Schizophrenia Research 142 (2012) 40–45

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Meta-analysis of repetitive transcranial magnetic stimulation in the treatment ofauditory verbal hallucinations: Update and effects after one month

C.W. Slotema a,⁎, A. Aleman b, Z.J. Daskalakis c, I.E. Sommer d

a Parnassia Bavo Psychiatric Institute, Lijnbaan 4, 2512 VA The Hague, the Netherlandsb Department of Cognitive Neuropsychiatry, University Medical Center Groningen, University of Groningen, Postbus 30001, 9700 RB Groningen, the Netherlandsc Centre for Addiction and Mental Health, University of Toronto, 250 College Street, 7th Floor, Toronto, Ontario, Canada M5T 1R8d Department of Psychiatry, Neuroscience Division & Rudolf Magnus Institute for Neuroscience, University Medical Centre Utrecht, the Netherlands

⁎ Corresponding author. Tel.: +31 883573344; fax: +E-mail addresses: c.slotema@psyq.nl (C.W. Slotema)

(A. Aleman), Jeff_Daskalakis@camh.net (Z.J. Daskalakis)(I.E. Sommer).

0920-9964/$ – see front matter © 2012 Elsevier B.V. Allhttp://dx.doi.org/10.1016/j.schres.2012.08.025

a b s t r a c t

a r t i c l e i n f o

Article history:

Received 10 April 2012Received in revised form 20 August 2012Accepted 28 August 2012Available online 30 September 2012

Keywords:Transcranial magnetic stimulationAuditory verbal hallucinationsMeta-analysis

Objective: Several meta-analyses considering repetitive transcranial magnetic stimulation (rTMS) for auditoryverbal hallucinations (AVH) have been performed with moderate to high mean weighted effect sizes. Sincethen several negative findings were reported in relatively large samples. The aim of this study was to providean update of the literature on the efficacy of rTMS for AVH and to investigate the effect of rTMS one monthafter the end of treatment.Data sources:A literature searchwas performed from1966 throughAugust 2012 using Cochrane Central Registerof Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects,Embase Psychiatry, Ovid Medline, PsycINFO and PubMed. Randomized, double blind, sham-controlled studieswith severity of AVH or severity of psychosis as an outcome measure were included.

Study selection: Data were obtained from 17 randomized studies of rTMS for AVH. Five studies fulfilled thecriteria for the meta-analysis on the effect of rTMS one month after the end of treatment.Data extraction: Standardized mean weighted effect sizes of rTMS versus sham were computed on pre- andposttreatment comparisons.Data synthesis: The meanweighted effect size of rTMS directed at the left temporoparietal area was 0.44 (95% CI0.19–0.68). A separate meta-analysis including studies directing rTMS at other brain regions revealed a meanweighted effect size of 0.33 (95% CI 0.17–0.50) in favor of real TMS.The effect of rTMS was no longer significant at one month of follow-up (mean weighted effect size=0.40, 95%CI−0.23–0.102). Side effects were mild and the number of dropouts in the real TMS group was not significantlyhigher than in the sham group.Conclusions: With the inclusion of studies with larger patient samples, the mean weighted effect size of rTMSdirected at the left temporoparietal area for AVH has decreased, although the effect is still significant. The dura-tion of the effect of rTMSmay be less than onemonth. More research is needed in order to optimize parametersand further evaluate the clinical relevance of this intervention.

© 2012 Elsevier B.V. All rights reserved.

1. Introduction

Repetitive transcranial magnetic stimulation (rTMS) is a safe treat-ment method with only mild side effects such as transient headacheand scalp discomfort during stimulation. Hoffman et al. (1999) werethe first to investigate the effect of rTMS in the treatment ofmedication-resistant auditory verbal hallucinations (AVH). In their ini-tial study, rTMS was directed at the left temporoparietal cortex at a

31 8823584218., a.aleman@med.umcg.nl, i.sommer@umcutrecht.nl

rights reserved.

frequency of 1 Hz. This site of stimulation is believed to overlayBrodmann area 40 (Homan et al., 1987) and was selected in light of re-sults of a previous positron emission tomography (PET) study demon-strating activation in this brain area during AVH (Silbersweig et al.,1995). Furthermore, this region has a central role in speech perception(Ojemann, 1978; Fiez et al., 1996; Benson et al., 2001). Since that firststudy several randomized sham-controlled studies on this subjecthave been published, some with positive, others with negative findings.These publications have been summarized in fourmeta-analyses reveal-ing moderate to high mean weighted effect sizes ranging from 0.54 to1.0 (Aleman et al., 2007; Tranulis et al., 2008; Freitas et al., 2009;Slotemaet al., 2010). Since the publication of thesemeta-analyses sever-al negative studies have become available which included relativelylarge sample sizes. In addition, these previous meta-analyses focussedon the direct effects of rTMS at the end of the treatment trial, and did

Table 1Number of excluded studies and reason for exclusion.

