Cognitive endophenotypes of bipolar disorder: A meta-analysis of neuropsychological deficits in euthymic patients and their first-degree relatives

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Journal of Affective Disorders xx (2008) xxxndashxxx

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Cognitive endophenotypes of bipolar disorder A meta-analysis ofneuropsychological deficits in euthymic patients and their

first-degree relatives

Emre Bora Murat Yucel Christos Pantelis

Melbourne Neuropsychiatry Centre University of Melbourne Australia

Received 24 April 2008 received in revised form 10 June 2008 accepted 10 June 2008

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Background Our aim was to delineate neuropsychological deficits related to genetic susceptibility illness process and iatrogenicfactors in bipolar disorder (BD)Methods Following an extensive publication search on several databases meta-analyses were conducted for 18 cognitive variablesin studies that compared performances of euthymic BD patients (45 studies 1423 subjects) or first-degree relatives of BD patients(17 studies 443 subjects) with healthy controls The effect of demographic variables and confounding factors like age of onsetduration of illness and medication status were analysed using the method of meta-regressionResults While response inhibition set shifting executive function verbal memory and sustained attention deficits were commonfeatures for both patient (medium to large effect sizes) and relative groups (small to medium effect sizes) processing speed visualmemory and verbal fluency deficits were only observed in patients Medication effects contributed to psychomotor slowing in BDpatients Earlier age of onset was associated with verbal memory impairment and psychomotor slowingLimitation Data related to some confounding variables was not reported in a substantial number of extracted studiesConclusions Response inhibition deficit a potential marker of ventral prefrontal dysfunction seems to be the most prominentendophenotype of BD The cognitive endophenotype of BD also appears to involve fronto-temporal and fronto-limbic relatedcognitive impairments Processing speed impairment is related at least partly to medication effects indicating the influence ofconfounding factors rather than genetic susceptibility Patterns of sustained attention and processing speed impairments differ fromschizophrenia Future work in this area should differentiate cognitive deficits associated with disease genotype from impairmentsrelated to other confounding factorscopy 2008 Elsevier BV All rights reserved

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CKeywords Bipolar disorder Cognitive Endophenotype Memory Executive function

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Corresponding author Melbourne Neuropsychiatry Centre University of Melbourne Alan Gilbert Building NNF level 3 Carlton VIC 3053Australia

E-mail address emreborahotmailcom (E Bora)

0165-0327$ - see front matter copy 2008 Elsevier BV All rights reserveddoi101016jjad200806009

Please cite this article as Bora E et al Cognitive endophenotypes of bipolar disorder A meta-analysis of neuropsychological deficits ineuthymic patients and their first-degree relatives J Affect Disord (2008) doi101016jjad200806009

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2 E Bora et al Journal of Affective Disorders xx (2008) xxxndashxxx

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Contents

1 Introduction 02 Method 0

21 Neuropsychological variables 0211 Verbal learning and memory 0212 Visual memory 0213 Sustained attention 0214 Processing speed 0215 Verbal fluency 0216 Set shifting 0217 Working memory 0218 Response inhibition 0219 Visuospatial abilities 02110 General intelligence 0

22 Statistical analyses 03 Results 0

31 Remission 032 Relatives 0

4 Discussion 0Role of funding source 0Conflict of interest 05 Uncited reference 0References 0

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1 Introduction

Endophenotypes are intermediate phenotypes thatare considered a more promising index of underlyinggenetic liability than the illness itself To be acceptedas an endophenotype intermediate phenotypes mustmeet several criteria proposed by Gottesman andGould (2003) Endophenotypes should be associatedwith illness they should be heritable and they shouldco-segregate within families with illness There aretwo additional conditions needed to meet criteria foran endophenotype (a) the endophenotype must bestate independent it must be demonstrable in remittedpatients (b) The endophenotypes should be morefrequent in unaffected relatives of patients comparedto the general population In this context while thereis convincing evidence regarding the value ofcognitive deficits as putative endophenotypes ofschizophrenia (Gur et al 2007 Pantelis et al inpress Snitz et al 2006) the value of such markers asendophenotypes of bipolar disorder (BD) is a largelyunderstudied subject

With respect to the first criterion (that markers arestate independent and observable in remitted patients)the most consistent cognitive findings that mayrepresent potential endophenotypes within euthymic

Please cite this article as Bora E et al Cognitive endophenotypes ofeuthymic patients and their first-degree relatives J Affect Disord (2008

TEpatients with BD are verbal memory executive functionand sustained attention deficits Recently three meta-analytic reports (Arts et al in press Robinson et al2006 Torres et al 2007) provided further evidence forcognitive impairment in BD However these findingsshould be interpreted cautiously as it is quite likely thatconfounding factors such as medication chronicity andsubthreshold affective symptoms are also contributingto the observed findings Furthermore it is still notknown whether these findings are signs of multipleindependent cognitive impairments or whether they arereflections of an underlying a single more basiccognitive abnormality (for example psychomotorspeed or working memory)

Regarding the second criterion (that markers are morefrequently observed in unaffected relatives of patients incomparison to the general population) only a handful ofstudies have investigated cognitive deficits of unaffectedrelatives of affected patients The findings of these studieshave been less consistent than those conducted in affectedpatients themselves For example while several studiessuggest that verbal memory deficits are themost prominentfindings in relatives ofBDpatients (Gourovitch et al 1999Keri et al 2001) other studies do not support this notion(Ferrier et al 2004 Clark et al 2005ab) The evidenceregarding executive dysfunction appears to be similarly

bipolar disorder A meta-analysis of neuropsychological deficits in) doi101016jjad200806009

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3E Bora et al Journal of Affective Disorders xx (2008) xxxndashxxx

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inconsistent For example Frangou et al (2005ab)suggested that executive functions attributable to theventral prefrontal cortex (VPFC) but not dorsal prefrontalcortex (DPFC) are associated with genetic risk for BDhowever some other studies (Clark et al 2005ab) do notsupport this proposal One important limitation of relativestudies is sample size wherein studies are typicallycharacterised by small numbers

Overall while verbal memory executive functionand sustained attention deficits are frequently reportedthe nature and magnitude of such impairments as wellas their consistency can vary markedly across studiesdue to differences in sample characteristics andresearch methodologies In this context meta-analysisis a useful tool for systematically combining allresearch in this area to identify cognitive deficitsshowing the most robust changes in BD It is also auseful methodology to workout the effect of confound-ing factors In this way we may be able to betterunderstand the pervasive cognitive disturbances thatcant be explained by the effects of iatrogenic factors orby the neurotoxic effects of recurrent episodes as wellas their neural underpinnings in bipolar disorder Todate only one meta-analytic study has analysed thestudies in first-degree relatives of BD To our knowl-edge the effects of clinical and iatrogenic confoundershave not been studied by meta-analytic methodspreviously Our aim was to investigate the possibilitythat there exist cognitive endophenotypes of BD To dothis we used published data in euthymic patients andfirst-degree relatives

2 Method

The relevant articles were searched using PubmedMedline Web of Science and Psychinfo with thefollowing search terms bipolar disorder (or manicdepress) and cognit neuropsych attention mem-ory learning executive The search was limited tostudies published in peer-reviewed journals in Englishavailable between 1995 and October 2007 Inclusioncriteria for studies were that they (1) includedneuropsychological data pertaining to a remitted adultBD patient group or first-degree relatives of patientswith BD (2) included a healthy control group (3)reported mean test scores and standard deviations (orstandard errors) of neuropsychological measures forhealthy controls and BD patients or their unaffectedrelatives (4) included at least one cognitive measurethat was studied in at least three studies in both BDpatients and unaffected relatives of BD patientsFollowing initial publication search the titles and


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abstracts of articles were assessed for potentialsuitability and references of these articles were alsocrosschecked for further relevant articles This stepidentified 185 studies When these articles wereexamined further only 68 of themmet all four inclusioncriteria Another 12 studies were excluded since theywere based on the same sample with other includedstudies Finally 56 studies that compared cognitiveperformances of patients with BD (45 studies) orrelatives of BD patients (17 studies) with healthycontrols were included in the current meta-analysis(Tables 1 and 2) (Altshuler et al 2004 Antila et al2007 Balanza-Martinez et al 2005 Bora et al 2007Bora et al in press Brambilla et al 2007 Cavanaghet al 2002 Christensen et al 2006 Clark et al 2002Clark et al 2005ab Clark et al 2005b Deckersbachet al 2004a Deckersbach et al 2004b Dittmann et al2007 Dixon et al 2004 El-Badri et al 2001 Ferrieret al 1999 Ferrier et al 2004 Fleck et al 2003Frangou et al 2005a Frangou et al 2005b Goswamiet al 2006 Gourovitch et al 1999 Harmer et al2002 Hawkins et al 1997 Jones et al 1994 Kayaet al 2007 Keri et al 2004 Kerr et al 2005Kieseppa et al 2005 Klimes-Dougan et al 2007Kolur et al 2006 Krabbendam et al 2000 Kremenet al 1998 Martinez-Aran et al 2007 McIntosh et al2005 Mur et al 2007 Nehra et al 2006 Paradisoet al 1997 Pirkola et al 2005 Rocca et al 2008Rossi et al 2000 Schouws et al 2007 Senturk et al2007 Smith et al 2006 Sobczak et al 2003 Stoddartet al 2007 Swann et al 2003 Szoke et al 2006Thompson et al 2005 Thompson et al 2007 VanGorp et al 1998 Van Gorp et al 1999 Varga et al2006 Zalla et al 2004 Zubieta et al 2001)

21 Neuropsychological variables

211 Verbal learning and memoryEffect sizes of 4 different measures of verbal memory

were included in the meta-analysis (Learning immedi-ate recall delayed recall and recognition) These scoreswere derived from the following tests Rey AuditoryVerbal Learning Test (RAVLT) (Rey 1964) CaliforniaVerbal Learning Test (CVLT) (Delis et al 1987) VisualVerbal Learning Test (VVT) (Lezak et al 1995)

212 Visual memoryRey Osterreich Complex Figure (ROCF) (Rey 1941)

and WMS-R (Wechsler Memory Scale-Revised) Visualmemory (Wechsler 1987) were used to assess visualmemory skills For both tests only delayed recall scoreswere extracted


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Table 1t11

Studies with bipolar patients included in the meta-analysist12

t13 Study Groups Matched Cognitive tests d a

t14 Jones et al (1995)Q2 (13) 26 BD Gender DSST 047t15 16 HC Stroop 046t16 CPT commission 050t17 CPT commission 055t18 Visual memory recall 047t19 Paradiso et al (1997) (14) 11 BD Gender DSST 065t110 19 HC Stroop 055t111 TMT-A 069t112 TMT-B 019t113 Hawkins et al (1997) (15) 22 BD Age edu gender DSST 082t114 22 HC TMT-A 054t115 TMT-B 078t116 Van Gorp et al (1998) (16) 13 BD Age edu IQ Fluency minus011t117 22 HC WCST cat 101t118 WCST per 095t119 Stroop 008t120 TMT-A 032t121 TMT-B 024t122 Verbal learning 096t123 Immediate recall 070t124 Delayed recall 052t125 Visual copy minus009t126 Visual memory recall 025t127 Ferrier et al (1999) (17) 41 BD Premorbid IQ Fluency 067t128 20 HC Age DSST 059t129 TMT-A 055t130 TMT-B 086t131 CPT commission 021t132 Rey Learning 068t133 Digit span forwards 021t134 Digit Span backwards 070t135 Visual copy 053t136 Visual memory recall 077t137 Van Gorp et al (1999) (18) 18 BD Age edu IQ CVLT recognition minus017t138 20 HCt139 Krabbendam et al (2000) (19) 22 BD Education age Fluency 054t140 22 HC Verbal learning 094t141 Delayed recall 094t142 Verbal recognition 050t143 Stroop 067t144 DSST 112t145 Rossi et al 2000 (20) 66 HC - WCST cat 082t146 40 BD WCST per 069t147 El-Badri et al (2001) (21) 29 BD Age IQ Fluency 042t148 26 HC TMT-B 080t149 DSST 073t150 Zubieta et al (2001) (22) 15 BD Age education Fluency 077t151 Ethnicity IQ Stroop 112t152 All patients has a history of psychotic episodes CPT commission 097t153 CPT commission 141t154 WCST cat 084t155 WCST per 152t156 Visual memory recall 042t157 Cavanagh et al (2002) (23) 20 BD Age gender premorbid IQ Fluency 031t158 20 HC Stroop 061t159 Verbal learning 106t160 Delayed recall 096t161 Verbal recognition 062


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t162 Table 1 (continued)


t164 Clark et al (2002) (24) 30 BD Gender edu IQ age Verbal learning 074t165 30 HC Immediate recall 044t166 Delayed recall 016t167 Verbal recognition 029t168 CPT commission 096t169 CPT commission minus018t170 CANTAB ED errors 071t171 Harmer et al (2002) (25) 19 BD Age edu premorbid IQ CPT commission 101t172 19 HC CPT commission 004t173 Fleck et al (2003) (26) 14 BD Gender age edu Verbal learning 125t174 40 HC Immediate recall 101t175 Delayed recall 077t176 Verbal recognition 000t177 Swann et al (2003) (27) 22 BD CPT commission 071t178 35 HC CPT commission 022t179 Altshuler et al (2004) (28) 40 BD Education age Fluency 016t180 22 HC Gender WCST cat 089t181 WCST per 077t182 TMT-A 039t183 TMT-B 040t184 Stroop 041t185 Verbal learning 091t186 Immediate recall 075t187 Delayed recall 078t188 Verbal recognition 022t189 Visual copy 030t190 Visual memory recall 057t191 Deckersbach et al (2004ab) (29) 30 BD Education age Verbal learning 203t192 30 HC Gender Immediate recall 140t193 Delayed recall 167t194 Verbal recognition 064t195 Deckersbach et al (2004ab) (30) 25 BD Education age Visual copy 006t196 25 HC Gender Visual memory recall 070t197 Dixon et al (2004) (31) 15 BD Gender age Fluency 017t198 30 HC Stroop 072t199 Zalla et al (2004) (32) 37 BD Gender age Stroop 117t1100 20 HC TMT-A 061t1101 TMT-B 083t1102 WCST cat 044t1103 WCST per 072t1104 Balanza-Martinez et al (2005) (33) 15 BD Gender age Fluency 128t1105 26 HC DSST 105t1106 Stroop 162t1107 TMT-A 068t1108 TMT-B 089t1109 WCST cat 148t1110 WCST per 167t1111 Clark et al (2005ab) (34) 15 BD IQ age gender CPT commission 100t1112 15 HCt1113 Frangou et al (2005ab) (35) 44 BD Gender age premorbid IQ Fluency 088t1114 44 HC WCST cat 025t1115 WCST per 038t1116 Stroop 057t1117 Visual memory recall 060t1118 Kerr et al (2005) (36) 15 BD Gender premorbid IQ Stroop 178t1119 18 HCt1120 Kieseppa et al (2005) (37) 26 BD Estimated IQ age Verbal learning 043t1121 114 HC Delayed recall 060

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t1124 Kieseppa et al (2005) (37) Digit span Backwards 037t1125 DSST 064t1126 Visual memory recall 108t1127 McIntosh et al (2005) (38) 47 BD Premorbid IQ Fluency 078t1128 50 HC DSST 139t1129 Pirkola et al (2005) (39) 22 BD Gender edu premorb IQ Digit span forwards 036t1130 100 HC Digit span backwards 041t1131 Thompson et al (2005) (40) 63 BD Age gender IQ edu Fluency 036t1132 63 HC TMT-A 047t1133 TMT-B 023t1134 DSST 091t1135 Stroop 058t1136 Digit span backwards 037t1137 Digit span forwards 005t1138 Verbal learning 059t1139 Immediate recall 053t1140 Delayed recall 053t1141 Verbal recognition 056t1142 CPT commission 063t1143 CPT commission 033t1144 Goswami et al (2006) (41) 37 BD Age gender education TMT-A 054t1145 37 HC TMT-B 199t1146 Digit span backwards 228t1147 Digit span forwards 050t1148 Verbal learning 069t1149 Immediate recall 030t1150 Delayed recall 041t1151 DSST 019t1152 Kolur et al (2006) (42) 30 BD Education age WCST cat 259t1153 30 HC Gender WCST per 196t1154 Stroop 186t1155 TMT-A 131t1156 TMT-B 193t1157 CPT commission 135t1158 CPT commission 040t1159 Nehra et al (2006) (43) 46 BD Gender Fluency 085t1160 20 HC TMT-A 076t1161 TMT-B 081t1162 WCST cat minus009t1163 WCST per 008t1164 Smith et al (2006) (44) 21 BD Age gender epre IQ Verbal learning 109t1165 33 HC Immediate recall 095t1166 Delayed recall 084t1167 Recog 090t1168 Stroop 081t1169 TMT-A 156t1170 TMT-B 152t1171 Szoke et al (2006) (45) 95 BD Age TMT-A 060t1172 48 HC TMT-B 061t1173 WCST per 034t1174 Varga et al (2006) (46) 19 BD Edu gender TMT-A 053t1175 31 HC TMT-B 118t1176 Verbal learning 102t1177 Immediate recall 153t1178 Delayed recall 104t1179 Stroop 071t1180 WCST cat minus015t1181 WCST per 055t1182 DSST 054


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t1185 Bora et al (2007) (47) 65 BD Gender age edu Fluency 078t1186 30 HC Stroop 073t1187 TMT-A 068t1188 TMT-B 084t1189 CPT commission 067t1190 CPT commission 058t1191 WCST cat 062t1192 WCST per 057t1193 Verbal learning 057t1194 Immediate recall 073t1195 Delayed recall 063t1196 Verbal recognition 054t1197 Brambilla et al (2007) (48) 15 BD Gender age CPT commission 114t1198 26 HC CPT commission 033t1199 Dittmann et al (2007) (49) 55 BD Age edu gender TMT-A 045t1200 17 HC TMT-B 050t1201 Kaya et al (2007) (50) 43 BD Gender age edu AVLT learning 101t1202 22 HC AVLT delayed 130t1203 AVLT recog 019t1204 Stroop 027t1205 Martinez-Aran et al (2007) (51) 77 BD Age education gender Fluency 039t1206 35 HC WCST cat 028t1207 WCST per 056t1208 Verbal learning 067t1209 Immediate recall 055t1210 Delayed recall 088t1211 Verbal recognition 056t1212 Stroop 057t1213 TMT-A 090t1214 TMT-B 060t1215 Digit Span forwards 077t1216 Digit span backwards 094t1217 Mur et al (2007) (52) 44 BD Age gender Fluency 091t1218 46 HC WCST cat 095t1219 WCST per 073t1220 Digit span forward 078t1221 Digit span backwards 097t1222 Stroop 090t1223 Verbal learning 049t1224 Immediate recall 043t1225 Delayed recall 065t1226 Verbal recognition 048t1227 Visual memory recall 023t1228 TMT-A 097t1229 TMT-B 105t1230 Rocca et al (2007)Q3 (53) 25 BD Age Fluency 087t1231 31 BD WCST cat minus008t1232 WCST per minus004t1233 Stroop minus001t1234 Schouws et al (2007) (54) 15 BD Edu gender age Fluency 128t1235 15 HC TMT-A 064t1236 TMT-B 065t1237 Stroop 108t1238 Digit span forwards 031t1239 Digit span backwards 052t1240 Verbal learning 130t1241 Senturk et al (2007) (55) 28 BD Edu gender WCST cat 058t1242 29 HC WCST per 067



