Supplementary Online Content population Subject with a CHR state of psychosis, identified with...

SupplementaryOnlineContent

Fusar-Poli P, Cappucciati M, Borgwardt S, et al. Heterogeneity of psychosis risk within individuals at clinical high risk: a meta-analytical stratification. JAMA Psychiatry. Published online December 30, 2015. doi:10.1001/jamapsychiatry.2015.2324.

eTable 1. MOOSE Checklist

eMethods. Quality Assessment

eTable 2. List of Included Studies

eResults. Characteristics of UHR Samples

eFigure 1. Meta-analyses

eTable 3. Meta-regression Analyses

eFigure 2. Meta-regression Analyses

eFigure 3. Funnel Plots

eFigure 4. Secondary Outcome: Risk of Psychosis in UHR vs BS Criteria

eTable 4. Table to eFigure 4

eDiscussion 1.

eDiscussion 2.

This supplementary material has been provided by the authors to give readers additional information about their work.

Downloaded From: on 05/20/2018

eTable 1. MOOSE checklist

Criteria Brief description of how the criteria were handled in the meta-analysis

Reporting of background should include

Problem definition CHR paradigm includes different subgroups: APS, BLIPS, GRD (UHR criteria) and the BS subgroup. The meta-analytical prognosis of these subgroups is unknown. In particular, the BLIPS (any) were proposed to display the highest level of risk, followed by the APS+GRD group, by the APS alone and in turn by the GRD alone.

Hypothesis statement We hypothesized a differential risk of psychosis across subgroups (any BLIPS>APS+GRD>APS alone>GRD alone>CHR-).

Description of study outcomes

Proportion of BLIPS, APS+GRD, APS, GRD and BS baseline patients with any psychotic disorder at 6, 12, 24, 36 and ≥48 month follow-up.

Type of exposure or intervention used

We included original articles that reported the risk of psychosis onset at follow-up in patients with BLIPS (any), APS+GRD, APS alone, GRD alone, BS and CHR-.

Type of study designs used Longitudinal cohort studies.

Study population Subject with a CHR state of psychosis, identified with standardized international psychometric instruments.

Reporting of search strategy should include

Qualifications of searchers The credentials of the two investigators MC and GR are indicated in the author list and in the acknowledgements.

Search strategy, including time period included in the synthesis and keywords

The search was extended until 18th June 2015, and included abstracts in English language only. The electronic research adopted several combinations of the following keywords: “at risk mental state”, “psychosis risk”, “prodrome”, “prodromal psychosis”, “ultra high risk”, “high risk”, “help seeking patients”, “psychosis prediction”, “psychosis onset” and name of the CHR assessment instruments. A second step involved the use of Scopus® and a manual search of the reference lists of the retrieved articles.

Databases and registries searched

Web of ScienceSM, MEDLINE® and Scopus®.

Search software used, name and version, including special features

Web of KnowledgeSM and Scopus®.


Use of hand searching We hand-searched bibliographies of retrieved papers for additional references.

List of citations located and those excluded, including justifications

Details of the literature search process are outlined in the supplementary materials.

Method of addressing articles published in languages other than English

The search included abstract in English language only.

Method of handling abstracts and unpublished studies

Abstracts and unpublished studies were excluded.

Description of any contact with authors

We contacted all the corresponding authors to request additional data when needed.

Reporting of methods should include

Description of relevance or appropriateness of studies assembled for assessing the hypothesis to be tested

Detailed inclusion and exclusion criteria were described in the methods section.

Rationale for the selection and coding of data

Data extracted from each of the studies were relevant to the population characteristics, study design, exposure, outcome, and possible effect of confounders.

Assessment of confounding Meta-regressions were used to examine the influence of year of publication, mean age of subgroup, proportion of females in each subgroup, baseline functional level in each subgroup, duration of untreated psychotic symptoms, exposure to antipsychotics from baseline to follow-up, psychometric CHR criteria, diagnostic criteria used to assess transition to psychosis at follow-up, and quality assessment.