No. ofretrievedstudies

No. of excludedstudies

Reasons forexclusion

Gatewayovid

No clinical trial 19No RCT with placebo 17No English 12Severity of AVHno outcome measure

6

Overlap 3Total 76 61PubMed No clinical trial 83

No English 11No RCT with placebo 5Overlap 3Severity of AVHno outcome measure

2

Total 121 104

RCT = randomized controlled trial.AVH = auditory verbal hallucinations.

41C.W. Slotema et al. / Schizophrenia Research 142 (2012) 40–45

not explore effects of rTMS at follow-up after some weeks or months.The aim of this study is therefore twofold:

1. to conduct a new meta-analysis considering the effect of rTMS forAVH

2. to investigate the long term effects of rTMS for AVH.

2. Experimental/materials and methods

A search of the literature was performed using Cochrane CentralRegister of Controlled Trials, Cochrane Database of Systematic Reviews,Database of Abstracts of Reviews of Effects, Embase Psychiatry 1997through August 2012, Ovid Medline through August 2012, PubMed1990 through August 2012 and PsycINFO 1990 through 2012. All arti-cles were searched for cross-references.

The search terms auditory verbal hallucinations, auditory hallucina-tions, psychosis, psychotic features, transcranial magnetic stimulation,repetitive transcranial magnetic stimulation, TMS and repetitive TMSwere used.

Criteria for inclusion were:

1. Treatment with rTMS using the frequency of 1 Hz.2. The summed score of the Auditory Hallucination Rating Scale

(AHRS) (Hoffman et al., 2003) was used as an outcome measure;if the summed score could not be obtained, the item ‘frequency’of the AHRS or a Visual Analogue Scale such as the HallucinationChange Scale was used as a second or third choice respectively.In case the severity of AVH was not included as an outcome mea-sure, the scores for a scale assessing positive symptoms (of schizo-phrenia) were obtained.

3. The study was performed in a double-blind, randomized con-trolled design using a sham condition. In a separate analysis cross-over studies were excluded as patients might not remain blindedduring this design, which may influence the results.

4. Sufficient data were needed to compute Hedges' g (i.e., samplesize, means, standard deviations or exact t or p values for rTMSmain effect for change scores).

5. The article was written in English.6. When different publications had an overlap in patient samples, the

article with the largest sample size was included.

The studies were screened conforming to the criteria for inclusion.The first author performed the screening.

2.1. Data extraction

The following data were acquired: number of treated patients pertreatment condition, pre- and posttreatment (defined as immediatelyafter the end of treatment and one month after cessation of treat-ment) means and standard deviations of the severity of AVH at base-line and at end of treatment, or exact F, t or p values. Furthermore, thestudy design and treatment parameters, such as frequency, percent-age of the individual motor threshold, number of TMS pulses, numberof sessions, focus of treatment and type of coil, were acquired. Finally,information considering dropouts and side effects was obtained.

Authors were contacted and invited to send additional data in casepublications contained insufficient or incomplete results.

2.2. Effect size calculation

The mean weighted effect size, Hedges' g, was computed with theaims of Comprehensive Meta-Analysis Version 2.0 (Biostat, Engle-wood, New Jersey) in a random effects model. First, the effect sizeswere calculated for the mean change in symptom severity betweenpre- and posttreatment for the separate conditions and weightedaccording to sample size. In studies with three treatment conditions,the two actual treatments were compared separately with the sham

condition. Then, meta-analytic methods were used to obtain a com-bined, weighted effect size. In order to investigate the effect of rTMSon the severity of psychosis, a separate analysis was conducted byusing the changes assessed with the summed score of the positiveitems of the Positive And Negative Syndrome Scale. Separate analyseswere confined to rTMS directed at the left temporoparietal area, rTMStargeted at all brain regions and interview-based clinician-rated ver-sus self‐report measures.

