cohort and nested case-control, and hereafter referred to as “cohort”) were analyzed separately from case-control studies, and further subgroup analyses were done on cohort results only. For the initial (main) pooled analysis, case-control studies were classified based on the selection of controls as stated by the authors. We indicated as “same population” case-control studies those in which the sampled controls were such that they would have become cases (according to the study's definition of case) had they developed the disease, and all the others as “non–same population,” which we considered to be of lower quality. Differences across study design were formally tested by fitting meta-regression models.

Publication Bias. Most prospective studies collect baseline data on anthropometry. Out of 31 publications from cohort studies included in this meta-analysis, 19 reported on height or anthropometry as (one of) their primary exposure(s) in the abstract: 18 from the systematic review and the ProtecT nested case-control study. However, 12 articles, not mentioning height in the title or abstract, included results on the height-prostate cancer association in the full text and we classified these as “incidental” findings. To assess whether positive results on the height-prostate cancer association were more likely to be published and included in the abstract, we further distinguished between primary versus incidental reporting and tested for the difference in the pooled effect estimates by fitting a linear meta-regression model.

Detection Bias. The advent of widespread use of PSA screening started in the early 1990s and changed the nature of the cases being identified from more advanced to early/small lesions. Choosing 1990 as the temporal cutoff, we did a further subgroup analysis, stratifying on whether the follow-up period was mostly pre-PSA (>50% of follow-up occurring <1990) or during the PSA era. The contribution of the proportion of pre-PSA follow-up time to explaining heterogeneity was explored in a meta-regression analysis.

Biological Significance. Because it is not known whether the mechanisms underlying the association with height act on progression rather than initiation, increasing the risk of poorly rather than well-differentiated lesions, we did subgroup analyses after restricting to data on advanced or aggressive cancers (available from 13 cohort studies). We referred to “advanced or aggressive” cases if the article specified any of the following in their case definition: (a) T stage 3 to 4 on the American Joint Committee on Cancer 1992 classification, (b) advanced cancer, (c) advanced or metastatic cancer, (d) metastatic cancer, (e) stage C or D on the Whitmore/Jewett scale, (f) fatal cancer, (g) “high-stage” or “high-grade,” or (h) Gleason score ≥7.

Due to the poor reporting of ethnicity, no stratified analysis was attempted. Results on subgroups of black men available from three cohort (20, 21) and two same population case-control studies (22, 23) from the United States were presented in narrative form.

Of the 1,357 PSA-detected cases of prostate cancer included in the analysis, 173 had advanced-stage disease (missing for 4 cases) and 402 had Gleason score ≥7 (missing for 19 cases; ≥8 for 59 cases). The distribution of demographic, anthropometric, and socioeconomic characteristics of the 1,357 cases and 7,990 controls are presented in Table 1.

There was a 6% (95% CI, −3;-16%) increased risk of PSA-detected prostate cancer per 10 cm increase in height but the statistical evidence supporting this association was weak (p_trend = 0.2). There was no evidence that associations were stronger comparing leg length versus trunk length (Table 2). Comparable results were found for localized and advanced-stage prostate cancer end points, for all height measures (all p for differences in effect estimates by stage ≥0.74; Table 2). Models including simultaneously leg and trunk length yielded very similar effect estimates to the ones from this main analysis (data not shown).

There was no evidence of an increased risk of low-grade tumors with increasing height, leg length, or trunk length. However, for high-grade tumors, we found strong evidence of a 23% increase in risk per 10 cm increase in height (p_trend < 0.01), with a p value of 0.02 for the difference in height associations for low-grade compared with high-grade cancers (Table 2). This seemed to be mainly due to the leg component and in particular to long-for-total-height legs, as in a model including both height components there remained some evidence for an effect of leg length (OR per 5 cm increase, 1.13; 95% CI, 1.01-1.27; p_trend = 0.04), but less so for trunk length (OR per 5 cm increase, 1.09; 95% CI, 0.98-1.21; p_trend = 0.12). As a sensitivity analysis, we reclassified as high grade only those cases with Gleason ≥8 and obtained similar point estimates with wider confidence intervals due to the limited number of cases (n = 59). Results were very similar when ORs were estimated per SD increase in height (SD 6.7 cm), leg length (SD 4.3 cm), and trunk length (SD 4.7 cm; data not shown). Further adjustments for family history of prostate cancer, socioeconomic position, birth weight, or number of siblings did not change the estimates and are thus not reported. There was no evidence of effect modification by family history of prostate cancer, age, or self-reported ethnic origin.