Assessment of study quality, including blinding of quality assessors; stratification or regression on possible predictors of study results

We adapted the Newcastle-Ottawa Scale for the evaluation of non-randomized studies. This tool has been adopted in recent meta-analyses.

Assessment of heterogeneity Heterogeneity was assessed with the I2 index.

Description of statistical methods in sufficient detail to be replicated

Random effect meta-analysis conducted with the “metaprop”,”metaninf”, “metafunnel”, “metabias”, “metareg” packages of STATA 13.1. Moderators were tested with meta-regression analyses, Bonferroni corrected. Heterogeneity was assessed with the I2 index. Sensitivity analyses tested robustness of results. Publication biases were assessed with funnel plots and Egger’s test.

Provision of appropriate tables and graphics

We included the PRISMA flow-chart and several tables to describe the literature search and its results. Several graphs were used to describe the main findings of the


analyses.

Reporting of results should include

Graph summarizing individual study estimates and overall estimate

We have appended them in the main text. Additional graphs were presented as supplementary material to fully describe the results.

Table giving descriptive information for each study included

eTable2

Results of sensitivity testing

Sensitivity analyses (i.e. exclusion of 1 study at a time) after outliers identification were reported in the main text.

Indication of statistical uncertainty of findings

We did report mean estimates for the main outcome and 95% CI.

Reporting of discussion should include

Quantitative assessment of bias

Descriptions of quantitative assessment of bias are detailed in the methods; results are described in the main text and supplementary materials.

Justification for exclusion Exclusion criteria were: (a) abstracts, pilot datasets, and paper in languages other than English; (b) articles that were not employing the internationally validated diagnoses for CHR; (c) articles with overlapping datasets; (d) articles which did not provide transition risks stratified across the above subgroups.

Assessment of quality of included studies

We entered the results of the Newcastle-Ottawa Quality Assessment Scale in meta-regression analyses.

Reporting of conclusions should include

Consideration of alternative explanations for observed results

We discussed alternative explanations for our findings, specifically considering potential methodological shortcomings.

Generalization of the conclusions

We have clearly addressed the generalization of the conclusions in the discussion section.

Guidelines for future research We have suggested possible streams of future development and research in the discussion.

Disclosure of funding source No separate funding was necessary for the undertaking of this systematic review.


eMethods. Quality assessment

Quality assessment in observational research is controversial, with no clear consensus on

rating methods or their appropriate use in analyses. We adapted the Newcastle-Ottawa Scale

for the evaluation of non-randomized studies

(http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp). The scale evaluates the

quality of observational studies allocating a maximum of 9 stars for higher quality. This tool

has been adopted in recent meta-analyses.1


eTable 2. List of included studies

Study NOS score (9=max.); Exposure to

antipsychotics at baseline

Exposure to antipsychotics

during follow-up

CHR instrument (criteria)

Psychosis diagnosis

CHR Age

(mean±SD, range)

CHR Gender

(% females)

Follow-up

(months)

CHR+

(baseline)

CHR-

(baseline)

1. Klosterkötter, et al. 20012 (c)

7;

NO

YES (Na) BSABS (BS) DSM‐IV 29.3±9.6 (a)

(15‐53)

47.5 (a) 0, ≥48 110 50

2. Mason, et al. 20043

6;

NO

NO BPRS (UHR) DSM‐IV 17.3±2.8

(13‐28)

47.3 0, 24 (e) 74 Na

3. Lam, et al. 20064

6;

NO

NO CAARMS (UHR) DSM‐IV 16.2±3.7

(7‐23)

41.9 O, 6, 24 62 Na

4. Riecher‐Rössler, et al. 20095

7;

NO

NO BSIP (UHR) BPRS 26.3±8.3

(Na)