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t1245 Senturk et al (2007) (55) DSST 065t1246 Stoddart et al (2007) (56) 22 BD Gender Stroop 129t1247 40 HC TMT-A 090t1248 TMT-B 123t1249 Thompson et al (2007) (57) 50 BD IQ edu gender age Fluency 035t1250 57 HC Stroop 058t1251 Digit span backwards 040t1252 Digit span forwards 005

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213 Sustained attentionTo assess sustained attention continuous performance

tests (CPT) (Clark and Goodwin 2004) were usedOmission error and commission error scores of CPTtasks were included in this study Target sensitivityindexes that are dependent on both omission andcommission errors were not included Reaction timemeasures were also not included since there was notenough data for the relatives of BD patients

214 Processing speedTwo different effect sizes were calculated to analyse

processing speed abilitiesTime to complete the part A of the Trail Making Test

(TMT-A) (Reitan 1958) and the Digit Symbol Sub-stitution test and symbol digit modalities test (DSST)

215 Verbal fluencyAmeasure of phonetic fluency (FAS) was included in

the current meta-analysis (Lezak 1995) Categoryfluency tasks were not included since there was nosufficient study for the relatives of the patients with BD

216 Set shiftingSet shifting is the ability to change the cognitive

strategies in response to change in the environment Toassess the impairment in the set shifting abilities twodifferent tests was included into the current meta-analysis

Trail Making Test^ndash^Part B (TMT-B) (Reitan 1958)

This test is a measure of set shifting and processingspeed

Wisconsin Cart Sorting Test (WCST) (Heaton1981) Perseverative errors scores of this test wereused as a measure of set shifting A measure ofCambridge Neuropsychological Test Automated Battery(CANTAB) (Downes et al 1989) extradimensionalintradimensional task (extradimensional shifting errors)


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OOwas also involved with this task Number of categoriesachieved scores of WCSTwas involved as a measure ofrule discovery

217 Working memoryAs a measure of working memory Backwards digit

span of the WAIS-R Digit Span (Wechsler 1987) wasused

218 Response inhibitionResponse inhibition refers to the suppression of

actions that are inappropriate in a given context In thismeta-analysis interference score (time to completion) ofthe Stroop Colour-Word test (Lezak 1995) was used toassess response inhibition deficits

219 Visuospatial abilitiesROCF copy score (Rey 1941) was included for

analysing visuospatial abilities

2110 General intelligenceWAIS-R (Wechsler Adult Intelligence Scale-

Revised) (Wechsler 1981) full Scale IQ and its shorterversions were used to assess current IQ abilities Foranalysing premorbid IQ effect sizes of the NART(National Adult Reading Test) (Nelson 1982) and theWAIS Vocabulary subtask (premorbid IQ) wereincluded

For the purpose of the study tasks measuring similarconstructs were assessed together For example wecombined the following (a) RAVLT CVLT and VVT(b) WCST perseverative errors and CANTAB extra-dimensional error scores (c) Digit Symbol Substitutiontest and symbol digit modalities test (d) ROCF andWMS visual memory Identical scores (omission andcommission error scores) from various different ver-sions of sustained attention tasks were also includedtogether Since different studies reported different


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Table 2t21

Studies with relatives of bipolar patients included in the meta-analysist22


t24 Kremen et al (1998) 15 BD Gender age DSST minus005t25 44 HC Edu-pre rel Stroop 042t26 TMT-A minus028t27 TMT-B minus011t28 WCST cat 045t29 WCST per 009t210 Visual copy minus024t211 Visual memory recall minus034t212 Gourovitch et al (1999) 7 BD Fluency 028t213 15 HC TMT-A minus010t214 TMT-B 001t215 Verbal learning 073t216 Immediate recall 032t217 Delayed recall 115t218 Verbal recognition 092t219 WCST cat 000t220 WCST per 052t221 Dig span forwards 116t222 Digit Span backwards 097t223 CPT commission 032t224 Visual copy 004t225 Visual memory recall 068t226 Keri et al (2001) 20 BD Gender age edu Fluency 012t227 20 HC WCST cat 011t228 WCST per 010t229 Digit span forwards minus033t230 Digit span backwards minus018t231 Sobczak et al (2003) 22 BD Fluency 025t232 15 HC Stroop 046t233 Verbal learning 025t234 Delayed recall 034t235 Verbal recognition minus009t236 Ferrier et al (2004) 17 BD Gender age edu Fluency minus012t237 17 HC Premorbid IQ DSST 024t238 Stroop 000t239 TMT-A 007t240 TMT-B 032t241 Verbal learning 018t242 Digit span forwards 040t243 Digit span backwards 099t244 Verbal recognition minus029t245 CPT commission 044t246 CPT commission minus006t247 Zalla et al (2004) 33 BD Gender age Stroop 096t248 20 HC TMT-A 031t249 TMT-B 060t250 WCST cat 012t251 WCST per 057t252 Clark et al (2005a) 27 BD Gender age edu Verbal learning 043t253 46 HC Immediate recall 020t254 Delayed recall 012t255 CANTAB IDED 077t256 Clark et al (2005b) 27 BD Gender age edu CPT commission 038t257 47 HCt258 Frangou et al (2005a) 15 BD IQ WCST cat minus053t259 43 HC WCST per minus040t260 Kieseppa et al (2005) 19 BD DSST minus012



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t263 Kieseppa et al (2005) 114 HC Verbal learning 013t264 Delayed recall 008t265 Visual memory recall 024t266 Visual copy minus004t267 Digit span backwards minus018t268 McIntosh et al (2005) 24 BD Gender age Fluency 058t269 50 HC DSST 050t270 Pirkola et al (2005) 16 BD Age Digit span forwards minus080t271 100 HC Digit span backwards minus031t272 Antilla et al (2006)Q4 40 BD Gender age DSST 044t273 55 HC Premorbid IQ TMT-A 027t274 TMT-B 026t275 Verbal learning 013t276 Immediate recall 019t277 Delayed recall 009t278 Verbal recognition 029t279 Digit span forwards 005t280 Digit span backwards 017t281 Christensen et al (2006) 21 BD Age Stroop 040t282 88 HC TMT-A 000t283 Klimes-Dougan et al (2006) 43 BD Age TMT-A 024t284 50 HC TMT-B 035t285 Verbal learning 039t286 Immediate recall 062t287 Delayed recall 062t288 WCST cat 060t289 WCST per 056t290 CPT commission 024t291 CPT commission 014t292 Szoke et al (2006) 63 BD Age TMT-A 032t293 48 HC TMT-B 050t294 WCST per 022t295 Bora et al (in press) 34 BD Gender age edu Stroop 072t296 25 HC Premorbid IQ TMT-A 015t297 TMT-B 072t298 Verbal learning 026t299 Immediate recall 027t2100 Delayed recall 004t2101 Verbal recognition 033t2102 WCST cat 068t2103 WCST per 069t2104 Digit span forwards 037t2105 Digit span backwards 056t2106 CPT commission 050t2107 CPT commission 039

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UNscoring systems for the Stroop task identical scores thatare sensitive to response inhibition were includedtogether

In some studies means and standard deviations(SDs) of more than one group with euthymic BD(Ferrier et al 1999 Nehra et al 2006 Senturk et al2007) or unaffected BD relatives (Christensen et al2006) were reported In these studies the mean values


and SDs are combined However in another study thatreported scores from two different groups (Van Gorpet al 1998) only patients without comorbid alcoholdependency were included in the current meta-analysisIf there were more than one publication from thecommon samples only the data from the study with thelarger sample was included unless results were reportedfor different cognitive tasks


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The current study reports the results of meta-analysesfor seventeen neurocognitive variables in 45 euthymicBD (1423 BD patients

^ndash1524 healthy controls) and 17

BD relative studies (443 relatives 797 healthy controls)Mean effect sizes for current IQ premorbid IQ andeducation were also calculated since these variables cansignificantly influence the magnitude of groupdifferences

22 Statistical analyses

Meta-analyses were conducted with MIX software(Bax et al 2006) We used the standardised meandifference method with Hedge

^s correction for bias in

small samples Whenever BD patients and their relativesperformed poorer than controls we reported between-group differences by positive effect sizes Therefore theeffect sizes for the relevant variables were multiplied byminus one Homogeneity of the resulting meanweighted effect sizes was tested with Q test Sincethere was heterogeneity for many of the analyses weused a random effects model rather than a fixed effectsmodel for the meta-analyses

Meta-analytic methods accept published studies as arepresentative of all valid studies undertaken Howeverdirection of results may influence the chance ofsubmission and publication of the studies and this factcan be a source of bias in results of meta-analyses(publication bias) Studies with negative

ôutcomes

(especially when the sample size is small) are less

UNCO

RRECTable 3

Mean weighted effect sizes for individual tasks and education for patient-co

Test Study Bipolar Control D

TMT-B 21 793 626 086Verbal learning 18 619 632 085CPT commission 10 303 279 083Delayed recall 17 578 612 077Stroop 24 746 707 076DSST 13 381 479 075Digit span backwards 9 375 487 075Immediate recall 12 453 419 073WCST per 17 663 543 070TMT-A 20 768 600 069WCST Cat 15 538 465 066FAS 19 681 594 060Visual memory recall 9 274 424 059Verbal recognition 13 488 411 044Current IQ 7 239 218 040Digit span forwards 8 349 373 037CPT commission 9 288 264 036Visual copy 4 119 89 023IQ premorbid 23 714 792 017Education 32 1017 1046 001


TEDPR

OOF

likely to be published In the current meta-analysispublication bias was tested with funnel plot and Eggerstest However Egger test may give false positive resultsespecially when effect sizes distributed heterogeneouslyTo reduce the risk of false positive results and to furtherinvestigate the source of funnel plot asymmetry taskswith a significant asymmetry (Eggers test pb005)were further analysed The individual characteristics ofthe studies were further investigated a Fail Safe number(number of negative studies necessary to make thegroup difference insignificant) was calculated and trimand fill method was used to estimate the actual effectsize A significance level of pb005 was used for therandom effects model homogeneity and publicationbias analyses

The effects of demographic variables medication(percentage of patients using antipsychotics antidepres-sants and lithium) clinical variables (age of onset andduration of illness number of manic and depressiveepisodes Hamilton depression score) between-groupdifferences of IQ and other cognitive skills wereanalysed with meta-regression One difficulty in per-forming meta-regression analyses was the limited datafor clinical and treatment variables Therefore toincrease the number of studies three combined scoresfor psychomotor speed (TMT-A DSST) executivefunction (WCST perseverations Stroop Interferencescore TMT-B) and memory recall (delayed verbalmemory ROCF delayed) were also calculated and usedfor meta-regression analyses Meta-regression analyses

ntrol differences

95 CI z P Q-test p Bias

065ndash106 820 b00001 b0001 013068ndash101 101 b00001 003 00004066ndash100 942 b00001 055 010061minus093 934 b00001 006 007059ndash093 868 b00001 00004 007057ndash094 798 b00001 01 075041ndash101 429 b00001 b0001 021053ndash093 715 b00001 004 002049ndash091 654 b00001 00001 002057ndash082 1109 b00001 031 059036ndash096 433 b00001 b00001 015045ndash074 795 b00001 007 050040ndash078 602 b00001 031 066031ndash058 633 b00001 046 013001ndash080 195 005 00003 079015ndash060 321 0001 006 062013ndash059 309 0002 01 043005ndash051 161 011 049 032

minus002ndash036 173 008 b00001 020minus013ndash016 014 089 b00001 004


CTED

PROO

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Fig 1


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UNCO

RREwere conducted in SPSS 110 by using the macros

written by David B Wilson This procedure allows theperformance of weighted generalized least squaresregression Meta-regression analyses were performedwith the random effects model using restricted-informa-tion maximum likelihood method with a significancelevel of pb005

3 Results

31 Remission

The meta-analysis for euthymic BD patients included45 studies These studies compared cognitive perfor-mance of a total of 1446 patients and 1524 healthycontrols There were no significant differences for age(reported in 44 studies) and gender composition(reported in 43 studies) between patients (meanage=388 percentage of males=488) and controls(mean age=383 percentage of males=499) There


were no significant between-group differences foreducation and premorbid IQ (Table 3) Current IQ hada tendency to be lower in patients There was asignificant level of heterogeneity for current andpremorbid IQ analyses

In 17 of 18 meta-analyses conducted for eachcognitive test BD patients performed significantlyworse than control subjects (Table 3) Medium orlarge effect sizes were noted in most measures ofexecutive functions verbal memory sustained attentionand psychomotor speed However effect sizes for visualmemory verbal recognition memory CPT commissionerrors and digits forward were small There was nobetween-group difference on the visual copying task

Five of the 18 analyses reported a significant degreeof heterogeneity (Trails B Digit Span-backwardsStroop WCST category WCST perseveration) Mostof the heterogeneity in these studies was explained byseveral studies The studies of Goswami (2006) Kolur(2006) and Smith (2006) were responsible for


PROO

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heterogeneity in the meta-analysis of TMT-B The studyof Goswami et al (2006) was also the cause of theheterogeneity of Digit Span-backwards In the case ofthe Stroop test (Fig 1) extreme positive effect sizes ofKerr et al (2005) Balanza-Martinez et al (2005) Koluret al (2006) and negative effect sizes of Rocca et al

UNCO

RRECTable 4

Mean weighted effect sizes for individual tasks and education for relative-co

Test Study Bipolar relatives Control relatives

Stroop 6 142 209TMT-B 8 252 274WCST per 9 257 312CPT commission 5 128 153Immediate recall 5 151 192Learning 8 209 338FAS 5 90 117Delayed recall 7 192 321WCST cat 7 167 217DSST 5 115 280Digit Span Backwards 7 153 346Memory recognition 5 120 127Current IQ 7 157 242CPT commission 3 94 92Edu 11 269 576TMT-A 9 277 358Visual memory recall 3 41 173Digit span forwards 6 134 232Premorbid IQ 8 165 441Visual copy 3 41 173


TED(2007) were responsible for the heterogeneity Finally

the heterogeneity in the analysis of WCST category andperseveration scores (Fig 2) was mostly due to thestudies of Balanza-Martinez et al (2005) and Koluret al (2006) After excluding all of these studies thatcaused the heterogeneity the findings Q-tests for all of

ntrol differences

D 95 CI z p Q-test p Bias

051 027ndash076 41 b00001 037 060038 020ndash055 415 b00001 052 052036 020ndash054 418 b00001 008 071036 012ndash060 293 0003 095 053033 011ndash055 294 0003 062 086028 009ndash046 297 0003 092 038027 minus001ndash055 185 006 056 034027 004ndash050 227 002 021 032024 minus008ndash056 148 014 005 022022 minus004ndash049 169 009 028 052022 minus014ndash057 121 023 002 024020 minus011ndash051 127 020 025 096020 minus024ndash063 089 037 00006 036018 minus011ndash047 121 023 055 083018 minus005ndash042 152 013 002 011017 0ndash033 197 005 082 007013 minus039ndash065 048 063 014 074008 minus038ndash054 032 075 0003 044

minus003 minus029ndash023 023 083 007 045minus01 minus044ndash025 056 058 084 084


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these five tasks were non-significant (pN015) Somedifferences in the characteristics of these studies mayexplain these results In the study of Balanza-Martinezet al (2005) the patients had lower education andpremorbid IQ while in the study of Rocca (2007) thepatients had a significantly higher IQ Further the studyof Smith et al (2006) was characterized by early onset(b15 years of age)

Eggers test for the meta-analyses for three tasksshowed a significant publication bias (Verbal learningand verbal memory early recall and WCST persevera-tion) The publication bias was especially significant forverbal learning score Fail Safe number for the verballearning was 836 studies and trim and fill methodpredicted a medium effect size of D=066 (CI=048-085) instead of a large effect size suggested by the prioranalysis Fail-safe numbers for verbal memory earlyrecall and WCST perseveration score were 297 and 513respectively Trim and fill method did not predict adifferent effect size for these tasks

Meta-regression analyses revealed that mean age ofBD patients was negatively associated with the increased

UNCO

R

Fig 4


TEDPR

OOnumber of omission errors (B=minus0029 SE=001p=002) IQ difference between-groups was onlyassociated with the effect size of the Stroop (B=

^045

SE=016 p=^0007 10 studies) Younger age of illness

onset was associated with larger effect sizes for verballearning (B=

^minus005 SE=002 p=

^0027 15 studies) and

TMT-A (B=^minus007 SE=002 p=

^00014 14 studies)

Medication was associated with the magnitude ofimpairment for psychomotor speed and sustainedattention Studies that had reported a higher percentageof antipsychotic usage found larger effect size impair-ments for psychomotor speed (B=

^005 SE=002

p=^004 24 studies) and omission errors (B=

^0011

SE=0005 p=^0037 9 studies) Antidepressant use was

also associated with psychomotor speed (B=^00107

SE=0004 p=^00039 17 studies) and TMT-A perfor-

mance (B=^001 SE=0004 p=

^001 12 studies)

Psychomotor slowness also increased the effect sizeof the impairment for WCST (B=

^11 SE=043

p=^0009 13 studies) and Stroop (B=

^066 SE=027

p=^0015 17 studies) Low performance on TMT-A

was also associated with larger effect sizes for the


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Stroop (B=^066 SE=030 p=

^0025 14 studies)

omission errors (B=^088 SE=04 p=

^003) and FAS

(B=^098 SE=0

^45 p=

^003 10 studies)

There was no association between verbal memoryand executive function impairments Patients who mademore omission errors performed more poorly on theStroop task (B=

^1^69 SE=0

^41 pb

^0^001) Working

memory impairment (reverse digit span) was alsoassociated with the magnitude of executive dysfunction(B=

^0^76 SE=0

^15 pb

^0^001 7 studies)

32 Relatives

Meta-analyses of relatives studies included 17studies (443 relatives of BD patients and 797 healthycontrols) The mean age (15 studies) and gendercompositions (16 studies) of relatives (385 years377 male) and healthy controls (414 years 436male) were comparable There were no significant groupdifferences for education current and premorbid IQbetween groups (Table 4)

Q-test revealed a significant heterogeneity for currentIQ In 6 of 18 cognitive measures relatives of BDpatients performed significantly poorer than controls(see Table 4) The greatest impairment was found on theStroop task (medium effect size) (Fig 3) The effectsizes for the impairments in TMT-B WCST persevera-tion (Fig 4) CPT omission verbal learning andimmediate recall were small

There was a significant heterogeneity for only onetask (Digit Span-forwards) Positive effect size in thestudy of Gourovitch et al (1999) and good performanceof the relatives in the study of Pirkola et al (2005) wereresponsible for this heterogeneity The study ofGourovitch had an extremely small sample size andincluded only monozygotic twins None of the analysesin relatives showed a significant publication bias

Meta-regression analyses revealed effects ofbetween-group IQ differences and the mean age offirst-degree relatives on some cognitive tasks Age had asignificant effect on relative-control differences ofpsychomotor speed (B=

^minus0022 SE=0007 p=

^0003

10 studies) and verbal memory delayed recall (B=^minus0016 SE=0008 p=

^003 5 studies) Thus the

studies with older samples reported smaller effectsizes Studies that reported lower IQ scores in relatives(compared to controls) also found larger effect sizes forexecutive function (B=