A homogeneity statistic, I2, was computed to test whether thestudies could be taken to share a common population effect size(Higgins et al., 2003). A percentage of 50% or higher indicates hetero-geneity of the individual study effect sizes, which poses a limitation toa reliable interpretation of the results. Whenever significant hetero-geneity was found, a moderator analysis was performed to investi-gate the potential moderating factors, such as localization of targetarea for stimulation, intensity of the individual motor threshold andnumber of TMS pulses. These parameters were correlated withHedges' g using Pearson's correlations in Statistical Packages for theSocial Sciences (SPSS, Chicago, Illinois) version 18.

The effect size can be overestimated in case of an omission of studieswith negative results in the literature. Therefore, a fail‐safe numberwascomputed, which is an estimation of the number ofmissing studies thatis needed to change the results of the meta-analysis to non-significant(Rosenthal, 1979). To visualize a putative decline of effect sizes overthe last years, the mean weighted effect sizes were plotted againstyear of publication.

3. Results

Fifteen studieswere included in themeta-analysis considering rTMSdirected at the left temporoparietal area. Two additional studies wereincluded for the meta-analysis for all rTMS foci. In Table 1 the numberof studies thatwas excluded and the reason for exclusion are presented.

Three hundred and thirty-seven patients were included (Hoffmanet al., 2000; McIntosh et al., 2004; Schonfeldt-Lecuona et al., 2004;Chibbaro et al., 2005; Fitzgerald et al., 2005; Hoffman et al., 2005; Leeet al., 2005; Poulet et al., 2005; Brunelin et al., 2006; Jandl et al., 2006;Rosa et al., 2007; Saba et al., 2006; Vercammen et al., 2009; Loo et al.,2010; Slotema et al., 2011; De Jesus et al., 2011; Blumberger et al., inpress; Bais et al., in preparation); 209 and 197 patients received realrTMS targeted at the left temporoparietal area and sham-treatment re-spectively. Details of the treatment-paradigms of all studies arepresented in Table 2. Ten out of fifteen studies included patients withtherapy-resistant AVH and Hoffman et al. (2005) included 42 out of 50patients with therapy-resistant AVH.

Table 2Repetitive TMS parameters of the included studies.

Studies Nactive

Nsham

Focus Hertz %MTa Stimuli Session Sham Coil Questionnaires

Hoffman et al. (2000) 12 12 T3P3b 1 80 600 4 45° F 8 HCS, PANSSc

McIntosh et al. (2004) crossover 16 16 T3P3 1 80 600 4 45° F 8 PANSSSchonfeldt-Lecuona et al. (2004)crossover

8 10 Broca 1 90 960 5 Parietal–occipitaltransition

F 8 Haddock self-ratingscale

Schonfeldt-Lecuona et al. (2004) 11 10 Superior temporalgyrus

1 90 960 5 Parietal–occipitaltransition

F 8 Haddock self-ratingscale

Chibbaro et al. (2005) 8 8 T3P3 1 90 900 4 45° F 8 SANSd, SAPSe, SAHf

Fitzgerald et al. (2005) 17 15 T3P3 1 90 900 10 45° F 8 HCSg, PSYRATSh, PANSS,GAFi

Hoffman et al. (2005) 27 23 T3P3 1 90 900 10 45° F 8 HCS, AHRSj, PANSS, CGILee et al. (2005) 13 14 T3P3 1 100 1600 10 90° F 8 AHRS, CGI-ILee et al. (2005) 12 14 T4P4k 1 100 1600 10 90° F 8 AHRS, CGI-IPoulet et al. (2005) 10 10 T3P3 1 90 2000 5 Sham coil F 8 AHRS, SAPSBrunelin et al. (2006) 14 10 T3P3 1 90 1000 10 Sham coil F 8 AHRS, SAPSJandl et al. (2006) crossover 16 16 T3P3 T4P4 1 100 900 5 45° F 8 PSYRATS, BDIl, SANSJandl et al. (2006) 16 16 T4P4 1 100 900 5 45° F 8 PSYRATS, BDI, SANSRosa et al. (2007) 6 5 T3P3 1 90 960 10 Sham coil AHRS, PANSS, CGI, VASm