39.6 0, ≥48 49 32

5. Woods, et al. 20096 (d)

8;

YES (11.6%)

YES (37.8%) SIPS (UHR) DSM‐IV or medical records

17.8±4.4

(12‐37)

40.9 0, 6, 12, 24, 36, ≥48

259 111

6. Kéri, et al. 20097

5;

NO


(Na)

46.3 0, 12 67 Na

7. Lemos‐Giráldez, et al. 20098

6;

Na

YES (78.7%) SIPS (UHR) DSM‐IV 21.2±3.8

(15‐31)

34.4 0, 6, 12, 24, 36

61 Na

8. Woodberry, et al. 20109

6;

YES (50%)

YES (Na) SIPS (UHR) DSM‐IV 16.5±2.7

(Na)

51 0, 6, 12, 24 73 Na


9. Nelson, et al. 201110

8;

NO

YES (13.6%) CAARMS, BPRS till 1999 (UHR)

CAARMS or Medical records

18.9±3.4

(15‐30)

54.3 0, 6, 12, 24, 36, ≥48

398 173

10. Liu, et al. 201111

4;

NO


(16‐32)

44.1 0, 6, 12, 24, 36

59 48

11. Ziermans, et al. 201112

7;

YES (25%)

YES (28.1) SIPS / BSABS‐P (UHR / BS)

DSM‐IV 15.3±1.9 (b)

(12‐18)

38.9 (b) 0, 6, 12, 24 32 (UHR)

6 (BS)

33 (UHR+BS)

Na

12. Addington, et al. 201213

8;

YES (1.8%)


(12‐31)

43 0, 6, 12, 24, 36, ≥48

172 100

13. Fusar‐Poli, et al. 201214

5;

NO


(15‐35)

52.5 0, 12 40 Na

14. Simon, et al. 201215

7;

NO

YES (15.1%)

SIPS / SPI‐A (UHR / BS)

DSM‐IV 20.7±5.0 (b)

(14‐40)

39.7 (b) 0, 12, 24 73 (UHR)

26 (BS)

49

15. Kim, et al. 201216

7;

Na

YES (74.4%) CAARMS (UHR) DSM‐IV 21.3±4.2

(Na)

32 0, 6, 12, 24, ≥48 (f)

78 Na

16. Lee, et al. 201317

6;

NO


(14‐29)

32.4 0, 6, 12, 24, 36 (g)

173 494

17. Hui, et al. 201318

7; NO CAARMS (UHR) DSM‐IV 20.2±2.9 48.3 0, 24 60 Na


NO (16‐35)18. Fusar‐Poli, et al. 201319

8;

NO

YES (22.4%) CAARMS (UHR) CAARMS 22.9±4.7

(14‐35)

44.2 0, 6, 12, 24, 36, ≥48

353 Na

19. Mossaheb, et al. 201320

7;

NO


(13‐25)

66.7 0, 12 81 Na

20. Koike, et al. 201321

6;

YES (Na)

YES (46%) SIPS (UHR) DSM‐IV 21.3±3.6

(15‐30)

45.9 0, 6, 12, 24 37 Na

21. Kayser, et al. 201322

6;

Na

YES (Na) SIPS (UHR) SIPS 21.4±3.8

(13‐27)

38.1 0, 6, 12, 24, 36, ≥48 (h)

21 Na

22. Nieman, et al. 201323

8;

YES (22.1)

YES (Na) SIPS / BSABS‐P (UHR / BS)

DSM‐IV 22.5±5.2 (b)

(Na)

44 (b) 0, 12, 24 (i) 75 (UHR)

25 (BS)

144 (UHR+BS)

Na

23. Schultze‐Lutter, et al. 201424

8;

YES (13.8%)

YES (21.6%) SIPS / SPI‐A, BSABS till 2000 (UHR / BS)

DSM‐IV 24.9±6.0 (a)

(15‐39)