^057 SE=024 p=

^0022 8

studies) psychomotor speed (B=^0559 SE=0218

p=^001 8 studies) verbal delayed recall (B=

^068

SE=030 p=^002 5 studies) Digit Span-backwards

(B=^141 SE=047 p=

^0003 6 studies) and Digit


TEDPR

OOF

Span-forwards (B=^171 SE=056 p=

^00025 5

studies)

4 Discussion

This meta-analytic study demonstrated that impairedresponse inhibition might be the most prominentcognitive endophenotype of BD Another executivemeasure set shifting and two other cognitive domainsverbal memory and sustained attention also met thecriteria as potential endophenotypes of BD Whileimpairments in processing speed verbal workingmemory and visual memory are related to the clinicalexpression of BD they were not observed in relativesand therefore do not seem to be associated with geneticsusceptibility to BD Processing speed impairments maybe partly secondary to medication and can alsocontribute to other cognitive impairments found ineuthymic patients with BD Early onset of illness maybe associated with more severe verbal memory impair-ment and psychomotor slowing in BD The observedpattern of sustained attention impairment and promi-nence of response inhibition deficit and lack ofimpairment in processing speed in relatives of patientswith BD partly contrast with reported findings of studiesin first-degree relatives of schizophrenia

Response inhibition seems to be the most significantendophenotype of BD In previous studies in BD inaddition to the Stroop test impaired response inhibitionwas also reported with the Hayling Sentence CompletionTask both in euthymic patients and relatives (Frangouet al 2005a) However we did not include this task in ouranalyses since fewer than three published studies havereported thismeasure in relatives of patients with BD Ourresults are partly consistent with Frangou et al (2005ab)who suggested that only VPFC related functions areendophenotypes of BDWhile it may be oversimplistic toequate response inhibition with VPFC and Cingulatefunction brain imaging studies provided evidenceregarding differential role of VPFC and dorsal prefrontalcortex for response inhibition (Blumberg et al 2003) andset shifting (Monchi et al 2001) respectively AnteriorCingulate gyrus and VPFC abnormalities may have a rolein the aetiology of BD However unlike Frangou et al(2005ab) current results also suggest a role for dorsalprefrontal cortex related set shifting abilities as cognitiveendophenotypes of BD We found a small but significantimpairment for TMT-B andWCST perseverative errors inrelatives of patients with BD In a recent meta-analysisArts et al (in press) found impairments in TMT-B but notin WCST perseverative errors in relatives of BD patientsThis difference may be related to their lower sample size


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for this aspect of their meta-analysis The current studyprovides evidence for a selective role for executivefunctions as endophenotypes of BD Thus while abilityon tasks of set shifting and response inhibition seemed tobe more related to genetic risk for BD other EF functionslike working memory and verbal fluency were not

In our study verbal memory was also impaired bothin euthymic patients and their relatives While arelatively large effect size for verbal memory wasfound in euthymic patients the effect sizes for verbalmemory in relatives were modest This result partlycontradicts the findings of Arts et al (in press) whoreported that relatives had the largest impairment inverbal memory Publication bias seems to exaggerate theactual impairment for verbal memory especially verballearning in euthymic patients with BD Originally wealso included visual memory skills in our analyses Theresults of the study do not suggest a role for nonverballearning abilities as endophenotypes of BD

Originally the current meta-analysis also providedsupport for the potential role of sustained attention as anendophenotype of BD As far as we know this is the firstmeta-analysis that has examined sustained attention inrelatives of BD patients Both the euthymic BD patientsand relatives made more omission errors on CPT tasksFailure to detect targets seems to be a possible traitmarker for BD We found larger effect size impairmentfor CPT in euthymic patients compared to meta-analysesof Robinson et al (2006) and Arts et al (in press) Thedifferent outcome seems to be related to the measures ofsustained attention examined by these other authorsThese studies analysed the measures of sensitivity indexof sustained attention and latency Sensitivity is a derivedscore from correct target detection percentage and falsealarm rates This measure depends on not only omissionerrors but also commission errors that do not seem to beincreased in euthymia (Bora et al 2006) The selectiveimpairment of target detection in BD differs from thepattern observed in schizophrenia (see below)

While the effect sizes for impairment on psychomotortasks were relatively large in patients with BD psycho-motor processing seems to be intact in first-degreerelatives of BD These results suggest that otherconfounding factors rather than genetic susceptibilitymay be the source of psychomotor slowness of BDpatients According to our results treatment effects maybe partly responsible for this finding in euthymic patientsAntipsychotic use was associated with psychomotorslowness There is some previous evidence regardingnegative impact of typical and atypical antipsychotics onpsychomotor abilities (Hughes et al 1999Morrens et al2007)Antipsychoticswere also associatedwith increased


TEDPR

OOF

magnitude of impairment for sustained attention Sincepsychomotor slowness was related to larger effect sizesfor verbal fluency sustained attention and WCSTperseverative errors antipsychotics may also have anindirect impact on other cognitive functions

The proposed cognitive endophenotypes of bipolardisorder partly differ from schizophrenia While meta-analytic studies in relatives of schizophrenia patientsrevealed psychomotor slowing and verbal fluency as animportant endophenotype of schizophrenia (Sitskoornet al 2004 Snitz et al 2006 Szoumlke et al 2005) thiswas not the case for BD in the current study Meta-analyses of the Stroop test in relatives of schizophreniapatients (Sitskoorn et al 2004 Snitz et al 2006)reported a milder deficit than in BD patients in thecurrent study despite the fact that they reported morepronounced general intellectual deficits compared to BDrelative studies Unlike in BD response inhibitiondeficit is not the most pronounced impairment inrelatives of patients with schizophrenia The observedpattern of sustained attention is also different inschizophrenia and BD Meta-analyses in relatives ofschizophrenia patients provided evidence for all aspectsof sustained attention but especially for false alarmingand target sensitivity (Sitskoorn et al 2004) In contrasttarget detection impairment rather than false alarminghas a role as an endophenotype of BD While responseinhibition and a selective type of sustained attentiondeficit are more specific endophenotypes of BDprocessing speed and general intelligence impairmentsmay be endophenotypes of schizophrenia Howeverthere is also evidence for shared endophenotypes in BDand schizophrenia Verbal memory and set shiftingimpairments are observed in relatives of both patientgroups This finding may be compatible with brainimaging findings which suggest there are shared fronto-limbic and fronto-subcortical deficits in schizophreniaas well as BD (McIntosh et al 2006) Heterogeneity ofschizophrenia and BD may also contribute to shared anddifferent endophenotypes of BD While verbal memoryand set-shifting abnormalities may be trait markers ofonly BD patients with a history of psychosis responseinhibition deficits may be an endophenotype for allpatients with BD (Bora et al 2005 Bora et al 2007Martinez-Aran et al 2008) This may also explain thelarger effect sizes for response inhibition in relatives ofpatients with BD Verbal memory and set shiftingimpairments may be endophenotypes of psychosisindependent of diagnosis

Not all of the cognitive impairments in euthymicpatients with BD are true endophenotypes even thoughthey are not secondary to iatrogenic effects or


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subsyndromal symptoms Since endophenotypes must bestable over time progressive impairments related todisease progression may contribute to the cognitiveprofile of established BD patients While longitudinalstudies are very rare in BD there is some evidence ofprogression of cognitive impairments in schizophreniastudies Late maturational changes that may start beforethe onset of illness and continue after the first episodemaycontribute to observed neurocognitive pattern in majorpsychoses (Pantelis et al 2005) Wood and colleaguesrecently examined progressive changes in cognitivefunction over the transition to psychosis as part of theMelbourne UHR studies (Wood et al in press) Whileperformance on most tests was stable or improvedvisuospatial memory verbal fluency and attention switch-ing showed significant decline over the transition topsychosis These progressive impairments were not seenin the non-psychotic UHR group These data would seemconsistent with progressive brain structural changes overtransition to psychosis (Pantelis et al 2005 Pantelis et al2007) Unfortunately there is very scarce data regardinglongitudinal studies in BD However it is interesting thatworking memory and verbal fluency are among theimpairments which are only observed in patientswith BDConsidering the overlaps between schizophrenia and BDit is likely that late-maturational changes can contribute tothe cognitive profile of BDAnother proposedmechanismfor illness related impairments in BD is the potentialneurotoxic effects of repeated illness episodes on limbicstructures Thus there is some evidence for the associa-tion between the number of manic episodes duration ofillness and cognitive impairment in BD (Robinson et al2007b) While our meta-regression analyses failed tosupport evidence for this association some methodolo-gical factors including the limitations of the meta-regression approach and factors related to sampleselection in published studies may explain this outcomeAnalysis of direct correlations from the individual studieswould be a better option however insufficiencies ofpublished data prevent us from performing a correlationalmeta-analysis Long term follow-up studies that investi-gate cognitive functions in high-risk groups and patientswith established diagnosis are necessary to tackle the pre-onset and post-onset cognitive changes in BD

Differences between underlying disease-severities ofpatients included in different studies may be anotherconfounding factor Consistent with this idea meta-regression analysis demonstrated an association betweenyoung onset verbal memory and psychomotor slownessA subgroup of BD patients may present with earlier onsetand more pronounced impairments in verbal memoryand processing speed A similar pattern was previously


TEDPR

OOF

observed in schizophrenia studies with more severeimpairment for verbal memory reported for early-onsetschizophrenia (Tuulio-Henriksson et al 2004) Residualmood symptoms also can have an impact on hetero-geneity of analyses and can increase the magnitude ofeffect sizes in euthymic patients This issue was simplynot investigated in many studies and in others verydifferent measures were used to assess residual symp-toms We were only able to undertake an analysis on asample of studies with regard to the effect of Ham-Dscores on cognition and failed to show any impact on anycognitive measures However the relationship betweenantidepressant use and lower processing speed may be asign of an impact of residual symptoms on cognitionThis issue deserves further investigation One otherpotential confounding factor that can have an impact onthe magnitude of impairment in first-degree relatives ofBD could be the type of family members included(siblings offspring twins) Since the number ofpublished relative studies was restricted it was notpossible to investigate this issue further

This meta-analytic study has several strengths andoriginal points It investigates the cognitive deficits bothin euthymic patients and relatives of patients with BDRegarding sample size and cognitive domains involvedit the most comprehensive meta-analytic study to dateTo our knowledge it is the first meta-analytical studythat attempts to address the impact of clinical andtreatment confounders on cognitive phenotypes of BD

In conclusion response inhibition set shifting verbalmemory and target detection impairments are potentialcandidate endophenotypes for BD Some of the cognitiveimpairments (including psychomotor slowness) observedin euthymic patients could be related to the effects ofmedication and illness-related factors Futurework shouldcarefully try to differentiate cognitive deficits associatedwith disease genotype from impairments related to otherconfounding factors Longitudinal studies studies inves-tigating heritability of cognitive impairment in BD and itsrelation with brain connectivity and genetics would beespecially useful

bipolar disorder A meta-analysis of neuropsych) doi101016jjad200806009

No funding source contributed to this paperRole of funding source

Authors report no conflict of interestConflict of interest

5 Uncited reference

Robinson and Ferrier 2006

ological deficits in

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^References

Altshuler LL Ventura J Van Gorp WG Green MF ThebergeDC Mintz J 2004 Neurocognitive function in clinically stablemen with bipolar disorder or schizophrenia and normal controlsubjects Biol Psychiatry 56 560ndash569

Antila A Tuulio-Henriksson A Kieseppa T Eerola M PartonenT Lonnqvist J 2007 Cognitive functioning in patients withfamilial bipolar I disorder and their unaffected relatives PsycholMed 37 679ndash687

Arts B Jabben N Krabbendam L Van Os J in press Meta-analyses of cognitive functioning in euthymic bipolar patients andtheir first-degree relatives Psychol Med

Balanza-Martinez V Tabares-Seisdedos R Selva-Vera G Martinez-Aran A Torrent C Salazar-Fraile J Leal-Cercoacutes C Vieta EGoacutemez-Beneyto M 2005 Persistent cognitive dysfunctions inbipolar I disorder and schizophrenic patients a 3-year follow-upstudy Psychother Psychosom 74 113ndash119

Bax L Yu LM Ikeda N Tsuruta H Moons KGM 2006Development and validation of MIX comprehensive free softwarefor meta-analysis of causal research data BMC Med ResMethodol 6 50

Blumberg HP Leung HC Skudlarski P Lacadie CMFredericks SA Harris BC 2003 A functional magneticresonance imaging study of bipolar disorder state and trait relateddysfunctions in ventral prefrontal cortices Arch Gen Psychiatry60 601ndash609

Bora E Vahip S Gonul AS Akdeniz F Alkan M Ogut MEryavuz A 2005 Evidence for theory of mind deficits in euthymicpatients with bipolar disorder Acta Psychiatr Scand 112 110ndash116

Bora E Vahip S Akdeniz F 2006 Sustained attention deficits inmanic and euthymic patients with bipolar disorder ProgNeuropsychopharmacol Biol Psychiatry 30 1097ndash1102

Bora E Vahip S Akdeniz F Gonul AS Eryavuz A Ogut MAlkan M 2007 The effect of previous psychotic mood episodeson cognitive impairment in euthymic bipolar patients BipolarDisord 9 468ndash477

Bora E Vahip S Akdeniz F İlerisoy H Aldemir E Alkan M inpress Executive and verbal working memory dysfunction in first-degree relatives of patients with bipolar disorder Psychiatry Res

Brambilla P MacDonald AW Sassi RB Johnson MK MallingerAG Carter S Soares JC 2007 Context processing performancein bipolar disorder patients Bipolar Disord 9 230ndash237

Cavanagh JT VanBeckMMuirW BlackwoodDHR 2002Casecontrol study of neurocognitive function in euthymic bipolardisorder an association with mania Br J Psychiatry 180 320ndash326

Christensen MV Kyvik KO Kessing LV 2006 Cognitivefunction in unaffected twins discordant for affective disorderPsychol Med 36 1119ndash1129

Clark L Goodwin GM 2004 State- and trait-related deficits insustained attention in bipolar disorder Eur Arch Psychiatry ClinNeurosci 254 61ndash68

Clark L Iversen SD Goodwin GM 2002 Sustained attentiondeficit in bipolar disorder Br J Psychiatry 180 313ndash319

Clark L Sarna A Goodwin GM 2005a Impairment of executivefunction but not memory in first-degree relatives of patients withbipolar I disorder and in euthymic patients with unipolardepression Am J Psychiatry 162 1980ndash1982

Clark L Kempton MJ Scarna A Grasby PM Goodwin GM2005b Sustained attention deficit confirmed in euthymic bipolardisorder but not in first degree relatives of bipolar patients oreuthymic unipolar depression Biol Psychiatry 57 183ndash187


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OOF

Deckersbach T Savage CR Reilly-Harrington N Clark LSachs G Rauch SL 2004a Episodic memory impairment inbipolar disorder and obsessive compulsive disorder the role ofmemory strategies Bipolar Disord 6 233ndash244

Deckersbach T McMurrich S Ogutha J Savage CR Sachs GRauch SL 2004b Characteristics of nonverbal memory impair-ment in bipolar disorder the role of encoding strategies PsycholMed 34 823ndash832

Delis DC Kramer JH Kaplan E Ober BA 1987 CaliforniaVerbal Learning Test Adult Version The Psychological Corpora-tion San Antonio TX

Dittmann S Seemuumlller F SchwarzMJ Kleindienst N Stampfer RZach J Born C Bernhard B Fast K Grunze H Engel RRSeverus E 2007 Association of cognitive deficits with elevatedhomocysteine levels in euthymic bipolar patients and its impact onpsychosocial functioning preliminary results Bipolar Disord 963ndash70

Dixon T Kravariti E Frith C Murray RM McGuire PK 2004Effects of symptoms on executive function in bipolar illnessPsychol Med 34 811ndash821

Downes JJ Roberts AC Sahakian BJ Evenden JL RobinsTW 1989 Impaired extradimensional shift performancein medicated and unmedicated Parkinsons disease evidencefor a specific attentional dysfunction Neuropsychologia 271329ndash1344

El-Badri SM Ashton CH Moore PB Marsh VR Ferrier IN2001 Electrophysiological and cognitive function in youngeuthymic patients with bipolar affective disorder Bipolar Disord3 79ndash87

Ferrier IN Stanton BR Kelly TP Scott J 1999 Neuropsycho-logical function in euthymic patients with bipolar disorder Br JPsychiatry 175 246ndash251

Ferrier IN Chowdury R Thompson JMWatson S Young AH2004 Neurocognitive function in unaffected first-degree relativesof patients with bipolar disorder a preliminary report BipolarDisord 6 319ndash322

Fleck DE Shear PK Zimmerman ME Getz GE Corey KBJak A Lebowitz BK Strakowski SM 2003 Verbal memoryin mania effects of clinical state and task requirements BipolarDisord 5 375ndash380

Frangou S Haldane M Roddy M Kumari V 2005a Evidence fordeficits in tasks of ventral but not dorsal prefrontal executivefunction as an endophenotypic marker for bipolar disorder BiolPsychiatry 58 838ndash839

Frangou S Donaldson S Hadjulis M Landau S Goldstein LH2005b The Maudsley bipolar disorder project executive dysfunc-tion in bipolar disorder I and its clinical correlates Biol Psychiatry58 859ndash864

Goswami U Sharma A Khastigir U Nicol I Ferrier AHGallagher P Thompson JM Moore PB 2006 Neuropsycho-logical dysfunction soft neurological signs and social disability ineuthymic patients with bipolar disorder Br J Psychiatry 188366ndash373

Gottesman II Gould TD 2003 The endophenotype concept inpsychiatry etymology and strategic intentions Am J Psychiatry160 636ndash645

Gourovitch ML Torrey EF Gold JM Randolph C WeinbergerDR Goldberg TE 1999 Neuropsychological performance ofmonozygotic twins discordant for bipolar disorder Biol Psychia-try 45 639ndash646

Gur RE Nimgaonkar VL Almasy L Calkins ME Ragland JDPogue-Geile MF Kanes S Blangero J Gur RC 2007


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Neurocognitive endophenotypes in a multiplex multigenerationalfamily study of schizophrenia Am J Psychiatry 164 813ndash819

Harmer CJ Clark L Grayson L Goodwin GM 2002 Sustainedattention deficit in bipolar disorder is not a working memoryimpairment in disguise Neuropsychologia 40 1586ndash1590

Hawkins KA Hoffman RE Quinlan DM Rakfeldt J DochertyNM Sledge WH 1997 Cognition negative symptoms anddiagnosis a comparison of schizophrenic bipolar and controlsamples J Neuropsychiatr Clin Neurosci 9 81ndash89

Heaton RK 1981 Wisconsin Cart Sorting Test Manual Odessa FLPsychological Assessment Resources Inc

Hughes AM Lynch P Rhodes J Ervine CM Yates RA 1999Electroencephalographic and psychomotor effects of chlorproma-zine and risperidone relative to placebo in normal healthyvolunteers Br J Clin Pharmacol 48 323ndash330

Jones PB Duncan CC Mirsky AF Post RM Theodore WH1994 Neuropsychological profiles in bipolar affective disorderand complex partial seizure disorder Neuropsychology 8 55ndash64