Saba et al. (2006) 8 8 T3P3 1 80 300 10 Sham coil F 8 PANSS, CGIn

Vercammen et al. (2009) 16 16 T3P3 1 90 1200 12 Sham coil F 8 AHRS, PANSS, PANASo

Vercammen et al. (2009) 14 16 T3P3 T4P4 1 90 1200 12 Sham coil F 8Loo et al. (2010), crossover 18 18 T3P3 1 110 240–

4803 Vertex Round AHRS, MADRSp

Loo et al. (2010) 18 18 T4P4 1 110 240–480

3 Vertex Round AHRS, MADRS

Slotema et al. (2011) 22 20 T3P3 1 90 1200 15 90° F 8 AHRS, PANSS, PSYRATS,VAS

Slotema et al. (2010) 20 20 fMRI 1 90 1200 15 90° F 8De Jesus et al. (2011) 8 9 T3P3 1 80 1200 20 45° F 8 BPRSq, QLSr, FASTs,

AHRS, CGIBlumberger et al. (in press) 17 17 Left primary auditory

cortex1 115 1200 20 90° single wing F 8 PSYRATS, PANSS, AHRS,

HCSBlumberger et al. (in press) 17 17 Left primary auditory

cortex6+1 90115 4200 20 90° single wing F 8

a Motor threshold.b Left temporoparietal cortex.c Positive And Negative Syndrome Scale.d Scale for the Assessment of Negative Symptoms.e Scale for the Assessment of Positive Symptoms.f Severity of Auditory Hallucinations.g Hallucination Change Scale.h Psychotic Symptoms Rating Scales.i Global Assessment of Functioning.j Auditory Hallucination Rating Scale.k Right temporoparietal cortex.l Beck Depression Inventory.m Visual Analogue Scale.n Clinical Global Impression.o Positive And Negative Affect Scale.p Montgomery–Asberg Depression Rating Scale.q Brief Psychiatric Rating Scale.r Quality of Life Scale.s Functional Assessment Staging.

42 C.W. Slotema et al. / Schizophrenia Research 142 (2012) 40–45

Themeanweighted effect sizewas 0.44 (95% CI 0.19–0.68, I2=35.7).This corresponds to a moderate effect. See Fig. 1 for the results of themeta-analysis. The fail‐safe number was 996 studies. A moderator anal-ysis did not reveal a correlation between specific treatment-paradigms(duration of each treatment, number of treatments, % of motor thresh-old for stimulation) and mean weighted effect sizes.

A separate analysis on 10 studies including only parallel designswith the temporoparietal cortex as a focus for treatment revealed amean weighted effect size of 0.40 (95% CI 0.10–0.70, I2=35.6) for atotal of 265 patients. This corresponds to amoderate effect. Amoderatoranalysis did not reveal a correlation between specific treatment-paradigms (duration of each treatment, number of treatments, % ofmotor threshold for stimulation) and mean weighted effect sizes.

A small but significant effect of rTMS directed at the lefttemporoparietal area on the severity of psychosis was found (meanweighted effect size=0.28, 95% CI 0.04–0.52, I2=0).

A meta-analysis of all rTMS-foci (n=17 studies) revealed a meanweighted effect size of 0.33 (95% CI 0.17–0.50) for 459 patients, corre-sponding to a small but significant effect size. I2 was 12.9, indicatinglow heterogeneity. A separate analysis of the interview-based clinician-rated measures resulted in a mean weighted effect size of 0.45 (95% CI0.22–0.67, I2=12.5). For self-report measures the mean weighted effectsize was 0.42 (95% CI 0.07–0.77, I2=46.6). The difference betweenself-report- and interview-based clinician-rated measures was not sig-nificant (t=1.87, df 19, p=0.85). No difference in effect could be re-vealed between therapy-resistant AVH and non-therapy-resistant AVH(t=0.436, df 16, p=0.67).