An analysis adjusted for age, center, and date of PSA testing showed evidence that PSA values were on average 9% lower (95% CI, 4-14%, p = 0.001) for controls in the tallest quartile compared with those in the shortest quartile. For both leg and trunk length, the corresponding average PSA difference was 6% (95% CI, 1-10%, p = 0.02).

The search strategy for the broad World Cancer Research Fund review yielded 19,448 hits, of which 1,070 were retrieved for full-text screening. From these, results on 30 cohort (20, 21, 24-48) and 27 case-control studies (22, 23, 49-73) could be included in the current meta-analysis (Fig. 1). Table 3 presents the characteristics of studies identified through the systematic searches and included in the meta-analysis. We included 20 of the 21 cohorts and all 18 case-control studies that were in the meta-analysis of MacInnis et al. (13), although the article by Giovannucci et al. (74) was excluded as we included a more recent report from the same study (43). Additionally, we included three more cohorts (36, 42, 75) and five case-control studies (57, 60, 64, 65, 70) published in the period covered by MacInnis' searches (up to October 31, 2004), and six (26, 35, 38, 39, 46, 47) and four (61, 66, 67, 69) new studies published between November 1, 2004, and July 31, 2007.

Overall, the meta-analysis pooling adjusted results from all 58 studies found evidence of a modest increase in risk of prostate cancer per 10 cm increase in height (random-effects OR, 1.06; 95% CI, 1.03-1.09; Fig. 2).

Results from the Egger test showed no evidence of small study effects for case-control studies, but some for prospective studies (cohorts, p = 0.013), which was not confirmed by Begg's test (cohorts: p = 0.424). There was no clear indication of asymmetry from the funnel plot, for any of the study designs (Supplementary Fig. S1).

Study Quality. There was evidence of heterogeneity across study design (p_{heterogeneity} = 0.001; Fig. 2). Evidence for, and the magnitude of, the effect of height on prostate cancer were strongest for cohorts (OR, 1.09; 95% CI, 1.06-1.12, n = 31) and heterogeneity was lower (I² = 23%) compared with all case-control studies. Only weak evidence of an association of height with prostate cancer was found pooling same-population case-control studies (OR, 1.03; 95% CI, 0.97-1.10, I² = 36%, n = 15), and there was no evidence of a height-prostate cancer association for non–same population studies (OR, 0.98; 95% CI, 0.86-1.10; I² = 49%, n = 12; Fig. 2).

Publication Bias. There was evidence that pooled estimates differed according to whether the study reported on height as (one of) the primary exposure(s) or only incidentally (p_{heterogeneity} = 0.002; Table 4). Based on data from the 19 publications focused on height-cancer associations, there was evidence of an 11% increase in prostate cancer risk per 10 cm increase in height (95% CI, 9-13%; I² = 7%). In contrast, the 12 studies reporting results as incidental findings yielded an OR of 1.01 (95% CI, 0.95-1.07; I² = 0%; Table 4).

Detection Bias. When stratifying on whether the follow-up period was mostly in the pre-PSA era (>50% of follow-up occurring <1990) or during the PSA era, we found similar effects (p_{heterogeneity} = 0.12), with the former studies carrying more heterogeneity (I² = 29% versus 4%; Table 4).

Stage and Grade. Results based on advanced or aggressive cancer outcomes, including fatal disease, were available from 13 cohorts (12 from the review and the current ProtecT data) and showed marked between-study heterogeneity (I² = 47%; Table 4). The pooled estimate was higher than for the all-prostate cancer analysis based on prospective studies (OR, 1.12; 95% CI, 1.05-1.19).

Ethnicity. None of the five studies (all from the United States) presenting ethnicity-specific results found evidence of a height-prostate cancer association among high-risk ethnic groups. Habel et al. (20) reported a hazard ratio of 0.75 (95% CI, 0.42-1.31) comparing the top versus bottom quintile of height among black men in a cohort study. Results on black men were included in a publication with results from rounds I and II of the Cancer Prevention Study: the hazard ratio for prostate cancer comparing black men ≥70 versus ≤66 inches were 0.63 (95% CI, 0.32-1.25) and 0.89 (95% CI, 0.66-1.21), respectively (21). One case-control study did not find any difference in mean height comparing black cases and controls (23). Another presented an OR of 0.9 (95% CI, 0.6-1.5) comparing black men who were tall in childhood versus those who were short (22).