Kaya E Aydemir O Selcuki D 2007 Residual symptoms inbipolar disorder The effect of last episode after remission ProgressNeurophramacol Biol Psychiatr 31 1387ndash1392

Keri S Kelemen O Benedek G Janka Z 2001 Different traitmarkers for schizophrenia and bipolar disorder a neurocognitiveapproach Psychol Med 31 915ndash922

Kerr N Scott J Phillips ML 2005 Patterns of attentional deficitsand emotional bias in bipolar and major depressive disorder Br JClin Psychol 44 343ndash356

Kieseppa T Tuulio-Herniksson A Haukka J Van Erp T GlahnD Cannon TD Partonen T Kaprio J Loumlnnqvist J 2005Memory and verbal learning functions in twins with bipolar-Idisorder and the role of information processing speed PsycholMed 35 205ndash215

Klimes-Dougan B Ronsaville D Wiggs EA Martinez PE 2006Neuropsychological functioning in adolescent children of motherswith a history of bipolar or major depressive disorders BiolPsychiatry 60 957ndash965

Kolur US Reddy YCJ John P Kandavel T Jain S 2006Sustained attention and executive functions in euthymic youngpeople with bipolar disorder Br J Psychiatry 189 453ndash458

Krabbendam L Honig A Wiersman J Vuurman EFPMHofman PAM Derix MMA Nolen WA Jolles J 2000Cognitive dysfunction and white matter lesions in patients withbipolar disorder in remission Acta Psychiatr Scand 101 274ndash280

Kremen WS Faraone SV Seidman LJ Pepple JR Tsuang MT1998 Neuropsychological risk indicators for schizophrenia apreliminary study of female relatives of schizophrenic and bipolarprobands Psychiatry Res 79 227ndash240

Lezak MD 1995 Neuropsychological Assessment New YorkOxford University Press

Martinez-Aran A Vieta E Torrent C Sanchez-Moreno JGoikolea JM Salamero M Malhi GS Gonzalez-Pinto ADaban C Alvarez-Grandi S Fountoulakis K Kaprinis GTabares-Seisdedos R Ayuso-Mateos JL 2007 Functionaloutcome in bipolar disorder the role of clinical and cognitivefactors Bipolar Disord 9 103ndash113

Martinez-Aran A Torrent C Tabares-Seisdedos R Salamero MDaban C Balanza-Martinez V Sanchez-Moreno J ManuelGoikolea J Benabarre A Colom F Vieta E 2008Neurocognitive impairment in bipolar patients with and withouthistory of psychosis J Clin Psychiatry 69 233ndash239

McIntosh AM Harrison LK Forrester K Lawrie SMJohnstone EC 2005 Neuropsychological impairments in people


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with schizophrenia or bipolar disorder and their unaffectedrelatives Br J Psychiatry 185 378ndash385

McIntosh AM Job DE Moorhead WJ Harrison LK WhalleyHC Johnstone EC Lawrie SM 2006 Genetic liability toschizophrenia or bipolar disorder and its relationship to brainstructure Am J Med Genet B Neuropsychiatr Genet 14176ndash83

Monchi O Petrides M Petre V Worsley K Dagher A 2001Wisconsin Card Sorting revisited distinct neural circuits partici-pating in different stages of the task identified by event relatedfunctional magnetic resonance imaging J Neurosci 21 773-741

Morrens M Wezenberg E Verkes RJ Hulstijn W Ruigt GSSabbe BG 2007 Psychomotor and memory effects ofhaloperidol olanzapine and paroxetine in healthy subjects aftershort-term administration J Clin Psychopharmacol 27 15ndash21

Mur M Portella MJ Martinez-Aran A Pifarre J Vieta E 2007Persistent neuropsychological deficit in euthymic bipolar patientsexecutive function as a core deficit J Clin Psychiatry 681078ndash1086

Nehra R Chakrabarti S Pradhan BK Khehra N 2006Comparison of cognitive functions between first- and multi-episode bipolar affective disorders J Affect Disord 93 185ndash192

Nelson HE 1982 National Adult Reading Test NFER-NelsonWindsor UK

Pantelis C Yucel M Wood SJ Velakoulis D Sun D Berger GStuart GW Yung A Phillips L McGorry PD 2005Structural brain imaging evidence for multiple pathologicalprocesses at different stages of brain development in schizo-phrenia Schizophrenia Bull 31 672ndash696

Pantelis C Velakoulis D Wood SJ Yucel M Yung ARPhillips LJ Sun DQ McGorry PD 2007 Neuroimaging andemerging psychotic disorders the Melbourne ultra-high riskstudies Int Rev Psychiatry 19 371ndash379

Pantelis C Yucel M Wood SJ Brewer WJ Fornito A BergerG Cannon T Velakoulis D in press Recognition andmanagement of early psychosis

â preventive approach 2nd

edition Cambridge Cambridge University PressParadiso S Lamberty GJ Garvey MJ Robinson RG 1997

Cognitive impairment in the euthymic phase of chronic unipolardepression J Nerv Ment Dis 185 748ndash754

Pirkola T Tuulio-Henriksson A Glahn D Kieseppauml T HaukkaJ Kaprio J Loumlnnqvist J Cannon TD 2005 Spatial workingmemory function in twins with schizophrenia and bipolar disorderBiol Psychiatry 58 930ndash936

Reitan RM 1958 Validity of trail making test as an indication oforganic brain disease Percept Mot Skills 8 271ndash276

Rey A 1941 Psychological examination of traumatic encephalo-pathy Archieves de Psychologic 28 286ndash340

Rey A 1964 Lexamen clinique en psychologie Presses Universi-taires de France Paris

Robinson LJ Ferrier IN 2006 Evolution of cognitive impairmentsin bipolar disorder a systemic review of cross-sectional evidenceBipolar disord 8 103ndash116

Robinson LJ Thompson JM Gallagher P Goswami U YoungAH Ferrier IN Moore PB 2006 A metaanalysis of cognitivedeficits in euthymic patients with bipolar disorder J AffectDisord 93 105ndash115

Rocca CC Macedo-Soares MB Gorenstein C Tamada RSIsller CK Dias RS Almeida KM Schwartzmann AMAmaral JA Lafer B 2008 Verbal fluency dysfunction ineuthymic bipolar patients

â controlled study J Affect Disord

107 187ndash192


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Rossi A Arduini A Daneluzzo E Bustini M Prosperini PStratta P 2000 Cognitive function in euthymic bipolar patientsstabilized schizophrenic patients and healthy controls J PsychiatrRes 34 333ndash339

Schouws SNTM Zoeterman JB Comijs HC Stek MLBeekman ATF 2007 Cognitive functioning in elderly patientswith early onset bipolar disorder I J Geriatric Psychiatr 22856ndash861

Senturk V Goker C Bilgic A Olmez S Tugcu H Oncu BAtbasoglu EC 2007 Impaired verbal memory and otherwisespared cognition in remitted bipolar patients on monotherapy withlithium and valproate Bipolar Disord 9 136ndash144

Sitskoorn MM Aleman A Ebisch SJ Appels MC Kahn RS2004 Cognitive deficits in relatives of patients with schizophreniaa meta-analysis Schizophr Res 71 285ndash295

Smith DJ Muir WJ Blackwood DHR 2006 Neurocognitiveimpairment in euthymic young adults with bipolar spectrumdisorder and recurrent major depressive disorder Bipolar Disord8 40ndash46

Snitz BE Macdonald 3rd AW Carter CS 2006 Cognitivedeficits in unaffected first-degree relatives of schizophreniapatients a meta-analytic review of putative endophenotypesSchizophr Bull 32 179ndash194

Sobczak S Honig A Schmitt JA Riedel WJ 2003 Pronouncedcognitive deficits following an intravenous L-tryptophan challengein first-degree relatives of bipolar patients compared to healthycontrols Neuropsychopharmacol 28 711ndash719

Stoddart SDR Craddock NJ Jones LA 2007 Differentiation ofexecutive and attention impairments in affective illness PsycholMed 37 1613ndash1623

Szoke A Schuroff F Golmard JL Alter C Roy I Meary AEtain B Bellivier F Leboyer M 2006 Familial resemblance ofexecutive functions in families of schizophrenic and bipolarpatients Psychiatry Res 14 131ndash138

SwannAC Pazzaglia P Nicholls A Dougherty DMMoeller FG2003 Impulsivity and phase of illness in bipolar disorder J AffectDisord 73 (1-2) 105ndash111

Szoumlke A Schuumlrhoff F Mathieu F Meary A Ionescu S LeboyerM 2005 Tests of executive functions in first-degree relatives ofschizophrenic patients a meta-analysis Psychol Med 35771ndash782

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Thompson JM Gallagher P Hughes JH Watson S Gray JMFerrier IN Young AH 2005 Neurocognitive impairment ineuthymic patients with bipolar disorder Br J Psychiatry 18632ndash40

Thompson JM Gray JM Hughes JH Watson S Young AHFerrier IN 2007 Impaired working memory monitoring ineuthymic bipolar patients Bipolar Disord 9 478ndash489

Torres IJ Boudreau VG Yatham LN 2007 Neuropsychologicalfunctioning in euthymic bipolar disorder a meta-analysis ActaPsychiatr Scand Suppl 434 17ndash26

Tuulio-Henriksson A Partonen T Suvisaari J Haukka JLoumlnnqvist J 2004 Age at onset and cognitive functioning inschizophrenia Br J Psychiatry 185 215ndash219

Van Gorp WG Altshuler L Theberge DC Wilkins J Dixon W1998 Cognitive impairment in euthymic patients with and withoutprior alcohol dependence Arch Gen Psychiatry 55 41ndash46

Van Gorp WG Altshuller L Theberge DC Mintz J 1999Declarative and procedural memory in bipolar disorder BiolPsychiatry 46 525ndash531

Varga M Magnusson A Flekkoy K Ronneberg U OpjordsmoenS 2006 Insight symptoms and neurocognition in bipolar Ipatients J Affect Disord 91 1ndash9

Wechsler D 1981 Wechsler Adult Intelligence Scale^mdash Revised

Psychological Corporation New YorkWechsler D 1987 Wechsler Memory Scale

^mdash Revised Manual The

Psychological Corporation New YorkWood SJ Brewer WJ Koutsouradis P Phillips LJ Francey SM

Proffitt TM Yung AR Jackson HJMcGorry PD Pantelis Cin press Cognitive decline following psychosis onset data from thePACE clinic Br J Psychiatry

Zalla T Joyce C Szoke A Schurhoff F Pillon B Komano OPerez-Diaz F Bellivier F Alter C Dubois B Rouillon FHoude O Leboyer M 2004 Executive dysfunctions as potentialmarkers of familial vulnerability to bipolar disorder and schizo-phrenia Psychiatry Res 121 207ndash217

Zubieta JK Huguelet P O Neil RL Giordani BJ 2001Cognitive function in euthymic bipolar I disorder Psychiatry Res(102) 9ndash20 2001

R


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Contents

1 Introduction 02 Method 0

21 Neuropsychological variables 0211 Verbal learning and memory 0212 Visual memory 0213 Sustained attention 0214 Processing speed 0215 Verbal fluency 0216 Set shifting 0217 Working memory 0218 Response inhibition 0219 Visuospatial abilities 02110 General intelligence 0

22 Statistical analyses 03 Results 0

31 Remission 032 Relatives 0

4 Discussion 0Role of funding source 0Conflict of interest 05 Uncited reference 0References 0

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1 Introduction

Endophenotypes are intermediate phenotypes thatare considered a more promising index of underlyinggenetic liability than the illness itself To be acceptedas an endophenotype intermediate phenotypes mustmeet several criteria proposed by Gottesman andGould (2003) Endophenotypes should be associatedwith illness they should be heritable and they shouldco-segregate within families with illness There aretwo additional conditions needed to meet criteria foran endophenotype (a) the endophenotype must bestate independent it must be demonstrable in remittedpatients (b) The endophenotypes should be morefrequent in unaffected relatives of patients comparedto the general population In this context while thereis convincing evidence regarding the value ofcognitive deficits as putative endophenotypes ofschizophrenia (Gur et al 2007 Pantelis et al inpress Snitz et al 2006) the value of such markers asendophenotypes of bipolar disorder (BD) is a largelyunderstudied subject

With respect to the first criterion (that markers arestate independent and observable in remitted patients)the most consistent cognitive findings that mayrepresent potential endophenotypes within euthymic


TEpatients with BD are verbal memory executive functionand sustained attention deficits Recently three meta-analytic reports (Arts et al in press Robinson et al2006 Torres et al 2007) provided further evidence forcognitive impairment in BD However these findingsshould be interpreted cautiously as it is quite likely thatconfounding factors such as medication chronicity andsubthreshold affective symptoms are also contributingto the observed findings Furthermore it is still notknown whether these findings are signs of multipleindependent cognitive impairments or whether they arereflections of an underlying a single more basiccognitive abnormality (for example psychomotorspeed or working memory)

Regarding the second criterion (that markers are morefrequently observed in unaffected relatives of patients incomparison to the general population) only a handful ofstudies have investigated cognitive deficits of unaffectedrelatives of affected patients The findings of these studieshave been less consistent than those conducted in affectedpatients themselves For example while several studiessuggest that verbal memory deficits are themost prominentfindings in relatives ofBDpatients (Gourovitch et al 1999Keri et al 2001) other studies do not support this notion(Ferrier et al 2004 Clark et al 2005ab) The evidenceregarding executive dysfunction appears to be similarly


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a =Cohen dt1253


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3 Results

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^045



^minus005 SE=002 p=



^00014 14 studies)


^005 SE=002


^0011




mance (B=^001 SE=0004 p=

^001 12 studies)


^11 SE=043


^066 SE=027




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^0025 14 studies)


^003) and FAS

(B=^098 SE=0

^45 p=

^003 10 studies)


^1^69 SE=0

^41 pb

^0^001) Working


^0^76 SE=0

^15 pb

^0^001 7 studies)

32 Relatives





^minus0022 SE=0007 p=

^0003




^057 SE=024 p=

^0022 8



^068


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^00025 5

studies)

4 Discussion




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617

618

619

620

621

622

623

624

625

626

627

628

629

630

631

632

633

634

635

636

637

638

639

640

641

642

643

644


ARTICLE IN PRESS

UNCO

RREC






TEDPR

OOF





645

646

647

648

649

650

651

652

653

654

655

656

657

658

659

660

661

662

663

664

665Q13

666

667

668

669

670

671

672

673

674

675

676

677Q14

678

679

680

681

682

683

684

685

686

687

688

689

690

691

692

693

694

695

696

697

698

699

700

701

702

703

704

705

706

707

708

709

710

711

712

713

714

715

716

717

718

719

720

721

722

723

724

725

726

727

728

729

730

731

732

733

734

735

736

737

738

739

740

741

742

743


ARTICLE IN PRESS

UNCO

RREC




TEDPR

OOF







5 Uncited reference



744

745

746

747

748

749

750

751

752

753Q15754

755

756

757

758

759

760

761

762

763

764

765

766

767

768

769

770

771

772

773

774

775

776

777

778

779

780Q16781

782

783

784

785

786

787

788

789

790

791

792

793

794

795

796

797

798

799

800

801

802

803

804

805

806

807

808

809

810

811

812

813

814

815

816

817

818

819

820

821

822

823

824

825

826

827

828

829

830

831

832

833

834

835

836

837

838

839

840

841

842

843

844

845

846

847

848

849

850

851

852

853

854

855

856

857

858

859

860

861

862

863

864

865

866


ARTICLE IN PRESS

UNCO

RREC

^References



















TEDPR

OOF


















867

868

869

870

871

872

873

874

875

876

877

878

879

880

881

882

883

884

885

886

887

888

889

890

891

892

893

894

895

896

897

898

899

900

901

902

903

904

905

906

907

908

909

910

911

912

913

914

915

916

917

918

919

920

921

922

923

924

925

926

927

928

929

930

931

932

933

934

935

936 Q17937

938

939

940

941

942

943

944

945

946

947

948

949

950

951

952

953

954

955

956

957

958

959

960

961

962 Q18963

964

965

966

967

968

969

970

971

972

973

974

975

976

977

978

979

980

981

982

983

984

985

986

987

988

989

990


ARTICLE IN PRESS

UNCO

RREC




















TEDPR

OOF






















107 187ndash192


991

992

993

994

995

996

997

998

999

1000

1001

1002

1003

1004

1005

1006

1007

1008

1009

1010

1011

1012

1013

1014

1015

1016

1017

1018

1019

1020

1021

1022

1023

1024

1025

1026

1027

1028

1029

1030

1031

1032

1033

1034

1035

1036

1037

1038

1039

1040

1041

1042

1043

1044

1045

1046

1047

1048

1049

1050

1051

1052

1053

1054

1055

1056

1057

1058

1059

1060

1061

1062

1063

1064

1065

1066

1067

1068

1069

1070


ARTICLE IN PRESS

EC












UNCO

R


TEDPR

OOF















R


106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178 Q5

179 Q6

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198 Q7

199

200

201

202

203

204


ARTICLE IN PRESS

UNCO

RREC



2 Method



TEDPR

OOF








UNCO

RREC

TEDPR

OOF

Table 1t11





ARTICLE IN PRESS


UNCO

RREC

TEDPR

OOF






ARTICLE IN PRESS


UNCO

RREC

TEDPR

OOF





ARTICLE IN PRESS


UNCO

RREC

TEDPR

OOF






ARTICLE IN PRESS


F

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238Q8

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273




a =Cohen dt1253


ARTICLE IN PRESS

UNCO

RREC














TEDPR












UNCO

RREC

TEDPR

OOF

Table 2t21






ARTICLE IN PRESS


CORR

ECTEDPR

OOF

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289




a =Cohen dt2108


ARTICLE IN PRESS






290

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

341

342

343

344

345

346

347

t31t32

t33

t34

t35t36

t37

t38

t39t310

t311

t312

t313t314

t315

t316

t317t318

t319

t320t321

t322

t323


ARTICLE IN PRESS









ôutcomes


UNCO

RRECTable 3





TEDPR

OOF



ntrol differences





CTED

PROO

F348

349

350

351

352

353

354

355

356

357

358

359

360

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375

376

377

378

379

380

381

382

383

384 Q9

Fig 1


ARTICLE IN PRESS

UNCO



3 Results

31 Remission







PROO

F385

386

387

388

389

390

391 Q10

392

393

394

395

396

Fig 2

t41t42

t43

t44

t45

t46t47

t48

t49t410

t411

t412

t413t414

t415

t416

t417t418

t419

t420t421

t422

t423


ARTICLE IN PRESS


UNCO

RRECTable 4







ntrol differences





F

397

398

399

400

401Q11

402

403

404

405

406

407

408

409

410

411

412

413

414

415

416

417

418

419

420

421

422

423

424

425

426

427

428

429

430

431

432

433

434

435

436

437

438

439

440

Fig 3


ARTICLE IN PRESS

REC




UNCO

R

Fig 4


TEDPR


^045



^minus005 SE=002 p=



^00014 14 studies)


^005 SE=002


^0011




mance (B=^001 SE=0004 p=

^001 12 studies)