37.0 (a) 0, 6, 12, 24, 36, ≥48

36 (UHR)

30 (BS)

128 (UHR+BS)

52

24. Zhang, et al. 201425

7;

YES (Na)


(Na)

49.4 0, 6, 12, 24 117 Na


25.Kotlicka‐Antczak et al 201426

5;

YES (10.2%)

YES (13.8%) CAARMS (UHR) ICD‐10 19.1±3.6

(15‐29)

51.1 0, 36 94 33

26.Katsura,etal.201427

5;

YES (29.3%)


(Na)

62.3 0, 36 106 Na

27.Braham,etal.201428

5;

NO

YES (4.0%) CAARMS (UHR) DSM‐IV 20.0±2.5

(16‐30)

45.5 0, 6, 12, 24, 36 (g)

25 25

28. Spada, et al. 201529

6;

NO


(12‐18)

45.5 0, 6 22 18

29. Labad, et al. 201530

7;

YES (18%)


(18‐35)

30.8 0, 6, 12 39 Na

30. Bang, et al. 201531

6;

YES (36.7%)


(13‐35)

41.7 0, 6, 12, 24 60 Na

31. Metzler, et al. 201532

5;

YES (18.6%)

YES (44.5%) SIPS / SPI‐A&C (UHR / BS)

ICD‐10 20.5±5.9 (b)

(Na)

56.9 (b) 0, 12 44 (UHR)

28 (BS)

Na

32. Katagiri, et al 201533

7;

NO

YES (73.2%) SIPS (UHR) SIPS 23.1±6.7

(Na)

75.6 12 41 Na

33. Addington, et al. 201534

8;

YES (Na)

YES (Na) SIPS (UHR) SIPS 18.5±4.2

(12‐35)

42.9 0, 24 743 Na

In case of multiple references or studies from the same group we have cited in the current table the reference reporting the last follow-up data. Please note that additional follow-up data stratified across each subgroup were provided by the individual authors. BPRS, Brief Psychiatric Rating Scale; BSABS, Bonn Scale for the Assessment of Basic Symptoms; BSIP, Basel Screening Instrument for Psychosis; CAARMS, Comprehensive Assessment of At Risk Mental State; CHR, Clinical high risk; DSM-IV,


Diagnostic and Statistical Manual of Mental Disorders; ICD-10, The International Classification of Diseases; Na, not available; NOS, Newcastle-Ottawa Quality Assessment Scale; SIPS, Structured Interview for Prodromal Syndromes; SPI-A&C, Schizophrenia Proneness Instrument (- Adult Version & - Children-Youth Version); UHR, Ultra High Risk, a) Values refer to the whole sample CHR+ and CHR-; b) Values refer to the whole sample CHR+ and BS+; c) at least 1 BS; d) NAPLS-1 sample only used; e) 26.3 months follow-up approximated to 24 months follow-up; f) 6, 12, 24 months data reported in Lee, et al 201435; g) 30 months follow-up approximated to 36 months follow-up; h) 6, 12, 24, 36 months data reported in DeVylder, et al 201436; i) 9 and 18 months follow-up approximated to 12 and 24 months follow-up.


eResults 1. Characteristics of UHR samples

Mean age of each UHR subgroups was: APS=20.07y (SD=2.7), BLIPS=21.11y (SD=3.9),

GRD=20.96y (SD=4.5). Mean baseline GAF was: APS=52.34 (SD=5.85), BLIPS=56.76

(SD=12.08), GRD=49.95 (SD). Mean duration of untreated attenuated psychotic symptoms

was: APS= 709.51days (SD=518.47), BLIPS=435.8days (SD=456.41), GRD=783.46days

(SD=798.62). Proportion of patients treated with antipsychotics was: APS=30.76%

(SD=21.32), BLIPS=39.34% (SD=30.48), GRD=21.5 (SD=26.48). Proportion of females

was: APS=40.75 (SD=8.08), BLIPS=41.45 (SD=25.05), GRD=45.47 (SD=24.28).