Based on a meta-analysis of 58 studies, including new results from a nested case-control of PSA-detected prostate cancer (ProtecT), we found evidence that greater stature is associated with an increased prostate cancer risk. The overall magnitude of the effect was modest and varied with study design, yet results from cohort studies were compatible with a 6% to 12% increase in risk per 10 cm increase in height, and a 5% to 19% increase in risk for more advanced and/or aggressive cancers. Between-study heterogeneity was higher for case-control studies and for those cohorts including higher proportions of clinically detected, more advanced, or aggressive cancers. Results from the ProtecT nested case-control study were in line with the meta-analysis, with a stronger association for high-grade cancers.

This article benefits both from the strengths offered by analyzing original data and from the power of a meta-analysis based on inclusive systematic searches. The ProtecT case-control series is a population-based study that allowed us to investigate the separate effects of different height components on cancer risk, split by both stage and grade (76). These data are unlikely to be affected by detection bias for two reasons. First, all men had been invited to PSA testing and therefore the likelihood of cancer detection should be unrelated to confounding factors associated with access to or take up of PSA testing. Second, we showed that PSA levels among controls were not positively associated with height, ruling out PSA-mediated access to biopsy as a potential explanation for our findings. Others also found a lower probability of detecting prostate cancer following PSA testing in taller men (77-79). Histologic confirmation of all cancers guarantees high specificity, and the 10-core biopsy protocol standardized the diagnosis of prostate cancer.

Strengths of the meta-analysis include its large power, derived from pooling results on 68,133 cases overall (54,152 from cohorts and 13,981 from case-control studies) and using dose-response models to assess trend effects per 10 cm increase in height. The extensive effort of the searches allowed us to minimize the effect of search and publication bias and to explore the pattern of reporting of the height-prostate cancer associations in prospective studies, as well as other potential sources of between-study heterogeneity that we had specified a priori. One of these was detection bias, potentially introduced by opportunistic use of PSA testing starting from the 1990s and leading to overdiagnosis of microscopic lesions that could have otherwise remained asymptomatic (80, 81). The effect of height could be artifactually overestimated, if taller people, often more educated and better off (82), were also more likely to undergo screening (81, 83). In the absence of data on national PSA screening practices and coverage over time for the countries included in the meta-analysis, we compared studies whose case ascertainment occurred mainly before 1990 (including predominantly clinically presenting cases) with those conducted subsequently (including increasing proportions of asymptomatic cases) and found a modestly increased effect of height for the former, against the suggestion of detection bias.

The dose-dependent nature of the observed height-cancer association adds strength to the evidence of an effect. However, whether this is causal should be assessed in light of the limitations of the studies included in this meta-analysis. Marked differences were observed across study designs, which could be explained by different biases affecting them, mainly selection bias from choice of control population or differential participation in case-control studies. More detailed investigation of heterogeneity across cohort studies suggested that positive results were more likely to be highlighted in the title or abstract of a publication, whereas those null findings that were published were usually only found in the body of any article. However, we found no evidence of a small-study effect, suggesting that such positive results may not be spurious.

None of the well-established risk factors are likely to explain the association with height. Age, which was adjusted for in all prospective studies but one, is expected to be inversely associated with height, if anything (because of marked cohort effects on height). Adjustment for family history of prostate cancer, carried out by some studies including this one, did not appreciably alter the effect estimates. Ethnicity did not seem to play a role in height-cancer associations, its relationship with stature not being obvious and ethnic-specific results for height-prostate cancer generally being similar to those from multiethnic populations. There are reports of an increased risk of more advanced/fatal prostate cancer associated with obesity (84); however, adjustment for body mass index did not change the observed effect estimates in our nested case-control study.

The present nested case-control and most of the studies included in the meta-analysis used self-reported data on height (and leg length), which are subject to measurement error. However, a validation carried out on data from the pilot phase of the study based on 4,708 men found a correlation of 0.96 for measured versus self-reported height, and no systematic misreporting (85), in line with the literature (86, 87). Data on measured and self-reported (inside leg) leg length were available for 3,673 men and showed that inside leg is a shorter measure of leg length (by around 6 cm). However, the difference was consistent across the range of leg lengths (85); thus, it would not result in a biased estimate of the leg length–prostate cancer association. Moreover, any error is likely to be nondifferential, because both exposures were reported before knowledge of prostate cancer diagnosis. Such error would attenuate rather than explain the observed associations. The same is true for trunk length, derived from total height and leg length, which is likely to have produced a large measurement error. The ProtecT and other studies included in the meta-analysis recorded height of subjects late in life. However, shrinkage in middle-aged men could produce a dilution of the effect (especially for the trunk component) but should not affect cancer incidence or mortality (88).