^11 SE=043


^066 SE=027




441

442

443

444

445

446

447

448

449

450

451

452

453

454

455

456

457

458

459

460

461

462

463

464

465

466

467

468

469

470

471

472

473

474

475

476

477

478

479

480

481

482

483

484

485

486

487

488

489

490

491

492

493

494

495

496

497

498

499

500

501

502

503

504

505

506

507

508

509

510

511

512

513

514

515

516

517

518

519

520

521

522

523

524

525

526

527

528

529 Q12

530

531

532

533

534

535

536

537

538

539

540


ARTICLE IN PRESS

UNCO

RREC


^0025 14 studies)


^003) and FAS

(B=^098 SE=0

^45 p=

^003 10 studies)


^1^69 SE=0

^41 pb

^0^001) Working


^0^76 SE=0

^15 pb

^0^001 7 studies)

32 Relatives





^minus0022 SE=0007 p=

^0003




^057 SE=024 p=

^0022 8



^068


(B=^141 SE=047 p=



TEDPR

OOF


^00025 5

studies)

4 Discussion




541

542

543

544

545

546

547

548

549

550

551

552

553

554

555

556

557

558

559

560

561

562

563

564

565

566

567

568

569

570

571

572

573

574

575

576

577

578

579

580

581

582

583

584

585

586

587

588

589

590

591

592

593

594

595

596

597

598

599

600

601

602

603

604

605

606

607

608

609

610

611

612

613

614

615

616

617

618

619

620

621

622

623

624

625

626

627

628

629

630

631

632

633

634

635

636

637

638

639

640

641

642

643

644


ARTICLE IN PRESS

UNCO

RREC






TEDPR

OOF





645

646

647

648

649

650

651

652

653

654

655

656

657

658

659

660

661

662

663

664

665Q13

666

667

668

669

670

671

672

673

674

675

676

677Q14

678

679

680

681

682

683

684

685

686

687

688

689

690

691

692

693

694

695

696

697

698

699

700

701

702

703

704

705

706

707

708

709

710

711

712

713

714

715

716

717

718

719

720

721

722

723

724

725

726

727

728

729

730

731

732

733

734

735

736

737

738

739

740

741

742

743


ARTICLE IN PRESS

UNCO

RREC




TEDPR

OOF







5 Uncited reference



744

745

746

747

748

749

750

751

752

753Q15754

755

756

757

758

759

760

761

762

763

764

765

766

767

768

769

770

771

772

773

774

775

776

777

778

779

780Q16781

782

783

784

785

786

787

788

789

790

791

792

793

794

795

796

797

798

799

800

801

802

803

804

805

806

807

808

809

810

811

812

813

814

815

816

817

818

819

820

821

822

823

824

825

826

827

828

829

830

831

832

833

834

835

836

837

838

839

840

841

842

843

844

845

846

847

848

849

850

851

852

853

854

855

856

857

858

859

860

861

862

863

864

865

866


ARTICLE IN PRESS

UNCO

RREC

^References



















TEDPR

OOF


















867

868

869

870

871

872

873

874

875

876

877

878

879

880

881

882

883

884

885

886

887

888

889

890

891

892

893

894

895

896

897

898

899

900

901

902

903

904

905

906

907

908

909

910

911

912

913

914

915

916

917

918

919

920

921

922

923

924

925

926

927

928

929

930

931

932

933

934

935

936 Q17937

938

939

940

941

942

943

944

945

946

947

948

949

950

951

952

953

954

955

956

957

958

959

960

961

962 Q18963

964

965

966

967

968

969

970

971

972

973

974

975

976

977

978

979

980

981

982

983

984

985

986

987

988

989

990


ARTICLE IN PRESS

UNCO

RREC




















TEDPR

OOF






















107 187ndash192


991

992

993

994

995

996

997

998

999

1000

1001

1002

1003

1004

1005

1006

1007

1008

1009

1010

1011

1012

1013

1014

1015

1016

1017

1018

1019

1020

1021

1022

1023

1024

1025

1026

1027

1028

1029

1030

1031

1032

1033

1034

1035

1036

1037

1038

1039

1040

1041

1042

1043

1044

1045

1046

1047

1048

1049

1050

1051

1052

1053

1054

1055

1056

1057

1058

1059

1060

1061

1062

1063

1064

1065

1066

1067

1068

1069

1070


ARTICLE IN PRESS

EC












UNCO

R


TEDPR

OOF















R


UNCO

RREC

TEDPR

OOF

Table 1t11





ARTICLE IN PRESS


UNCO

RREC

TEDPR

OOF






ARTICLE IN PRESS


UNCO

RREC

TEDPR

OOF





ARTICLE IN PRESS


UNCO

RREC

TEDPR

OOF






ARTICLE IN PRESS


F

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238Q8

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273




a =Cohen dt1253


ARTICLE IN PRESS

UNCO

RREC














TEDPR












UNCO

RREC

TEDPR

OOF

Table 2t21






ARTICLE IN PRESS


CORR

ECTEDPR

OOF

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289




a =Cohen dt2108


ARTICLE IN PRESS






290

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

341

342

343

344

345

346

347

t31t32

t33

t34

t35t36

t37

t38

t39t310

t311

t312

t313t314

t315

t316

t317t318

t319

t320t321

t322

t323


ARTICLE IN PRESS









ôutcomes


UNCO

RRECTable 3





TEDPR

OOF



ntrol differences





CTED

PROO

F348

349

350

351

352

353

354

355

356

357

358

359

360

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375

376

377

378

379

380

381

382

383

384 Q9

Fig 1


ARTICLE IN PRESS

UNCO



3 Results

31 Remission







PROO

F385

386

387

388

389

390

391 Q10

392

393

394

395

396

Fig 2

t41t42

t43

t44

t45

t46t47

t48

t49t410

t411

t412

t413t414

t415

t416

t417t418

t419

t420t421

t422

t423


ARTICLE IN PRESS


UNCO

RRECTable 4







ntrol differences





F

397

398

399

400

401Q11

402

403

404

405

406

407

408

409

410

411

412

413

414

415

416

417

418

419

420

421

422

423

424

425

426

427

428

429

430

431

432

433

434

435

436

437

438

439

440

Fig 3


ARTICLE IN PRESS

REC




UNCO

R

Fig 4


TEDPR


^045



^minus005 SE=002 p=



^00014 14 studies)


^005 SE=002


^0011




mance (B=^001 SE=0004 p=

^001 12 studies)


^11 SE=043


^066 SE=027




441

442

443

444

445

446

447

448

449

450

451

452

453

454

455

456

457

458

459

460

461

462

463

464

465

466

467

468

469

470

471

472

473

474

475

476

477

478

479

480

481

482

483

484

485

486

487

488

489

490

491

492

493

494

495

496

497

498

499

500

501

502

503

504

505

506

507

508

509

510

511

512

513

514

515

516

517

518

519

520

521

522

523

524

525

526

527

528

529 Q12

530

531

532

533

534

535

536

537

538

539

540


ARTICLE IN PRESS

UNCO

RREC


^0025 14 studies)


^003) and FAS

(B=^098 SE=0

^45 p=

^003 10 studies)


^1^69 SE=0

^41 pb

^0^001) Working


^0^76 SE=0

^15 pb

^0^001 7 studies)

32 Relatives





^minus0022 SE=0007 p=

^0003




^057 SE=024 p=

^0022 8



^068


(B=^141 SE=047 p=



TEDPR

OOF


^00025 5

studies)

4 Discussion




541

542

543

544

545

546

547

548

549

550

551

552

553

554

555

556

557

558

559

560

561

562

563

564

565

566

567

568

569

570

571

572

573

574

575

576

577

578

579

580

581

582

583

584

585

586

587

588

589

590

591

592

593

594

595

596

597

598

599

600

601

602

603

604

605

606

607

608

609

610

611

612

613

614

615

616

617

618

619

620

621

622

623

624

625

626

627

628

629

630

631

632

633

634

635

636

637

638

639

640

641

642

643

644


ARTICLE IN PRESS

UNCO

RREC






TEDPR

OOF





645

646

647

648

649

650

651

652

653

654

655

656

657

658

659

660

661

662

663

664

665Q13

666

667

668

669

670

671

672

673

674

675

676

677Q14

678

679

680

681

682

683

684

685

686

687

688

689

690

691

692

693

694

695

696

697

698

699

700

701

702

703

704

705

706

707

708

709

710

711

712

713

714

715

716

717

718

719

720

721

722

723

724

725

726

727

728

729

730

731

732

733

734

735

736

737

738

739

740

741

742

743


ARTICLE IN PRESS

UNCO

RREC




TEDPR

OOF







5 Uncited reference



744

745

746

747

748

749

750

751

752

753Q15754

755

756

757

758

759

760

761

762

763

764

765

766

767

768

769

770

771

772

773

774

775

776

777

778

779

780Q16781

782

783

784

785

786

787

788

789

790

791

792

793

794

795

796

797

798

799

800

801

802

803

804

805

806

807

808

809

810

811

812

813

814

815

816

817

818

819

820

821

822

823

824

825

826

827

828

829

830

831

832

833

834

835

836

837

838

839

840

841

842

843

844

845

846

847

848

849

850

851

852

853

854

855

856

857

858

859

860

861

862

863

864

865

866


ARTICLE IN PRESS

UNCO

RREC

^References



















TEDPR

OOF


















867

868

869

870

871

872

873

874

875

876

877

878

879

880

881

882

883

884

885

886

887

888

889

890

891

892

893

894

895

896

897

898

899

900

901

902

903

904

905

906

907

908

909

910

911

912

913

914

915

916

917

918

919

920

921

922

923

924

925

926

927

928

929

930

931

932

933

934

935

936 Q17937

938

939

940

941

942

943

944

945

946

947

948

949

950

951

952

953

954

955

956

957

958

959

960

961

962 Q18963

964

965

966

967

968

969

970

971

972

973

974

975

976

977

978

979

980

981

982

983

984

985

986

987

988

989

990


ARTICLE IN PRESS

UNCO

RREC




















TEDPR

OOF






















107 187ndash192


991

992

993

994

995

996

997

998

999

1000

1001

1002

1003

1004

1005

1006

1007

1008

1009

1010

1011

1012

1013

1014

1015

1016

1017

1018

1019

1020

1021

1022

1023

1024

1025

1026

1027

1028

1029

1030

1031

1032

1033

1034

1035

1036

1037

1038

1039

1040

1041

1042

1043

1044

1045

1046

1047

1048

1049

1050

1051

1052

1053

1054

1055

1056

1057

1058

1059

1060

1061

1062

1063

1064

1065

1066

1067

1068

1069

1070


ARTICLE IN PRESS

EC












UNCO

R


TEDPR

OOF















R


UNCO

RREC

TEDPR

OOF






ARTICLE IN PRESS


UNCO

RREC

TEDPR

OOF





ARTICLE IN PRESS


UNCO

RREC

TEDPR

OOF






ARTICLE IN PRESS


F

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238Q8

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273




a =Cohen dt1253


ARTICLE IN PRESS

UNCO

RREC














TEDPR












UNCO

RREC

TEDPR

OOF

Table 2t21






ARTICLE IN PRESS


CORR

ECTEDPR

OOF

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289




a =Cohen dt2108


ARTICLE IN PRESS






290

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

341

342

343

344

345

346

347

t31t32

t33

t34

t35t36

t37

t38

t39t310

t311

t312

t313t314

t315

t316

t317t318

t319

t320t321

t322

t323


ARTICLE IN PRESS









ôutcomes


UNCO

RRECTable 3





TEDPR

OOF



ntrol differences





CTED

PROO

F348

349

350

351

352

353

354

355

356

357

358

359

360

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375

376

377

378

379

380

381

382

383

384 Q9

Fig 1


ARTICLE IN PRESS

UNCO



3 Results

31 Remission







PROO

F385

386

387

388

389

390

391 Q10

392

393

394

395

396

Fig 2

t41t42

t43

t44

t45

t46t47

t48

t49t410

t411

t412

t413t414

t415

t416

t417t418

t419

t420t421

t422

t423


ARTICLE IN PRESS


UNCO

RRECTable 4







ntrol differences





F

397

398

399

400

401Q11

402

403

404

405

406

407

408

409

410

411

412

413

414

415

416

417

418

419

420

421

422

423

424

425

426

427

428

429

430

431

432

433

434

435

436

437

438

439

440

Fig 3


ARTICLE IN PRESS

REC




UNCO

R

Fig 4


TEDPR


^045



^minus005 SE=002 p=



^00014 14 studies)


^005 SE=002


^0011




mance (B=^001 SE=0004 p=

^001 12 studies)


^11 SE=043


^066 SE=027




441

442

443

444

445

446

447

448

449

450

451

452

453

454

455

456

457

458

459

460

461

462

463

464

465

466

467

468

469

470

471

472

473

474

475

476

477

478

479

480

481

482

483

484

485

486

487

488

489

490

491

492

493

494

495

496

497

498

499

500

501

502

503

504

505

506

507

508

509

510

511

512

513

514

515

516

517

518

519

520

521

522

523

524

525

526

527

528

529 Q12

530

531

532

533

534

535

536

537

538

539

540


ARTICLE IN PRESS

UNCO

RREC


^0025 14 studies)


^003) and FAS

(B=^098 SE=0

^45 p=

^003 10 studies)


^1^69 SE=0

^41 pb

^0^001) Working


^0^76 SE=0

^15 pb

^0^001 7 studies)

32 Relatives





^minus0022 SE=0007 p=

^0003




^057 SE=024 p=

^0022 8



^068


(B=^141 SE=047 p=



TEDPR

OOF


^00025 5

studies)

4 Discussion




541

542

543

544

545

546

547

548

549

550

551

552

553

554

555

556

557

558

559

560

561

562

563

564

565

566

567

568

569

570

571

572

573

574

575

576

577

578

579

580

581

582

583

584

585

586

587

588

589

590

591

592

593

594

595

596

597

598

599

600

601

602

603

604

605

606

607

608

609

610

611

612

613

614

615

616

617

618

619

620

621

622

623

624

625

626

627

628

629

630

631

632

633

634

635

636

637

638

639

640

641

642

643

644


ARTICLE IN PRESS

UNCO

RREC






TEDPR

OOF





645

646

647

648

649

650

651

652

653

654

655

656

657

658

659

660

661

662

663

664

665Q13

666

667

668

669

670

671

672

673

674

675

676

677Q14

678

679

680

681

682

683

684

685

686

687

688

689

690

691

692

693

694

695

696

697

698

699

700

701

702

703

704

705

706

707

708

709

710

711

712

713

714

715

716

717

718

719

720

721

722

723

724

725

726

727

728

729

730

731

732

733

734

735

736

737

738

739

740

741

742

743


ARTICLE IN PRESS

UNCO

RREC




TEDPR

OOF







5 Uncited reference



744

745

746

747

748

749

750

751

752

753Q15754

755

756

757

758

759

760

761

762

763

764

765

766

767

768

769

770

771

772

773

774

775

776

777

778

779

780Q16781

782

783

784

785

786

787

788

789

790

791

792

793

794

795

796

797

798

799

800

801

802

803

804

805

806

807

808

809

810

811

812

813

814

815

816

817

818

819

820

821

822

823

824

825

826

827

828

829

830

831

832

833

834

835

836

837

838

839

840

841

842

843

844

845

846

847

848

849

850

851

852

853

854

855

856

857

858

859

860

861

862

863

864

865

866


ARTICLE IN PRESS

UNCO

RREC

^References



















TEDPR

OOF


















867

868

869

870

871

872

873

874

875

876

877

878

879

880

881

882

883

884

885

886

887

888

889

890

891

892

893

894

895

896

897

898

899

900

901

902

903

904

905

906

907

908

909

910

911

912

913

914

915

916

917

918

919

920

921

922

923

924

925

926

927

928

929

930

931

932

933

934

935

936 Q17937

938

939

940

941

942

943

944

945

946

947

948

949

950

951

952

953

954

955

956

957

958

959

960

961

962 Q18963

964

965

966

967

968

969

970

971

972

973

974

975

976

977

978

979

980

981

982

983

984

985

986

987

988

989

990


ARTICLE IN PRESS

UNCO

RREC




















TEDPR

OOF






















107 187ndash192


991

992

993

994

995

996

997

998

999

1000

1001

1002

1003

1004

1005

1006

1007

1008

1009

1010

1011

1012

1013

1014

1015

1016

1017

1018

1019

1020

1021

1022

1023

1024

1025

1026

1027

1028

1029

1030

1031

1032

1033

1034

1035

1036

1037

1038

1039

1040

1041

1042

1043

1044

1045

1046

1047

1048

1049

1050

1051

1052

1053

1054

1055

1056

1057

1058

1059

1060

1061

1062

1063

1064

1065

1066

1067

1068

1069

1070


ARTICLE IN PRESS

EC












UNCO

R


TEDPR

OOF















R


UNCO

RREC

TEDPR

OOF





ARTICLE IN PRESS


UNCO

RREC

TEDPR

OOF






ARTICLE IN PRESS


F

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238Q8

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273




a =Cohen dt1253


ARTICLE IN PRESS

UNCO

RREC














TEDPR












UNCO

RREC

TEDPR

OOF

Table 2t21






ARTICLE IN PRESS


CORR

ECTEDPR

OOF

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289




a =Cohen dt2108


ARTICLE IN PRESS






290

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

341

342

343

344

345

346

347

t31t32

t33

t34

t35t36

t37

t38

t39t310

t311

t312

t313t314

t315

t316

t317t318

t319

t320t321

t322

t323


ARTICLE IN PRESS









ôutcomes


UNCO

RRECTable 3





TEDPR

OOF



ntrol differences





CTED

PROO

F348

349

350

351

352

353

354

355

356

357

358

359

360

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375

376

377

378

379

380

381

382

383

384 Q9

Fig 1


ARTICLE IN PRESS

UNCO



3 Results

31 Remission







PROO

F385

386

387

388

389

390

391 Q10

392

393

394

395

396

Fig 2

t41t42

t43

t44

t45

t46t47

t48

t49t410

t411

t412

t413t414

t415

t416

t417t418

t419

t420t421

t422

t423


ARTICLE IN PRESS


UNCO

RRECTable 4







ntrol differences





F

397

398

399

400

401Q11

402

403

404

405

406

407

408

409

410

411

412

413

414

415

416

417

418

419

420

421

422

423

424

425

426

427

428

429

430

431

432

433

434

435

436

437

438

439

440

Fig 3


ARTICLE IN PRESS

REC




UNCO

R

Fig 4


TEDPR


^045



^minus005 SE=002 p=



^00014 14 studies)


^005 SE=002


^0011




mance (B=^001 SE=0004 p=

^001 12 studies)


^11 SE=043


^066 SE=027




441

442

443

444

445

446

447

448

449

450

451

452

453

454

455

456

457

458

459

460

461

462

463

464

465

466

467

468

469

470

471

472

473

474

475

476

477

478

479

480

481

482

483

484

485

486

487

488

489

490

491

492

493

494

495

496

497

498

499

500

501

502

503

504

505

506

507

508

509

510

511

512

513

514

515

516

517

518

519

520

521

522

523

524

525

526

527

528

529 Q12

530

531

532

533

534

535

536

537

538

539

540


ARTICLE IN PRESS

UNCO

RREC


^0025 14 studies)


^003) and FAS

(B=^098 SE=0

^45 p=

^003 10 studies)


^1^69 SE=0

^41 pb

^0^001) Working


^0^76 SE=0

^15 pb

^0^001 7 studies)