eFigure 1a. Meta-analytical proportion of APS cases over the total UHR cases at intake (n=3624). There was significant and high between studies heterogeneity (I2=91.57, p<0.001). Subjects meeting multiple intake criteria were categorized as planned BLIPS>APS>GRD10.


eFigure 1b. Meta-analytical proportion of BLIPS cases over the total UHR cases at intake (n=3624). There was significant and high between studies heterogeneity (I2=91.91, p<0.001). Subjects meeting multiple intake criteria were categorized as planned BLIPS>APS>GRD10.


eFigure 1c. Meta-analytical proportion of GRD cases over the total UHR cases at intake (n=3624). There was significant and high between studies heterogeneity (I2=85.43, p<0.001). Subjects meeting multiple intake criteria were categorized as planned BLIPS>APS>GRD10.


eTable 3. Metaregression analyses

Covariate n β t p 95%CI 6 month follow up Age of subgroup (mean y) 39 -0.005 -0.520 0.605 -0.025 0.015 Gender of subgroup (% females) 39 0.001 0.510 0.615 -0.003 0.007 Exposure to antipsychotics over follow-up time 36 0.001 0.620 0.536 -0.002 0.003 Global Assessment of Functioning of subgroup (mean) 37 -0.001 -0.250 0.806 -0.008 0.007 Duration of untreated attenuated psychotic symptoms 16 0.000 -0.610 0.554 -0.003 0.001 UHR psychometric instrument (CAARMS vs SIPS) 53 0.000 -0.010 0.991 -0.042 0.041 Diagnostic criteria used to define psychosis onset (CAARMS/SIPS/BPRS vs DSM/ICD) 53 -0.008 -0.020 0.841 -0.094 0.077Publication year (y) 53 0.000 -1.450 0.153 -0.002 0.001 Newcastle Ottawa Scale (total score) 53 0.000 -0.010 0.991 -0.042 0.042

12 month follow up Age of subgroup (mean y) 39 -0.009 -0.910 0.370 -0.028 0.011 Gender of subgroup (% females) 39 0.001 0.320 0.751 -0.005 0.006 Exposure to antipsychotics over follow-up time 35 0.001 1.290 0.206 -0.001 0.004 Global Assessment of Functioning of subgroup (mean) 39 -0.002 -0.410 0.684 -0.009 0.005 Duration of untreated attenuated psychotic symptoms 16 0.000 -0.940 0.363 -0.003 0.001 UHR psychometric instrument (CAARMS vs SIPS) 67 0.020 0.510 0.615 -0.060 0.099 Diagnostic criteria used to define psychosis onset (CAARMS/SIPS/BPRS vs DSM/ICD) 67 0.017 0.420 0.676 -0.064 0.097 Publication year (y) 67 -0.011 1.340 0.187 -0.018 0.006 Newcastle Ottawa Scale (total score) 67 -0.016 -0.860 0.391 -0.053 0.021

24 month follow up Age of subgroup (mean y) 34 -0.005 -0.590 0.558 -0.026 0.015 Gender of subgroup (% females) 33 0.001 0.430 0.672 -0.004 0.007 Exposure to antipsychotics over follow-up time 28 0.001 0.800 0.433 -0.002 0.004 Global Assessment of Functioning of subgroup (mean) 32 -0.003 -0.810 0.425 -0.010 0.005 Duration of untreated attenuated psychotic symptoms 32 -0.003 -0.810 0.425 -0.011 0.004 UHR psychometric instrument (CAARMS vs SIPS) 60 -0.002 -0.040 0.970 -0.082 0.079 Diagnostic criteria used to define psychosis onset (CAARMS/SIPS/BPRS vs DSM/ICD) 60 0.060 1.670 0.100 -0.012 0.131