The case definition in the ProtecT nested case-control only included men with screen-detected cancers. Although the association of height with prostate cancer is unlikely to be seen only in PSA-diagnosed men, this was done to ensure homogeneity in case definition. In any case, only two men in total were excluded who developed “incident” prostate cancer and the results are not altered by their inclusion in our analyses. It is possible that among our group of men with localized, low-grade prostate cancers, some would have been recently initiated and, despite aggressive potential in some, might not have had time to become more advanced. This heterogeneity in the localized, low-grade group may have attenuated any differences in associations between height and localized versus advanced cancers in the ProtecT study.

Between-study heterogeneity was investigated among the prospective studies. If height, as a marker of early environmental factors, had a different effect on various clinical subtypes of prostate cancer, then heterogeneity of findings could be due to differing proportions (or definitions) of the clinical subtypes. This was suggested by our ProtecT results for low-grade versus high-grade cancers and by the pooled estimate from cohorts reporting on advanced/aggressive cancers, consistently showing stronger effects compared with localized or well-differentiated cancers. It was also supported by the modest difference between estimates from pre-PSA and PSA era studies, the latter likely to include a higher proportion of smaller asymptomatic tumors. Therefore, factors associated with height could be risk factors for progression to fatal prostate cancer, rather than for the initiation of a well-differentiated tumor (76).

A plausible mechanism to explain the association of height with breast and prostate cancer risk involves dietary programming of the IGF-I system (89, 90). IGF-I plays an important role in the regulation of postnatal growth, and there is evidence that its levels in adulthood can be influenced (“programmed”) by dietary manipulation in early childhood (91). IGF-I levels are also associated with prepubertal growth in height (10), although no stronger association was found for leg versus trunk length in the current study and in three published cohort studies (24, 32, 92). In line with our height findings, there is some evidence that associations of IGF-I with prostate cancer are stronger for advanced versus local disease (11). It is therefore possible that variations in the IGF-I system may underlie associations of height with prostate cancers that are more likely to progress (11).

We conclude that there is evidence that height is positively associated with prostate cancer risk, but the magnitude of the effect is modest and the literature is influenced by publication bias. Overall, these data indicate only a small role for childhood environmental exposures—as indexed by adult height—on prostate cancer incidence. However, the positive association with high-grade cancers in ProtecT was consistent with the evidence on advanced or aggressive cancers from the meta-analysis, suggesting that early life environmental factors may play some role in the development and/or progression of neoplasia with a worse prognosis. Mechanisms that could underlie a height effect on the more aggressive forms of the disease now need to be elucidated.

No potential conflicts of interest were disclosed.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

We thank the tremendous contribution of all members of the ProtecT study research group and especially the following who were involved in this research: Prasad Bollina, Sue Bonnington, Debbie Cooper, Andrew Doble, Alan Doherty, Emma Elliott, David Gillatt, Pippa Herbert, Peter Holding, Joanne Howson, Mandy Jones, Roger Kockelbergh, Howard Kynaston, Teresa Lennon, Norma Lyons, Hilary Moody, Philip Powell, Stephen Prescott, Liz Salter, and Pauline Thompson. We thank Prof. Jonathan Sterne, Dr. Trudy Bekkering, Margaret Burke, and Dr. Anne-Marie Mayer for their help and assistance at different stages of the systematic review.

Department of Health disclaimer: The views and opinions expressed herein are those of the authors and do not necessarily reflect those of the Department of Health.

Contributions: The hypothesis was developed by D. Gunnell, R.M. Martin, and S. Oliver. L. Zuccolo and R. Harris conducted the statistical analyses. L. Zuccolo and R.M. Martin cowrote the first draft and L. Zuccolo coordinated completion of the article. R.M. Martin and L. Zuccolo had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. R. Beynon, J. Savovic, and L. Zuccolo conducted the systematic review, deciding on inclusion/exclusion of manuscripts and extracting data for the meta-analysis. M. Davis and J.A. Lane managed the data collection and the study database. J. Donovan, D. Neal, and F. Hamdy designed the study and obtained funding for data collection. All authors critically commented on and edited earlier drafts and approved the final version of the article.