32 Relatives





^minus0022 SE=0007 p=

^0003




^057 SE=024 p=

^0022 8



^068


(B=^141 SE=047 p=



TEDPR

OOF


^00025 5

studies)

4 Discussion




541

542

543

544

545

546

547

548

549

550

551

552

553

554

555

556

557

558

559

560

561

562

563

564

565

566

567

568

569

570

571

572

573

574

575

576

577

578

579

580

581

582

583

584

585

586

587

588

589

590

591

592

593

594

595

596

597

598

599

600

601

602

603

604

605

606

607

608

609

610

611

612

613

614

615

616

617

618

619

620

621

622

623

624

625

626

627

628

629

630

631

632

633

634

635

636

637

638

639

640

641

642

643

644


ARTICLE IN PRESS

UNCO

RREC






TEDPR

OOF





645

646

647

648

649

650

651

652

653

654

655

656

657

658

659

660

661

662

663

664

665Q13

666

667

668

669

670

671

672

673

674

675

676

677Q14

678

679

680

681

682

683

684

685

686

687

688

689

690

691

692

693

694

695

696

697

698

699

700

701

702

703

704

705

706

707

708

709

710

711

712

713

714

715

716

717

718

719

720

721

722

723

724

725

726

727

728

729

730

731

732

733

734

735

736

737

738

739

740

741

742

743


ARTICLE IN PRESS

UNCO

RREC




TEDPR

OOF







5 Uncited reference



744

745

746

747

748

749

750

751

752

753Q15754

755

756

757

758

759

760

761

762

763

764

765

766

767

768

769

770

771

772

773

774

775

776

777

778

779

780Q16781

782

783

784

785

786

787

788

789

790

791

792

793

794

795

796

797

798

799

800

801

802

803

804

805

806

807

808

809

810

811

812

813

814

815

816

817

818

819

820

821

822

823

824

825

826

827

828

829

830

831

832

833

834

835

836

837

838

839

840

841

842

843

844

845

846

847

848

849

850

851

852

853

854

855

856

857

858

859

860

861

862

863

864

865

866


ARTICLE IN PRESS

UNCO

RREC

^References



















TEDPR

OOF


















867

868

869

870

871

872

873

874

875

876

877

878

879

880

881

882

883

884

885

886

887

888

889

890

891

892

893

894

895

896

897

898

899

900

901

902

903

904

905

906

907

908

909

910

911

912

913

914

915

916

917

918

919

920

921

922

923

924

925

926

927

928

929

930

931

932

933

934

935

936 Q17937

938

939

940

941

942

943

944

945

946

947

948

949

950

951

952

953

954

955

956

957

958

959

960

961

962 Q18963

964

965

966

967

968

969

970

971

972

973

974

975

976

977

978

979

980

981

982

983

984

985

986

987

988

989

990


ARTICLE IN PRESS

UNCO

RREC




















TEDPR

OOF






















107 187ndash192


991

992

993

994

995

996

997

998

999

1000

1001

1002

1003

1004

1005

1006

1007

1008

1009

1010

1011

1012

1013

1014

1015

1016

1017

1018

1019

1020

1021

1022

1023

1024

1025

1026

1027

1028

1029

1030

1031

1032

1033

1034

1035

1036

1037

1038

1039

1040

1041

1042

1043

1044

1045

1046

1047

1048

1049

1050

1051

1052

1053

1054

1055

1056

1057

1058

1059

1060

1061

1062

1063

1064

1065

1066

1067

1068

1069

1070


ARTICLE IN PRESS

EC












UNCO

R


TEDPR

OOF















R


UNCO

RREC

TEDPR

OOF






ARTICLE IN PRESS


F

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238Q8

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273




a =Cohen dt1253


ARTICLE IN PRESS

UNCO

RREC














TEDPR












UNCO

RREC

TEDPR

OOF

Table 2t21






ARTICLE IN PRESS


CORR

ECTEDPR

OOF

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289




a =Cohen dt2108


ARTICLE IN PRESS






290

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

341

342

343

344

345

346

347

t31t32

t33

t34

t35t36

t37

t38

t39t310

t311

t312

t313t314

t315

t316

t317t318

t319

t320t321

t322

t323


ARTICLE IN PRESS









ôutcomes


UNCO

RRECTable 3





TEDPR

OOF



ntrol differences





CTED

PROO

F348

349

350

351

352

353

354

355

356

357

358

359

360

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375

376

377

378

379

380

381

382

383

384 Q9

Fig 1


ARTICLE IN PRESS

UNCO



3 Results

31 Remission







PROO

F385

386

387

388

389

390

391 Q10

392

393

394

395

396

Fig 2

t41t42

t43

t44

t45

t46t47

t48

t49t410

t411

t412

t413t414

t415

t416

t417t418

t419

t420t421

t422

t423


ARTICLE IN PRESS


UNCO

RRECTable 4







ntrol differences





F

397

398

399

400

401Q11

402

403

404

405

406

407

408

409

410

411

412

413

414

415

416

417

418

419

420

421

422

423

424

425

426

427

428

429

430

431

432

433

434

435

436

437

438

439

440

Fig 3


ARTICLE IN PRESS

REC




UNCO

R

Fig 4


TEDPR


^045



^minus005 SE=002 p=



^00014 14 studies)


^005 SE=002


^0011




mance (B=^001 SE=0004 p=

^001 12 studies)


^11 SE=043


^066 SE=027




441

442

443

444

445

446

447

448

449

450

451

452

453

454

455

456

457

458

459

460

461

462

463

464

465

466

467

468

469

470

471

472

473

474

475

476

477

478

479

480

481

482

483

484

485

486

487

488

489

490

491

492

493

494

495

496

497

498

499

500

501

502

503

504

505

506

507

508

509

510

511

512

513

514

515

516

517

518

519

520

521

522

523

524

525

526

527

528

529 Q12

530

531

532

533

534

535

536

537

538

539

540


ARTICLE IN PRESS

UNCO

RREC


^0025 14 studies)


^003) and FAS

(B=^098 SE=0

^45 p=

^003 10 studies)


^1^69 SE=0

^41 pb

^0^001) Working


^0^76 SE=0

^15 pb

^0^001 7 studies)

32 Relatives





^minus0022 SE=0007 p=

^0003




^057 SE=024 p=

^0022 8



^068


(B=^141 SE=047 p=



TEDPR

OOF


^00025 5

studies)

4 Discussion




541

542

543

544

545

546

547

548

549

550

551

552

553

554

555

556

557

558

559

560

561

562

563

564

565

566

567

568

569

570

571

572

573

574

575

576

577

578

579

580

581

582

583

584

585

586

587

588

589

590

591

592

593

594

595

596

597

598

599

600

601

602

603

604

605

606

607

608

609

610

611

612

613

614

615

616

617

618

619

620

621

622

623

624

625

626

627

628

629

630

631

632

633

634

635

636

637

638

639

640

641

642

643

644


ARTICLE IN PRESS

UNCO

RREC






TEDPR

OOF





645

646

647

648

649

650

651

652

653

654

655

656

657

658

659

660

661

662

663

664

665Q13

666

667

668

669

670

671

672

673

674

675

676

677Q14

678

679

680

681

682

683

684

685

686

687

688

689

690

691

692

693

694

695

696

697

698

699

700

701

702

703

704

705

706

707

708

709

710

711

712

713

714

715

716

717

718

719

720

721

722

723

724

725

726

727

728

729

730

731

732

733

734

735

736

737

738

739

740

741

742

743


ARTICLE IN PRESS

UNCO

RREC




TEDPR

OOF







5 Uncited reference



744

745

746

747

748

749

750

751

752

753Q15754

755

756

757

758

759

760

761

762

763

764

765

766

767

768

769

770

771

772

773

774

775

776

777

778

779

780Q16781

782

783

784

785

786

787

788

789

790

791

792

793

794

795

796

797

798

799

800

801

802

803

804

805

806

807

808

809

810

811

812

813

814

815

816

817

818

819

820

821

822

823

824

825

826

827

828

829

830

831

832

833

834

835

836

837

838

839

840

841

842

843

844

845

846

847

848

849

850

851

852

853

854

855

856

857

858

859

860

861

862

863

864

865

866


ARTICLE IN PRESS

UNCO

RREC

^References



















TEDPR

OOF


















867

868

869

870

871

872

873

874

875

876

877

878

879

880

881

882

883

884

885

886

887

888

889

890

891

892

893

894

895

896

897

898

899

900

901

902

903

904

905

906

907

908

909

910

911

912

913

914

915

916

917

918

919

920

921

922

923

924

925

926

927

928

929

930

931

932

933

934

935

936 Q17937

938

939

940

941

942

943

944

945

946

947

948

949

950

951

952

953

954

955

956

957

958

959

960

961

962 Q18963

964

965

966

967

968

969

970

971

972

973

974

975

976

977

978

979

980

981

982

983

984

985

986

987

988

989

990


ARTICLE IN PRESS

UNCO

RREC




















TEDPR

OOF






















107 187ndash192


991

992

993

994

995

996

997

998

999

1000

1001

1002

1003

1004

1005

1006

1007

1008

1009

1010

1011

1012

1013

1014

1015

1016

1017

1018

1019

1020

1021

1022

1023

1024

1025

1026

1027

1028

1029

1030

1031

1032

1033

1034

1035

1036

1037

1038

1039

1040

1041

1042

1043

1044

1045

1046

1047

1048

1049

1050

1051

1052

1053

1054

1055

1056

1057

1058

1059

1060

1061

1062

1063

1064

1065

1066

1067

1068

1069

1070


ARTICLE IN PRESS

EC












UNCO

R


TEDPR

OOF















R


F

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238Q8

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273




a =Cohen dt1253


ARTICLE IN PRESS

UNCO

RREC














TEDPR












UNCO

RREC

TEDPR

OOF

Table 2t21






ARTICLE IN PRESS


CORR

ECTEDPR

OOF

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289




a =Cohen dt2108


ARTICLE IN PRESS






290

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

341

342

343

344

345

346

347

t31t32

t33

t34

t35t36

t37

t38

t39t310

t311

t312

t313t314

t315

t316

t317t318

t319

t320t321

t322

t323


ARTICLE IN PRESS









ôutcomes


UNCO

RRECTable 3





TEDPR

OOF



ntrol differences





CTED

PROO

F348

349

350

351

352

353

354

355

356

357

358

359

360

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375

376

377

378

379

380

381

382

383

384 Q9

Fig 1


ARTICLE IN PRESS

UNCO



3 Results

31 Remission







PROO

F385

386

387

388

389

390

391 Q10

392

393

394

395

396

Fig 2

t41t42

t43

t44

t45

t46t47

t48

t49t410

t411

t412

t413t414

t415

t416

t417t418

t419

t420t421

t422

t423


ARTICLE IN PRESS


UNCO

RRECTable 4







ntrol differences





F

397

398

399

400

401Q11

402

403

404

405

406

407

408

409

410

411

412

413

414

415

416

417

418

419

420

421

422

423

424

425

426

427

428

429

430

431

432

433

434

435

436

437

438

439

440

Fig 3


ARTICLE IN PRESS

REC




UNCO

R

Fig 4


TEDPR


^045



^minus005 SE=002 p=



^00014 14 studies)


^005 SE=002


^0011




mance (B=^001 SE=0004 p=

^001 12 studies)


^11 SE=043


^066 SE=027




441

442

443

444

445

446

447

448

449

450

451

452

453

454

455

456

457

458

459

460

461

462

463

464

465

466

467

468

469

470

471

472

473

474

475

476

477

478

479

480

481

482

483

484

485

486

487

488

489

490

491

492

493

494

495

496

497

498

499

500

501

502

503

504

505

506

507

508

509

510

511

512

513

514

515

516

517

518

519

520

521

522

523

524

525

526

527

528

529 Q12

530

531

532

533

534

535

536

537

538

539

540


ARTICLE IN PRESS

UNCO

RREC


^0025 14 studies)


^003) and FAS

(B=^098 SE=0

^45 p=

^003 10 studies)


^1^69 SE=0

^41 pb

^0^001) Working


^0^76 SE=0

^15 pb

^0^001 7 studies)

32 Relatives





^minus0022 SE=0007 p=

^0003




^057 SE=024 p=

^0022 8



^068


(B=^141 SE=047 p=



TEDPR

OOF


^00025 5

studies)

4 Discussion




541

542

543

544

545

546

547

548

549

550

551

552

553

554

555

556

557

558

559

560

561

562

563

564

565

566

567

568

569

570

571

572

573

574

575

576

577

578

579

580

581

582

583

584

585

586

587

588

589

590

591

592

593

594

595

596

597

598

599

600

601

602

603

604

605

606

607

608

609

610

611

612

613

614

615

616

617

618

619

620

621

622

623

624

625

626

627

628

629

630

631

632

633

634

635

636

637

638

639

640

641

642

643

644


ARTICLE IN PRESS

UNCO

RREC






TEDPR

OOF





645

646

647

648

649

650

651

652

653

654

655

656

657

658

659

660

661

662

663

664

665Q13

666

667

668

669

670

671

672

673

674

675

676

677Q14

678

679

680

681

682

683

684

685

686

687

688

689

690

691

692

693

694

695

696

697

698

699

700

701

702

703

704

705

706

707

708

709

710

711

712

713

714

715

716

717

718

719

720

721

722

723

724

725

726

727

728

729

730

731

732

733

734

735

736

737

738

739

740

741

742

743


ARTICLE IN PRESS

UNCO

RREC




TEDPR

OOF







5 Uncited reference



744

745

746

747

748

749

750

751

752

753Q15754

755

756

757

758

759

760

761

762

763

764

765

766

767

768

769

770

771

772

773

774

775

776

777

778

779

780Q16781

782

783

784

785

786

787

788

789

790

791

792

793

794

795

796

797

798

799

800

801

802

803

804

805

806

807

808

809

810

811

812

813

814

815

816

817

818

819

820

821

822

823

824

825

826

827

828

829

830

831

832

833

834

835

836

837

838

839

840

841

842

843

844

845

846

847

848

849

850

851

852

853

854

855

856

857

858

859

860

861

862

863

864

865

866


ARTICLE IN PRESS

UNCO

RREC

^References



















TEDPR

OOF


















867

868

869

870

871

872

873

874

875

876

877

878

879

880

881

882

883

884

885

886

887

888

889

890

891

892

893

894

895

896

897

898

899

900

901

902

903

904

905

906

907

908

909

910

911

912

913

914

915

916

917

918

919

920

921

922

923

924

925

926

927

928

929

930

931

932

933

934

935

936 Q17937

938

939

940

941

942

943

944

945

946

947

948

949

950

951

952

953

954

955

956

957

958

959

960

961

962 Q18963

964

965

966

967

968

969

970

971

972

973

974

975

976

977

978

979

980

981

982

983

984

985

986

987

988

989

990


ARTICLE IN PRESS

UNCO

RREC




















TEDPR

OOF






















107 187ndash192


991

992

993

994

995

996

997

998

999

1000

1001

1002

1003

1004

1005

1006

1007

1008

1009

1010

1011

1012

1013

1014

1015

1016

1017

1018

1019

1020

1021

1022

1023

1024

1025

1026

1027

1028

1029

1030

1031

1032

1033

1034

1035

1036

1037

1038

1039

1040

1041

1042

1043

1044

1045

1046

1047

1048

1049

1050

1051

1052

1053

1054

1055

1056

1057

1058

1059

1060

1061

1062

1063

1064

1065

1066

1067

1068

1069

1070


ARTICLE IN PRESS

EC












UNCO

R


TEDPR

OOF















R


UNCO

RREC

TEDPR

OOF

Table 2t21






ARTICLE IN PRESS


CORR

ECTEDPR

OOF

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289




a =Cohen dt2108


ARTICLE IN PRESS






290

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

341

342

343

344

345

346

347

t31t32

t33

t34

t35t36

t37

t38

t39t310

t311

t312

t313t314

t315

t316

t317t318

t319

t320t321

t322

t323


ARTICLE IN PRESS









ôutcomes


UNCO

RRECTable 3





TEDPR

OOF



ntrol differences





CTED

PROO

F348

349

350

351

352

353

354

355

356

357

358

359

360

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375

376

377

378

379

380

381

382

383

384 Q9

Fig 1


ARTICLE IN PRESS

UNCO



3 Results

31 Remission







PROO

F385

386

387

388

389

390

391 Q10

392

393

394

395

396

Fig 2

t41t42

t43

t44

t45

t46t47

t48

t49t410

t411

t412

t413t414

t415

t416

t417t418

t419

t420t421

t422

t423


ARTICLE IN PRESS


UNCO

RRECTable 4







ntrol differences





F

397

398

399

400

401Q11

402

403

404

405

406

407

408

409

410

411

412

413

414

415

416

417

418

419

420

421

422

423

424

425

426

427

428

429

430

431

432

433

434

435

436

437

438

439

440

Fig 3


ARTICLE IN PRESS

REC




UNCO

R

Fig 4


TEDPR


^045



^minus005 SE=002 p=



^00014 14 studies)


^005 SE=002


^0011




mance (B=^001 SE=0004 p=

^001 12 studies)


^11 SE=043


^066 SE=027




441

442

443

444

445

446

447

448

449

450

451

452

453

454

455

456

457

458

459

460

461

462

463

464

465

466

467

468

469

470

471

472

473

474

475

476

477

478

479

480

481

482

483

484

485

486

487

488

489

490

491

492

493

494

495

496

497

498

499

500

501

502

503

504

505

506

507

508

509

510

511

512

513

514

515

516

517

518

519

520

521

522

523

524

525

526

527

528

529 Q12

530

531

532

533

534

535

536

537

538

539

540


ARTICLE IN PRESS

UNCO

RREC


^0025 14 studies)


^003) and FAS

(B=^098 SE=0

^45 p=

^003 10 studies)


^1^69 SE=0

^41 pb

^0^001) Working


^0^76 SE=0

^15 pb

^0^001 7 studies)

32 Relatives





^minus0022 SE=0007 p=

^0003




^057 SE=024 p=

^0022 8



^068


(B=^141 SE=047 p=



TEDPR

OOF


^00025 5

studies)