Publication year (y) 60 -0.021 -3.220 0.002** -0.034 -0.008Newcastle Ottawa Scale (total score) 60 -0.020 -1.000 0.323 -0.060 0.020

36 month follow up Age of subgroup (mean y) 19 -0.013 -0.950 0.353 -0.041 0.015 Gender of subgroup (% females) 19 0.002 0.550 0.593 -0.005 0.010 Exposure to antipsychotics over follow-up time 17 0.005 2.690 0.017* 0.001 0.008 Global Assessment of Functioning of subgroup (mean) 17 -0.005 -1.110 0.285 -0.016 0.005 Duration of untreated attenuated psychotic symptoms 5 - - - - - UHR psychometric instrument (CAARMS vs SIPS) 33 0.012 0.270 0.786 -0.082 0.107 Diagnostic criteria used to define psychosis onset (CAARMS/SIPS/BPRS vs DSM/ICD) 33 0.013 0.280 0.780 -0.081 0.108 Publication year (y) 33 -0.009 -0.900 0.374 -0.030 0.012 Newcastle Ottawa Scale (total score) 33 0.011 0.610 0.548 -0.027 0.050

≥48 month follow up Age of subgroup (mean y) 12 0.110 0.710 0.494 -0.023 0.046 Gender of subgroup (% females) 12 -0.001 -0.010 0.990 -0.001 0.009 Exposure to antipsychotics over follow-up time 12 -0.002 -0.890 0.394 -0.006 0.003 Global Assessment of Functioning of subgroup (mean) 9 - - - - - Duration of untreated attenuated psychotic symptoms 11 -0.001 -0.070 0.945 -0.001 0.001 UHR psychometric instrument (CAARMS vs SIPS) 15 -0.048 -0.350 0.730 -0.339 0.244 Diagnostic criteria used to define psychosis onset (CAARMS/SIPS/BPRS vs DSM/ICD) 15 -0.019 -0.220 0.829 -0.203 0.166 Publication year (y) 15 -0.009 -0.430 0.676 -0.055 0.037 Newcastle Ottawa Scale (total score) 15 -0.003 -0.030 0.977 -0.194 0.188

*not surviving correction for multiple comparisons, ** significant after correction for multiple comparisons; BPRS, Brief Psychiatry Rating Scale; CAARMS; Comprehensive Assessment of At Risk Mental States; GAF, Global Assessment of Functioning; SIPS, Structured Interview for Psychosis Syndrome.


eFigure 2a. Meta-regression analysis: effect of publication year on psychosis risk in UHR subjects at 24 months; ES, Effect Size


eFigure 2b. Meta-regression analysis: effect of antipsychotic exposure over follow-up (%) on psychosis risk in UHR subjects at 36 months; ES, Effect Size.


eFigure 3a. Funnel plot investigating publication bias at 6 months. Egger test = 0.489, ES, effect size..


eFigure 3b. Funnel plot investigating publication bias at 12 months. Egger test = 0.266, ES, effect size.


eFigure 3c. Funnel plot investigating publication bias at 24 months. Egger test = 0.300, ES, effect size.


eFigure 3d. Funnel plot investigating publication bias at 36 months. Egger test = 0.899, ES, effect size.


eFigure 3e. Funnel plot investigating publication bias at 48 months. Egger test = 0.246, ES, effect size.


eFigure 4. Secondary outcome. Risk of psychosis in UHR vs BS criteria

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

6 12 24 36 ≥48

Ris

k o

f p

sych

osi

s

(mea

n a

nd

95%

CI)

Follow-up time (months)

UHR onlyBS onlyUHR+BSCHR-


eTable 4. Table to eFigure 4

Follow‐up 6 months 12 months 24 months 36 months (a) ≥48months (a)

Studies (subjects)