A confound analysis did not show a difference in effect size forstudies measuring changes in hallucinations (Hallucination ChangeScale) instead of level of hallucinations (Auditory Hallucination RatingScale, Psychotic Symptoms Rating Scales, Positive And Negative Syn-drome Scale) (Pearson's correlation 0.289, p=0.32). Furthermore,

Study name Subgroup within study Hedges's g and 95% CI

Hedges's g p-Value

Slotema T3P3 0,000 1,000Brunelin T3P3 1,158 0,008Vercammen T3P3 -0,175 0,613de Jesus T3P3 0,464 0,321Hoffman T3P3 0,552 0,052Rosa PANSS pos T3P3 -0,084 0,880Chibbaro SAH T3P3 1,283 0,014Saba PANSS pos T3P3 -0,053 0,910Lee frequency T3P3 0,498 0,189Fitzgerald HCS T3P3 0,329 0,344Jandl PSYRATS T3P3 0,534 0,154Loo T3P3 0,034 0,916Poulet T3P3 1,350 0,005McIntoshc PANSS pos T3P3 0,195 0,573Hoffman hcs T3P3 1,219 0,005

0,437 0,000-2,00 -1,00 0,00 1,00 2,00

sham rTMS

Meta Analysis

Fig. 1. Results of the meta-analysis of rTMS for auditory verbal hallucinations. The summed score of the Auditory Hallucination Rating Scales was used as an outcome measureunless otherwise described. HCS = Hallucination Change Scale; PANSS pos = Positive And Negative Syndrome Scale positive items; SAH = Severity of Auditory Hallucinations;T3P3 = left temporoparietal area; STG = superior temporal gyrus.

43C.W. Slotema et al. / Schizophrenia Research 142 (2012) 40–45

no difference in effect size could be revealed between the differentquestionnaires (Pearson's correlation 0.360, p=0.19).

Five studies with 61 patients in the real TMS condition and 57 inthe sham condition were included for the meta-analysis on long-term effects of rTMS applied at the left temporoparietal cortex onemonth after the end of treatment. The mean weighted effect sizewas 0.40 (95% CI −0.23–1.02), I2=63.6. The results of thismeta-analysis are presented in Fig. 2. The fail‐safe number was 10studies. No correlation between treatment paradigms and meanweighted effect sizes was found.

Side effects and reasons for dropouts for parallel designs are de-scribed in Tables 3 and 4. These data could be obtained from eightout of eleven studies. No significant differences could be found inthe number of dropouts between real and sham-treatment (Fisher'sExact Test p=0.11).

A funnel plot of the effect sizes and years of publication ispresented in Fig. 3. The effect sizes of studies targeting the lefttemporoparietal area that have been published before 2007 were sig-nificantly higher than those of more recently published studies(Pearson's correlation −0.658, p=0.002).

Study name Subgroup within study

Hedges's g p

de Jesus T3P3 0,359Rosa frequency T3P3 0,770Slotema T3P3 0,018Bais T3P3 -0,327Chibbaro T3P3 1,713

0,396

Meta Analysis

Fig. 2. Results of the meta-analysis of the effect of rTMS one month after the cessation of treoutcome measure unless otherwise described. T3P3 = left temporoparietal area; frequency

4. Discussion

Four previous meta-analyses of repetitive transcranial magneticstimulation (rTMS) in the treatment of auditory verbal hallucinations(AVH), revealed moderate to large effect sizes (Aleman et al., 2007;Tranulis et al., 2008; Freitas et al., 2009; Slotema et al., 2010). Anew meta-analysis was conducted to evaluate the effect of rTMS di-rected at the left temporoparietal area versus sham in the treatmentof AVH. Furthermore, the long term effect of rTMS was investigatedby exploring the results one month after the cessation of rTMStreatment.

In the current meta-analysis the mean weighted effect size ofstudies that targeted the left temporoparietal cortex was moderate(i.e., 0.44). In an additional analysis a significant, but small meanweighted effect size of 0.33 was found in favor of all rTMS-foci. Theresults did not change if separate analyses of (types of) scales wereperformed nor when cross-over studies were excluded from themeta-analyses. The influence of rTMS on the severity of psychosis asassessed using the PANSS positive subscore was small but significant(i.e., 0.28).

-2,00 -1,00 0,00 1,00 2,00

Hedges's g and 95% CI

-Value

0,4410,1820,9530,3460,0020,215

sham rTMS

atment. The summed score of the Auditory Hallucination Rating Scales was used as an= ‘frequency’ item of the Auditory Hallucination Rating Scale.

Table 3Side effects of rTMS for auditory verbal hallucinations.

Side effects Real TMS (n=219) Sham treatment (n=145)

Headache 28 5Twitching facial musculature 18 1Dizziness 4 2Other 8 2Total 58 10

Table 4Reasons for dropouts.