4 Discussion




541

542

543

544

545

546

547

548

549

550

551

552

553

554

555

556

557

558

559

560

561

562

563

564

565

566

567

568

569

570

571

572

573

574

575

576

577

578

579

580

581

582

583

584

585

586

587

588

589

590

591

592

593

594

595

596

597

598

599

600

601

602

603

604

605

606

607

608

609

610

611

612

613

614

615

616

617

618

619

620

621

622

623

624

625

626

627

628

629

630

631

632

633

634

635

636

637

638

639

640

641

642

643

644


ARTICLE IN PRESS

UNCO

RREC






TEDPR

OOF





645

646

647

648

649

650

651

652

653

654

655

656

657

658

659

660

661

662

663

664

665Q13

666

667

668

669

670

671

672

673

674

675

676

677Q14

678

679

680

681

682

683

684

685

686

687

688

689

690

691

692

693

694

695

696

697

698

699

700

701

702

703

704

705

706

707

708

709

710

711

712

713

714

715

716

717

718

719

720

721

722

723

724

725

726

727

728

729

730

731

732

733

734

735

736

737

738

739

740

741

742

743


ARTICLE IN PRESS

UNCO

RREC




TEDPR

OOF







5 Uncited reference



744

745

746

747

748

749

750

751

752

753Q15754

755

756

757

758

759

760

761

762

763

764

765

766

767

768

769

770

771

772

773

774

775

776

777

778

779

780Q16781

782

783

784

785

786

787

788

789

790

791

792

793

794

795

796

797

798

799

800

801

802

803

804

805

806

807

808

809

810

811

812

813

814

815

816

817

818

819

820

821

822

823

824

825

826

827

828

829

830

831

832

833

834

835

836

837

838

839

840

841

842

843

844

845

846

847

848

849

850

851

852

853

854

855

856

857

858

859

860

861

862

863

864

865

866


ARTICLE IN PRESS

UNCO

RREC

^References



















TEDPR

OOF


















867

868

869

870

871

872

873

874

875

876

877

878

879

880

881

882

883

884

885

886

887

888

889

890

891

892

893

894

895

896

897

898

899

900

901

902

903

904

905

906

907

908

909

910

911

912

913

914

915

916

917

918

919

920

921

922

923

924

925

926

927

928

929

930

931

932

933

934

935

936 Q17937

938

939

940

941

942

943

944

945

946

947

948

949

950

951

952

953

954

955

956

957

958

959

960

961

962 Q18963

964

965

966

967

968

969

970

971

972

973

974

975

976

977

978

979

980

981

982

983

984

985

986

987

988

989

990


ARTICLE IN PRESS

UNCO

RREC




















TEDPR

OOF






















107 187ndash192


991

992

993

994

995

996

997

998

999

1000

1001

1002

1003

1004

1005

1006

1007

1008

1009

1010

1011

1012

1013

1014

1015

1016

1017

1018

1019

1020

1021

1022

1023

1024

1025

1026

1027

1028

1029

1030

1031

1032

1033

1034

1035

1036

1037

1038

1039

1040

1041

1042

1043

1044

1045

1046

1047

1048

1049

1050

1051

1052

1053

1054

1055

1056

1057

1058

1059

1060

1061

1062

1063

1064

1065

1066

1067

1068

1069

1070


ARTICLE IN PRESS

EC












UNCO

R


TEDPR

OOF















R


CORR

ECTEDPR

OOF

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289




a =Cohen dt2108


ARTICLE IN PRESS






290

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

341

342

343

344

345

346

347

t31t32

t33

t34

t35t36

t37

t38

t39t310

t311

t312

t313t314

t315

t316

t317t318

t319

t320t321

t322

t323


ARTICLE IN PRESS









ôutcomes


UNCO

RRECTable 3





TEDPR

OOF



ntrol differences





CTED

PROO

F348

349

350

351

352

353

354

355

356

357

358

359

360

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375

376

377

378

379

380

381

382

383

384 Q9

Fig 1


ARTICLE IN PRESS

UNCO



3 Results

31 Remission







PROO

F385

386

387

388

389

390

391 Q10

392

393

394

395

396

Fig 2

t41t42

t43

t44

t45

t46t47

t48

t49t410

t411

t412

t413t414

t415

t416

t417t418

t419

t420t421

t422

t423


ARTICLE IN PRESS


UNCO

RRECTable 4







ntrol differences





F

397

398

399

400

401Q11

402

403

404

405

406

407

408

409

410

411

412

413

414

415

416

417

418

419

420

421

422

423

424

425

426

427

428

429

430

431

432

433

434

435

436

437

438

439

440

Fig 3


ARTICLE IN PRESS

REC




UNCO

R

Fig 4


TEDPR


^045



^minus005 SE=002 p=



^00014 14 studies)


^005 SE=002


^0011




mance (B=^001 SE=0004 p=

^001 12 studies)


^11 SE=043


^066 SE=027




441

442

443

444

445

446

447

448

449

450

451

452

453

454

455

456

457

458

459

460

461

462

463

464

465

466

467

468

469

470

471

472

473

474

475

476

477

478

479

480

481

482

483

484

485

486

487

488

489

490

491

492

493

494

495

496

497

498

499

500

501

502

503

504

505

506

507

508

509

510

511

512

513

514

515

516

517

518

519

520

521

522

523

524

525

526

527

528

529 Q12

530

531

532

533

534

535

536

537

538

539

540


ARTICLE IN PRESS

UNCO

RREC


^0025 14 studies)


^003) and FAS

(B=^098 SE=0

^45 p=

^003 10 studies)


^1^69 SE=0

^41 pb

^0^001) Working


^0^76 SE=0

^15 pb

^0^001 7 studies)

32 Relatives





^minus0022 SE=0007 p=

^0003




^057 SE=024 p=

^0022 8



^068


(B=^141 SE=047 p=



TEDPR

OOF


^00025 5

studies)

4 Discussion




541

542

543

544

545

546

547

548

549

550

551

552

553

554

555

556

557

558

559

560

561

562

563

564

565

566

567

568

569

570

571

572

573

574

575

576

577

578

579

580

581

582

583

584

585

586

587

588

589

590

591

592

593

594

595

596

597

598

599

600

601

602

603

604

605

606

607

608

609

610

611

612

613

614

615

616

617

618

619

620

621

622

623

624

625

626

627

628

629

630

631

632

633

634

635

636

637

638

639

640

641

642

643

644


ARTICLE IN PRESS

UNCO

RREC






TEDPR

OOF





645

646

647

648

649

650

651

652

653

654

655

656

657

658

659

660

661

662

663

664

665Q13

666

667

668

669

670

671

672

673

674

675

676

677Q14

678

679

680

681

682

683

684

685

686

687

688

689

690

691

692

693

694

695

696

697

698

699

700

701

702

703

704

705

706

707

708

709

710

711

712

713

714

715

716

717

718

719

720

721

722

723

724

725

726

727

728

729

730

731

732

733

734

735

736

737

738

739

740

741

742

743


ARTICLE IN PRESS

UNCO

RREC




TEDPR

OOF







5 Uncited reference



744

745

746

747

748

749

750

751

752

753Q15754

755

756

757

758

759

760

761

762

763

764

765

766

767

768

769

770

771

772

773

774

775

776

777

778

779

780Q16781

782

783

784

785

786

787

788

789

790

791

792

793

794

795

796

797

798

799

800

801

802

803

804

805

806

807

808

809

810

811

812

813

814

815

816

817

818

819

820

821

822

823

824

825

826

827

828

829

830

831

832

833

834

835

836

837

838

839

840

841

842

843

844

845

846

847

848

849

850

851

852

853

854

855

856

857

858

859

860

861

862

863

864

865

866


ARTICLE IN PRESS

UNCO

RREC

^References



















TEDPR

OOF


















867

868

869

870

871

872

873

874

875

876

877

878

879

880

881

882

883

884

885

886

887

888

889

890

891

892

893

894

895

896

897

898

899

900

901

902

903

904

905

906

907

908

909

910

911

912

913

914

915

916

917

918

919

920

921

922

923

924

925

926

927

928

929

930

931

932

933

934

935

936 Q17937

938

939

940

941

942

943

944

945

946

947

948

949

950

951

952

953

954

955

956

957

958

959

960

961

962 Q18963

964

965

966

967

968

969

970

971

972

973

974

975

976

977

978

979

980

981

982

983

984

985

986

987

988

989

990


ARTICLE IN PRESS

UNCO

RREC




















TEDPR

OOF






















107 187ndash192


991

992

993

994

995

996

997

998

999

1000

1001

1002

1003

1004

1005

1006

1007

1008

1009

1010

1011

1012

1013

1014

1015

1016

1017

1018

1019

1020

1021

1022

1023

1024

1025

1026

1027

1028

1029

1030

1031

1032

1033

1034

1035

1036

1037

1038

1039

1040

1041

1042

1043

1044

1045

1046

1047

1048

1049

1050

1051

1052

1053

1054

1055

1056

1057

1058

1059

1060

1061

1062

1063

1064

1065

1066

1067

1068

1069

1070


ARTICLE IN PRESS

EC












UNCO

R


TEDPR

OOF















R


290

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

341

342

343

344

345

346

347

t31t32

t33

t34

t35t36

t37

t38

t39t310

t311

t312

t313t314

t315

t316

t317t318

t319

t320t321

t322

t323


ARTICLE IN PRESS









ôutcomes


UNCO

RRECTable 3





TEDPR

OOF



ntrol differences





CTED

PROO

F348

349

350

351

352

353

354

355

356

357

358

359

360

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375

376

377

378

379

380

381

382

383

384 Q9

Fig 1


ARTICLE IN PRESS

UNCO



3 Results

31 Remission







PROO

F385

386

387

388

389

390

391 Q10

392

393

394

395

396

Fig 2

t41t42

t43

t44

t45

t46t47

t48

t49t410

t411

t412

t413t414

t415

t416

t417t418

t419

t420t421

t422

t423


ARTICLE IN PRESS


UNCO

RRECTable 4







ntrol differences





F

397

398

399

400

401Q11

402

403

404

405

406

407

408

409

410

411

412

413

414

415

416

417

418

419

420

421

422

423

424

425

426

427

428

429

430

431

432

433

434

435

436

437

438

439

440

Fig 3


ARTICLE IN PRESS

REC




UNCO

R

Fig 4


TEDPR


^045



^minus005 SE=002 p=



^00014 14 studies)


^005 SE=002


^0011




mance (B=^001 SE=0004 p=

^001 12 studies)


^11 SE=043


^066 SE=027




441

442

443

444

445

446

447

448

449

450

451

452

453

454

455

456

457

458

459

460

461

462

463

464

465

466

467

468

469

470

471

472

473

474

475

476

477

478

479

480

481

482

483

484

485

486

487

488

489

490

491

492

493

494

495

496

497

498

499

500

501

502

503

504

505

506

507

508

509

510

511

512

513

514

515

516

517

518

519

520

521

522

523

524

525

526

527

528

529 Q12

530

531

532

533

534

535

536

537

538

539

540


ARTICLE IN PRESS

UNCO

RREC


^0025 14 studies)


^003) and FAS

(B=^098 SE=0

^45 p=

^003 10 studies)


^1^69 SE=0

^41 pb

^0^001) Working


^0^76 SE=0

^15 pb

^0^001 7 studies)

32 Relatives





^minus0022 SE=0007 p=

^0003




^057 SE=024 p=

^0022 8



^068


(B=^141 SE=047 p=



TEDPR

OOF


^00025 5

studies)

4 Discussion




541

542

543

544

545

546

547

548

549

550

551

552

553

554

555

556

557

558

559

560

561

562

563

564

565

566

567

568

569

570

571

572

573

574

575

576

577

578

579

580

581

582

583

584

585

586

587

588

589

590

591

592

593

594

595

596

597

598

599

600

601

602

603

604

605

606

607

608

609

610

611

612

613

614

615

616

617

618

619

620

621

622

623

624

625

626

627

628

629

630

631

632

633

634

635

636

637

638

639

640

641

642

643

644


ARTICLE IN PRESS

UNCO

RREC






TEDPR

OOF





645

646

647

648

649

650

651

652

653

654

655

656

657

658

659

660

661

662

663

664

665Q13

666

667

668

669

670

671

672

673

674

675

676

677Q14

678

679

680

681

682

683

684

685

686

687

688

689

690

691

692

693

694

695

696

697

698

699

700

701

702

703

704

705

706

707

708

709

710

711

712

713

714

715

716

717

718

719

720

721

722

723

724

725

726

727

728

729

730

731

732

733

734

735

736

737

738

739

740

741

742

743


ARTICLE IN PRESS

UNCO

RREC




TEDPR

OOF







5 Uncited reference



744

745

746

747

748

749

750

751

752

753Q15754

755

756

757

758

759

760

761

762

763

764

765

766

767

768

769

770

771

772

773

774

775

776

777

778

779

780Q16781

782

783

784

785

786

787

788

789

790

791

792

793

794

795

796

797

798

799

800

801

802

803

804

805

806

807

808

809

810

811

812

813

814

815

816

817

818

819

820

821

822

823

824

825

826

827

828

829

830

831

832

833

834

835

836

837

838

839

840

841

842

843

844

845

846

847

848

849

850

851

852

853

854

855

856

857

858

859

860

861

862

863

864

865

866


ARTICLE IN PRESS

UNCO

RREC

^References



















TEDPR

OOF


















867

868

869

870

871

872

873

874

875

876

877

878

879

880

881

882

883

884

885

886

887

888

889

890

891

892

893

894

895

896

897

898

899

900

901

902

903

904

905

906

907

908

909

910

911

912

913

914

915

916

917

918

919

920

921

922

923

924

925

926

927

928

929

930

931

932

933

934

935

936 Q17937

938

939

940

941

942

943

944

945

946

947

948

949

950

951

952

953

954

955

956

957

958

959

960

961

962 Q18963

964

965

966

967

968

969

970

971

972

973

974

975

976

977

978

979

980

981

982

983

984

985

986

987

988

989

990


ARTICLE IN PRESS

UNCO

RREC




















TEDPR

OOF






















107 187ndash192


991

992

993

994

995

996

997

998

999

1000

1001

1002

1003

1004

1005

1006

1007

1008

1009

1010

1011

1012

1013

1014

1015

1016

1017

1018

1019

1020

1021

1022

1023

1024

1025

1026

1027

1028

1029

1030

1031

1032

1033

1034

1035

1036

1037

1038

1039

1040

1041

1042

1043

1044

1045

1046

1047

1048

1049

1050

1051

1052

1053

1054

1055

1056

1057

1058

1059

1060

1061

1062

1063

1064

1065

1066

1067

1068

1069

1070


ARTICLE IN PRESS

EC












UNCO

R


TEDPR

OOF















R


CTED

PROO

F348

349

350

351

352

353

354

355

356

357

358

359

360

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375

376

377

378

379

380

381

382

383

384 Q9

Fig 1


ARTICLE IN PRESS

UNCO



3 Results

31 Remission







PROO

F385

386

387

388

389

390

391 Q10

392

393

394

395

396

Fig 2

t41t42

t43

t44

t45

t46t47

t48

t49t410

t411

t412

t413t414

t415

t416

t417t418

t419

t420t421

t422

t423


ARTICLE IN PRESS


UNCO

RRECTable 4







ntrol differences





F

397

398

399

400

401Q11

402

403

404

405

406

407

408

409

410

411

412

413

414

415

416

417

418

419

420

421

422

423

424

425

426

427

428

429

430

431

432

433

434

435

436

437

438

439

440

Fig 3


ARTICLE IN PRESS

REC




UNCO

R

Fig 4


TEDPR


^045



^minus005 SE=002 p=



^00014 14 studies)


^005 SE=002


^0011




mance (B=^001 SE=0004 p=

^001 12 studies)


^11 SE=043


^066 SE=027




441

442

443

444

445

446

447

448

449

450

451

452

453

454

455

456

457

458

459

460

461

462

463

464

465

466

467

468

469

470

471

472

473

474

475

476

477

478

479

480

481

482

483

484

485

486

487

488

489

490

491

492

493

494

495

496

497

498

499

500

501

502

503

504

505

506

507

508

509

510

511

512

513

514

515

516

517

518

519

520

521

522

523

524

525

526

527

528

529 Q12

530

531

532

533

534

535

536

537

538

539

540


ARTICLE IN PRESS

UNCO

RREC


^0025 14 studies)


^003) and FAS

(B=^098 SE=0

^45 p=

^003 10 studies)


^1^69 SE=0

^41 pb

^0^001) Working


^0^76 SE=0

^15 pb

^0^001 7 studies)

32 Relatives





^minus0022 SE=0007 p=

^0003




^057 SE=024 p=

^0022 8



^068


(B=^141 SE=047 p=



TEDPR

OOF


^00025 5

studies)

4 Discussion




541

542

543

544

545

546

547

548

549

550

551

552

553

554

555

556

557

558

559

560

561

562

563

564

565

566

567

568

569

570

571

572

573

574

575

576

577

578

579

580

581

582

583

584

585

586

587

588

589

590

591

592

593

594

595

596

597

598

599

600

601

602

603

604

605

606

607

608

609

610

611

612

613

614

615

616

617

618

619

620

621

622

623

624

625

626

627

628

629

630

631

632

633

634

635

636

637

638

639

640

641

642

643

644


ARTICLE IN PRESS

UNCO

RREC






TEDPR

OOF





645

646

647

648

649

650

651

652

653

654

655

656

657

658

659

660

661

662

663

664

665Q13

666

667

668

669

670

671

672

673

674

675

676

677Q14

678

679

680

681

682

683

684

685

686

687

688

689

690

691

692

693

694

695

696

697

698

699

700

701

702

703

704

705

706

707

708

709

710

711

712

713

714

715

716

717

718

719

720

721

722

723

724

725

726

727

728

729

730

731

732

733

734

735

736

737

738

739

740

741

742

743


ARTICLE IN PRESS

UNCO

RREC




TEDPR

OOF







5 Uncited reference



744

745

746

747

748

749

750

751

752

753Q15754

755

756

757

758

759

760

761

762

763

764

765

766

767

768

769

770

771

772

773

774

775

776

777

778

779

780Q16781

782

783

784

785

786

787

788

789

790

791

792

793

794

795

796

797

798

799

800

801

802

803

804

805

806

807

808

809

810

811

812

813

814

815

816

817

818

819

820

821

822

823

824

825

826

827

828

829

830

831

832

833

834

835

836

837

838

839

840

841

842

843

844

845

846

847

848

849

850

851

852

853

854

855

856

857

858

859

860

861

862

863

864

865

866


ARTICLE IN PRESS

UNCO

RREC

^References



















TEDPR

OOF


















867

868

869

870

871

872

873

874

875

876

877

878

879

880

881

882

883

884

885

886

887

888

889

890

891

892

893

894

895

896

897

898

899

900

901

902

903

904

905

906

907

908

909

910

911

912

913

914

915

916

917

918

919

920

921

922

923

924

925

926

927

928

929

930

931

932

933

934

935

936 Q17937

938

939

940

941

942

943

944

945

946

947

948

949

950

951

952

953

954

955

956

957

958

959

960

961

962 Q18963

964

965

966

967

968

969

970

971

972

973

974

975

976

977

978

979

980

981

982

983

984

985

986

987

988

989

990


ARTICLE IN PRESS

UNCO

RREC




















TEDPR

OOF






















107 187ndash192


991

992

993

994

995

996

997

998

999

1000

1001

1002

1003

1004

1005

1006

1007

1008

1009

1010

1011

1012

1013

1014

1015

1016

1017

1018

1019

1020

1021

1022

1023

1024

1025

1026

1027

1028

1029

1030

1031

1032

1033

1034

1035

1036

1037

1038

1039

1040

1041

1042

1043

1044

1045

1046

1047

1048

1049

1050

1051

1052

1053

1054

1055

1056

1057

1058

1059

1060

1061

1062

1063

1064

1065

1066

1067

1068

1069

1070


ARTICLE IN PRESS

EC












UNCO

R


TEDPR

OOF















R


PROO

F385

386

387

388

389

390

391 Q10

392

393

394

395

396

Fig 2

t41t42

t43

t44

t45

t46t47

t48

t49t410

t411

t412

t413t414

t415

t416

t417t418

t419

t420t421

t422

t423


ARTICLE IN PRESS


UNCO

RRECTable 4







ntrol differences





F

397

398

399

400

401Q11

402

403

404

405

406

407

408

409

410

411

412

413

414

415

416

417

418

419

420

421

422

423

424

425

426

427

428

429

430

431

432

433

434

435

436

437

438

439

440

Fig 3


ARTICLE IN PRESS

REC




UNCO

R

Fig 4


TEDPR


^045



^minus005 SE=002 p=



^00014 14 studies)