Mean 95%CI Studies

(subjects) Mean 95%CI Studies



(subjects) Mean 95%CI

UHR only 19 (2212) 0.10 0.08 0.13 24 (2549) 0.17 0.14 0.20 22 (3176) 0.20 0.17 0.25 12 (1836) 0.25 0.17 0.26 6 (935) 0.25 0.19 0.30 BS only 2 (36) 0.01 0.00 0.10 5 (115) 0.03 0.00 0.07 4 (87) 0.03 0.00 0.11 1 (30) 0.59 0.10 0.37 2 (140) 0.59 0.51 0.68 UHR+BS 2 (161) 0.13 0.08 0.19 3 (305) 0.16 0.03 0.35 3 (305) 0.22 0.05 0.48 1 (128) 0.47 0.38 0.55 1 (128) 0.47 0.38 0.55 CHR‐ 8 (1021) 0.00 0.00 0.00 7 (879) 0.00 0.00 0.01 8 (1052) 0.01 0.00 0.03 7 (863) 0.04 0.00 0.05 3 (134) 0.04 0.00 0.13 Total sample 31 (3430) 39 (3848) 37 (4620) 21 (2857) 12 (1337) Test for between group heterogeneity

Q p Q p Q p Q p Q p

114 <0.001 111 <0.001 84 <0.001 61 <0.001 107 <0.001

UHR, Ultra High Risk; BS, Basic Symptoms; CHR‐, help seeking subjects not at risk for psychosis; a) Exploratory analysis: only 1 BS study and 1 BS+UHR study at 36 months and only 2 BS studies and 1 BS+UHR studies at ≥48months.


eDiscussion 1, Proportion of UHR subgroups at intake

We first estimated the actual meta-analytical distribution of UHR intake criteria; the vast

majority of UHR subjects were included based on APS (85%), with a significant proportion

based on BLIPS (10%) and a small proportion based on GRD (5%). However, we uncovered

significant and high between studies heterogeneity (all I2 >85, p<0.001) in the composition of

UHR samples. Such heterogeneity may reflect local differences in either the epidemiological

composition of referrals to high-risk services or recruitment practices (eFigure 1a,b,c),

impacting the intake of APS vs BLIPS vs GRD subgroups. For example, incidence of

psychotic disorders varied markedly by age, sex, place and migration status/ethnicity37.

Because of high sociodemographic risk factors for psychosis and frequent cannabis use38,

south London has one of the highest incidences of psychosis worldwide39. This may explain

the very high proportion of BLIPS (19% of the total UHR subjects) in the local OASIS high

risk service19. Conversely, in other CHR samples13 there were no BLIPS included. Similar

heterogeneity was observed with respect to the proportion of GRD cases, potentially also an

effect of recruitment strategies. Indeed studies actively recruiting from the community had a

relatively high proportion of GRD17 (14%), whereas others deliberately excluded GRD cases

from their intake criteria24.

eDiscussion 2, Previous pilot studies

A previous systematic review by the European Psychiatry Association (EPA) should be

credited as the first pilot attempt to address the heterogeneity or psychosis risk across

different CHR subgroups40. The review is authoritative and proposes useful guidelines for the

early identification of CHR subjects. Our current meta-analysis overcomes some

methodological limitations presented by this pilot study. Limitations impacting the quality of

the quantitative analyses were: inclusion of overlapping datasets (e.g. three cross-overlapping

samples for the PACE clinic were all included10, 41, 42, STable 1 page 4-5 from40), use of

unconventional meta-analytical approaches (e.g. “exploratory one dimensional X2-tests

unadjusted for multiple testing”, S2 page 340), use of moderators not specific for each CHR

subgroups (e.g age and gender), and lack of adherence to recommended reporting guidelines

for meta-analysis (eg. PRISMA43 flow-chart with reason for study exclusion and MOOSE


checklist44 not published). Despite these meta-analytical limitations, the overall conclusions

of the EPA review are consistent with our main findings.


© 2015 American Medical Association. All rights reserved.28

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