Reasons for dropout Real TMS (n=219) Sham treatment (n=145)

Worsening psychotic symptoms 2 4Deterioration of mental state 0 2Side effects 4 2Lack of effect and inability toattend appointments

2 2

Other 2 1Unknown 0 2Total n (%) 10 (4.6) 13 (9.1)

44 C.W. Slotema et al. / Schizophrenia Research 142 (2012) 40–45

The effect of rTMS on AVH was no longer significant at one monthfollow-up. This short duration of the effect of rTMS is a matter of con-cern; an intensive daily treatment of 2 to 4 weeks with a small treat-ment effect combined with lack of persistence, may call into questionits utility as a meaningful treatment for patients troubled with persis-tent symptoms.

The results of thismeta-analysis show a lowermeanweighted effectsize of 0.33 than previous meta-analyses, which yielded effect sizesbetween 0.52 and 1.0 (Aleman et al., 2007; Tranulis et al., 2008;Freitas et al., 2009; Slotema et al., 2010), but are in line with a letter tothe editor that has recently been published (Demeulemeester et al., inpress #278). This decline over the years may be due to an initialpositive-outcome or publication bias. When new treatment strategiesare introduced, initial reports tend to include relatively small samplesizes and provide favorable results, while small sampled studies withnegative findings do not become published (Emerson et al., 2010).

Fig. 3. Scatter plot of mean weighted effect sizes of rTMS directed

Such trends have led effect sizes to decrease with year of publication(Munafo and Flint, 2010). As rTMS is a relatively new technique, futurestudies may show less positive results. The scatter plot of the random-ized, sham-controlled studies investigating the effect of rTMS for AVHper year of publication, presented in Fig. 3, does not show evidencefor a publication bias as small studies with negative results can befound in the early literature of rTMS as well. However, the effect sizesof studies that have been published more recently are significantlylower. Thus, there seems to be a decrease of the effect of rTMS overthe years.

A matter of concern is that all included studies except Slotema et al.(2011) and Hoffman et al. (2005) are underpowered; with a meanweighted effect size of 0.5, minimum correlation 0.5, power 0.8 andalpha 0.05, 34 participants are needed per condition (Maxwell andDelaney, 2004). Therefore, future studies should direct at includinglarge samples in a multicentre setting as was performed by O'Reardonet al. (2007) for depression.

4.1. Limitations

The majority of studies included patients with therapy-resistantAVH. The literature proposed medication-resistance to be associatedwith smaller effect sizes, but this could not be confirmed in twometa-analyses considering rTMS for depression (Kirsch et al., 2008;Schutter, 2009), neither in this meta-analysis.

Furthermore, the results of the meta-analysis considering the effectof rTMS onemonth after treatmentwere not homogenous and the num-ber of studieswas low. This underlines the need for additional, larger tri-als, to identify moderator variables. Patient characteristics (e.g. lesschronic populations) and localization of the TMS coil (e.g. targetinglanguage regionswith fMRI-based neuronavigation)might be very rele-vant in this regard.

5. Conclusion

This meta-analysis, which could include 17 randomized, sham-controlled trials, found a small, yet significant mean weighted effect

at the left temporoparietal cortex versus year of publication.

45C.W. Slotema et al. / Schizophrenia Research 142 (2012) 40–45

size of 0.33 for repetitive TMS as compared to sham-treatment fortreatment-resistant AVH. Onemonth after treatment, the difference be-tween real and sham rTMS appeared to be no longer significant.

The mean weighted effect size of rTMS is decreasing due to theinclusion of studies with larger patient samples and negative findings.This may imply that early studies, with typically small samples,overestimated the clinical efficacy of rTMS. Alternatively, only sub-groups of patients may benefit from rTMS, and the more recent studiesmay have had small proportions of those patients due to chance. Clearly,more research is needed in order to optimize parameters and furtherevaluate the clinical relevance of this intervention.

Role of funding sourceNeither funding nor approval by a Regional Committee for Medical Research Ethics

Health Region was needed.

ContributorsI.E. Sommer and C.W. Slotema designed the study and wrote the study protocol.C.W. Slotema managed literature searches and analyses.C.W. Slotema undertook the statistical analysis.C.W. Slotema wrote the first draft of the manuscript.All authors contributed to and have approved the final manuscript.

Conflict of interestAll authors declare that they have no conflicts of interest.

AcknowledgmentsWe have no acknowledgments.

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