^005 SE=002


^0011




mance (B=^001 SE=0004 p=

^001 12 studies)


^11 SE=043


^066 SE=027




441

442

443

444

445

446

447

448

449

450

451

452

453

454

455

456

457

458

459

460

461

462

463

464

465

466

467

468

469

470

471

472

473

474

475

476

477

478

479

480

481

482

483

484

485

486

487

488

489

490

491

492

493

494

495

496

497

498

499

500

501

502

503

504

505

506

507

508

509

510

511

512

513

514

515

516

517

518

519

520

521

522

523

524

525

526

527

528

529 Q12

530

531

532

533

534

535

536

537

538

539

540


ARTICLE IN PRESS

UNCO

RREC


^0025 14 studies)


^003) and FAS

(B=^098 SE=0

^45 p=

^003 10 studies)


^1^69 SE=0

^41 pb

^0^001) Working


^0^76 SE=0

^15 pb

^0^001 7 studies)

32 Relatives





^minus0022 SE=0007 p=

^0003




^057 SE=024 p=

^0022 8



^068


(B=^141 SE=047 p=



TEDPR

OOF


^00025 5

studies)

4 Discussion




541

542

543

544

545

546

547

548

549

550

551

552

553

554

555

556

557

558

559

560

561

562

563

564

565

566

567

568

569

570

571

572

573

574

575

576

577

578

579

580

581

582

583

584

585

586

587

588

589

590

591

592

593

594

595

596

597

598

599

600

601

602

603

604

605

606

607

608

609

610

611

612

613

614

615

616

617

618

619

620

621

622

623

624

625

626

627

628

629

630

631

632

633

634

635

636

637

638

639

640

641

642

643

644


ARTICLE IN PRESS

UNCO

RREC






TEDPR

OOF





645

646

647

648

649

650

651

652

653

654

655

656

657

658

659

660

661

662

663

664

665Q13

666

667

668

669

670

671

672

673

674

675

676

677Q14

678

679

680

681

682

683

684

685

686

687

688

689

690

691

692

693

694

695

696

697

698

699

700

701

702

703

704

705

706

707

708

709

710

711

712

713

714

715

716

717

718

719

720

721

722

723

724

725

726

727

728

729

730

731

732

733

734

735

736

737

738

739

740

741

742

743


ARTICLE IN PRESS

UNCO

RREC




TEDPR

OOF







5 Uncited reference



744

745

746

747

748

749

750

751

752

753Q15754

755

756

757

758

759

760

761

762

763

764

765

766

767

768

769

770

771

772

773

774

775

776

777

778

779

780Q16781

782

783

784

785

786

787

788

789

790

791

792

793

794

795

796

797

798

799

800

801

802

803

804

805

806

807

808

809

810

811

812

813

814

815

816

817

818

819

820

821

822

823

824

825

826

827

828

829

830

831

832

833

834

835

836

837

838

839

840

841

842

843

844

845

846

847

848

849

850

851

852

853

854

855

856

857

858

859

860

861

862

863

864

865

866


ARTICLE IN PRESS

UNCO

RREC

^References



















TEDPR

OOF


















867

868

869

870

871

872

873

874

875

876

877

878

879

880

881

882

883

884

885

886

887

888

889

890

891

892

893

894

895

896

897

898

899

900

901

902

903

904

905

906

907

908

909

910

911

912

913

914

915

916

917

918

919

920

921

922

923

924

925

926

927

928

929

930

931

932

933

934

935

936 Q17937

938

939

940

941

942

943

944

945

946

947

948

949

950

951

952

953

954

955

956

957

958

959

960

961

962 Q18963

964

965

966

967

968

969

970

971

972

973

974

975

976

977

978

979

980

981

982

983

984

985

986

987

988

989

990


ARTICLE IN PRESS

UNCO

RREC




















TEDPR

OOF






















107 187ndash192


991

992

993

994

995

996

997

998

999

1000

1001

1002

1003

1004

1005

1006

1007

1008

1009

1010

1011

1012

1013

1014

1015

1016

1017

1018

1019

1020

1021

1022

1023

1024

1025

1026

1027

1028

1029

1030

1031

1032

1033

1034

1035

1036

1037

1038

1039

1040

1041

1042

1043

1044

1045

1046

1047

1048

1049

1050

1051

1052

1053

1054

1055

1056

1057

1058

1059

1060

1061

1062

1063

1064

1065

1066

1067

1068

1069

1070


ARTICLE IN PRESS

EC












UNCO

R


TEDPR

OOF















R


F

397

398

399

400

401Q11

402

403

404

405

406

407

408

409

410

411

412

413

414

415

416

417

418

419

420

421

422

423

424

425

426

427

428

429

430

431

432

433

434

435

436

437

438

439

440

Fig 3


ARTICLE IN PRESS

REC




UNCO

R

Fig 4


TEDPR


^045



^minus005 SE=002 p=



^00014 14 studies)


^005 SE=002


^0011




mance (B=^001 SE=0004 p=

^001 12 studies)


^11 SE=043


^066 SE=027




441

442

443

444

445

446

447

448

449

450

451

452

453

454

455

456

457

458

459

460

461

462

463

464

465

466

467

468

469

470

471

472

473

474

475

476

477

478

479

480

481

482

483

484

485

486

487

488

489

490

491

492

493

494

495

496

497

498

499

500

501

502

503

504

505

506

507

508

509

510

511

512

513

514

515

516

517

518

519

520

521

522

523

524

525

526

527

528

529 Q12

530

531

532

533

534

535

536

537

538

539

540


ARTICLE IN PRESS

UNCO

RREC


^0025 14 studies)


^003) and FAS

(B=^098 SE=0

^45 p=

^003 10 studies)


^1^69 SE=0

^41 pb

^0^001) Working


^0^76 SE=0

^15 pb

^0^001 7 studies)

32 Relatives





^minus0022 SE=0007 p=

^0003




^057 SE=024 p=

^0022 8



^068


(B=^141 SE=047 p=



TEDPR

OOF


^00025 5

studies)

4 Discussion




541

542

543

544

545

546

547

548

549

550

551

552

553

554

555

556

557

558

559

560

561

562

563

564

565

566

567

568

569

570

571

572

573

574

575

576

577

578

579

580

581

582

583

584

585

586

587

588

589

590

591

592

593

594

595

596

597

598

599

600

601

602

603

604

605

606

607

608

609

610

611

612

613

614

615

616

617

618

619

620

621

622

623

624

625

626

627

628

629

630

631

632

633

634

635

636

637

638

639

640

641

642

643

644


ARTICLE IN PRESS

UNCO

RREC






TEDPR

OOF





645

646

647

648

649

650

651

652

653

654

655

656

657

658

659

660

661

662

663

664

665Q13

666

667

668

669

670

671

672

673

674

675

676

677Q14

678

679

680

681

682

683

684

685

686

687

688

689

690

691

692

693

694

695

696

697

698

699

700

701

702

703

704

705

706

707

708

709

710

711

712

713

714

715

716

717

718

719

720

721

722

723

724

725

726

727

728

729

730

731

732

733

734

735

736

737

738

739

740

741

742

743


ARTICLE IN PRESS

UNCO

RREC




TEDPR

OOF







5 Uncited reference



744

745

746

747

748

749

750

751

752

753Q15754

755

756

757

758

759

760

761

762

763

764

765

766

767

768

769

770

771

772

773

774

775

776

777

778

779

780Q16781

782

783

784

785

786

787

788

789

790

791

792

793

794

795

796

797

798

799

800

801

802

803

804

805

806

807

808

809

810

811

812

813

814

815

816

817

818

819

820

821

822

823

824

825

826

827

828

829

830

831

832

833

834

835

836

837

838

839

840

841

842

843

844

845

846

847

848

849

850

851

852

853

854

855

856

857

858

859

860

861

862

863

864

865

866


ARTICLE IN PRESS

UNCO

RREC

^References



















TEDPR

OOF


















867

868

869

870

871

872

873

874

875

876

877

878

879

880

881

882

883

884

885

886

887

888

889

890

891

892

893

894

895

896

897

898

899

900

901

902

903

904

905

906

907

908

909

910

911

912

913

914

915

916

917

918

919

920

921

922

923

924

925

926

927

928

929

930

931

932

933

934

935

936 Q17937

938

939

940

941

942

943

944

945

946

947

948

949

950

951

952

953

954

955

956

957

958

959

960

961

962 Q18963

964

965

966

967

968

969

970

971

972

973

974

975

976

977

978

979

980

981

982

983

984

985

986

987

988

989

990


ARTICLE IN PRESS

UNCO

RREC




















TEDPR

OOF






















107 187ndash192


991

992

993

994

995

996

997

998

999

1000

1001

1002

1003

1004

1005

1006

1007

1008

1009

1010

1011

1012

1013

1014

1015

1016

1017

1018

1019

1020

1021

1022

1023

1024

1025

1026

1027

1028

1029

1030

1031

1032

1033

1034

1035

1036

1037

1038

1039

1040

1041

1042

1043

1044

1045

1046

1047

1048

1049

1050

1051

1052

1053

1054

1055

1056

1057

1058

1059

1060

1061

1062

1063

1064

1065

1066

1067

1068

1069

1070


ARTICLE IN PRESS

EC












UNCO

R


TEDPR

OOF















R


441

442

443

444

445

446

447

448

449

450

451

452

453

454

455

456

457

458

459

460

461

462

463

464

465

466

467

468

469

470

471

472

473

474

475

476

477

478

479

480

481

482

483

484

485

486

487

488

489

490

491

492

493

494

495

496

497

498

499

500

501

502

503

504

505

506

507

508

509

510

511

512

513

514

515

516

517

518

519

520

521

522

523

524

525

526

527

528

529 Q12

530

531

532

533

534

535

536

537

538

539

540


ARTICLE IN PRESS

UNCO

RREC


^0025 14 studies)


^003) and FAS

(B=^098 SE=0

^45 p=

^003 10 studies)


^1^69 SE=0

^41 pb

^0^001) Working


^0^76 SE=0

^15 pb

^0^001 7 studies)

32 Relatives





^minus0022 SE=0007 p=

^0003




^057 SE=024 p=

^0022 8



^068


(B=^141 SE=047 p=



TEDPR

OOF


^00025 5

studies)

4 Discussion




541

542

543

544

545

546

547

548

549

550

551

552

553

554

555

556

557

558

559

560

561

562

563

564

565

566

567

568

569

570

571

572

573

574

575

576

577

578

579

580

581

582

583

584

585

586

587

588

589

590

591

592

593

594

595

596

597

598

599

600

601

602

603

604

605

606

607

608

609

610

611

612

613

614

615

616

617

618

619

620

621

622

623

624

625

626

627

628

629

630

631

632

633

634

635

636

637

638

639

640

641

642

643

644


ARTICLE IN PRESS

UNCO

RREC






TEDPR

OOF





645

646

647

648

649

650

651

652

653

654

655

656

657

658

659

660

661

662

663

664

665Q13

666

667

668

669

670

671

672

673

674

675

676

677Q14

678

679

680

681

682

683

684

685

686

687

688

689

690

691

692

693

694

695

696

697

698

699

700

701

702

703

704

705

706

707

708

709

710

711

712

713

714

715

716

717

718

719

720

721

722

723

724

725

726

727

728

729

730

731

732

733

734

735

736

737

738

739

740

741

742

743


ARTICLE IN PRESS

UNCO

RREC




TEDPR

OOF







5 Uncited reference



744

745

746

747

748

749

750

751

752

753Q15754

755

756

757

758

759

760

761

762

763

764

765

766

767

768

769

770

771

772

773

774

775

776

777

778

779

780Q16781

782

783

784

785

786

787

788

789

790

791

792

793

794

795

796

797

798

799

800

801

802

803

804

805

806

807

808

809

810

811

812

813

814

815

816

817

818

819

820

821

822

823

824

825

826

827

828

829

830

831

832

833

834

835

836

837

838

839

840

841

842

843

844

845

846

847

848

849

850

851

852

853

854

855

856

857

858

859

860

861

862

863

864

865

866


ARTICLE IN PRESS

UNCO

RREC

^References



















TEDPR

OOF


















867

868

869

870

871

872

873

874

875

876

877

878

879

880

881

882

883

884

885

886

887

888

889

890

891

892

893

894

895

896

897

898

899

900

901

902

903

904

905

906

907

908

909

910

911

912

913

914

915

916

917

918

919

920

921

922

923

924

925

926

927

928

929

930

931

932

933

934

935

936 Q17937

938

939

940

941

942

943

944

945

946

947

948

949

950

951

952

953

954

955

956

957

958

959

960

961

962 Q18963

964

965

966

967

968

969

970

971

972

973

974

975

976

977

978

979

980

981

982

983

984

985

986

987

988

989

990


ARTICLE IN PRESS

UNCO

RREC




















TEDPR

OOF






















107 187ndash192


991

992

993

994

995

996

997

998

999

1000

1001

1002

1003

1004

1005

1006

1007

1008

1009

1010

1011

1012

1013

1014

1015

1016

1017

1018

1019

1020

1021

1022

1023

1024

1025

1026

1027

1028

1029

1030

1031

1032

1033

1034

1035

1036

1037

1038

1039

1040

1041

1042

1043

1044

1045

1046

1047

1048

1049

1050

1051

1052

1053

1054

1055

1056

1057

1058

1059

1060

1061

1062

1063

1064

1065

1066

1067

1068

1069

1070


ARTICLE IN PRESS

EC












UNCO

R


TEDPR

OOF















R


541

542

543

544

545

546

547

548

549

550

551

552

553

554

555

556

557

558

559

560

561

562

563

564

565

566

567

568

569

570

571

572

573

574

575

576

577

578

579

580

581

582

583

584

585

586

587

588

589

590

591

592

593

594

595

596

597

598

599

600

601

602

603

604

605

606

607

608

609

610

611

612

613

614

615

616

617

618

619

620

621

622

623

624

625

626

627

628

629

630

631

632

633

634

635

636

637

638

639

640

641

642

643

644


ARTICLE IN PRESS

UNCO

RREC






TEDPR

OOF





645

646

647

648

649

650

651

652

653

654

655

656

657

658

659

660

661

662

663

664

665Q13

666

667

668

669

670

671

672

673

674

675

676

677Q14

678

679

680

681

682

683

684

685

686

687

688

689

690

691

692

693

694

695

696

697

698

699

700

701

702

703

704

705

706

707

708

709

710

711

712

713

714

715

716

717

718

719

720

721

722

723

724

725

726

727

728

729

730

731

732

733

734

735

736

737

738

739

740

741

742

743


ARTICLE IN PRESS

UNCO

RREC




TEDPR

OOF







5 Uncited reference



744

745

746

747

748

749

750

751

752

753Q15754

755

756

757

758

759

760

761

762

763

764

765

766

767

768

769

770

771

772

773

774

775

776

777

778

779

780Q16781

782

783

784

785

786

787

788

789

790

791

792

793

794

795

796

797

798

799

800

801

802

803

804

805

806

807

808

809

810

811

812

813

814

815

816

817

818

819

820

821

822

823

824

825

826

827

828

829

830

831

832

833

834

835

836

837

838

839

840

841

842

843

844

845

846

847

848

849

850

851

852

853

854

855

856

857

858

859

860

861

862

863

864

865

866


ARTICLE IN PRESS

UNCO

RREC

^References



















TEDPR

OOF


















867

868

869

870

871

872

873

874

875

876

877

878

879

880

881

882

883

884

885

886

887

888

889

890

891

892

893

894

895

896

897

898

899

900

901

902

903

904

905

906

907

908

909

910

911

912

913

914

915

916

917

918

919

920

921

922

923

924

925

926

927

928

929

930

931

932

933

934

935

936 Q17937

938

939

940

941

942

943

944

945

946

947

948

949

950

951

952

953

954

955

956

957

958

959

960

961

962 Q18963

964

965

966

967

968

969

970

971

972

973

974

975

976

977

978

979

980

981

982

983

984

985

986

987

988

989

990


ARTICLE IN PRESS

UNCO

RREC




















TEDPR

OOF






















107 187ndash192


991

992

993

994

995

996

997

998

999

1000

1001

1002

1003

1004

1005

1006

1007

1008

1009

1010

1011

1012

1013

1014

1015

1016

1017

1018

1019

1020

1021

1022

1023

1024

1025

1026

1027

1028

1029

1030

1031

1032

1033

1034

1035

1036

1037

1038

1039

1040

1041

1042

1043

1044

1045

1046

1047

1048

1049

1050

1051

1052

1053

1054

1055

1056

1057

1058

1059

1060

1061

1062

1063

1064

1065

1066

1067

1068

1069

1070


ARTICLE IN PRESS

EC












UNCO

R


TEDPR

OOF















R


645

646

647

648

649

650

651

652

653

654

655

656

657

658

659

660

661

662

663

664

665Q13

666

667

668

669

670

671

672

673

674

675

676

677Q14

678

679

680

681

682

683

684

685

686

687

688

689

690

691

692

693

694

695

696

697

698

699

700

701

702

703

704

705

706

707

708

709

710

711

712

713

714

715

716

717

718

719

720

721

722

723

724

725

726

727

728

729

730

731

732

733

734

735

736

737

738

739

740

741

742

743


ARTICLE IN PRESS

UNCO

RREC




TEDPR

OOF







5 Uncited reference



744

745

746

747

748

749

750

751

752

753Q15754

755

756

757

758

759

760

761

762

763

764

765

766

767

768

769

770

771

772

773

774

775

776

777

778

779

780Q16781

782

783

784

785

786

787

788

789

790

791

792

793

794

795

796

797

798

799

800

801

802

803

804

805

806

807

808

809

810

811

812

813

814

815

816

817

818

819

820

821

822

823

824

825

826

827

828

829

830

831

832

833

834

835

836

837

838

839

840

841

842

843

844

845

846

847

848

849

850

851

852

853

854

855

856

857

858

859

860

861

862

863

864

865

866


ARTICLE IN PRESS

UNCO

RREC

^References



















TEDPR

OOF


















867

868

869

870

871

872

873

874

875

876

877

878

879

880

881

882

883

884

885

886

887

888

889

890

891

892

893

894

895

896

897

898

899

900

901

902

903

904

905

906

907

908

909

910

911

912

913

914

915

916

917

918

919

920

921

922

923

924

925

926

927

928

929

930

931

932

933

934

935

936 Q17937

938

939

940

941

942

943

944

945

946

947

948

949

950

951

952

953

954

955

956

957

958

959

960

961

962 Q18963

964

965

966

967

968

969

970

971

972

973

974

975

976

977

978

979

980

981

982

983

984

985

986

987

988

989

990


ARTICLE IN PRESS

UNCO

RREC




















TEDPR

OOF






















107 187ndash192


991

992

993

994

995

996

997

998

999

1000

1001

1002

1003

1004

1005

1006

1007

1008

1009

1010

1011

1012

1013

1014

1015

1016

1017

1018

1019

1020

1021

1022

1023

1024

1025

1026

1027

1028

1029

1030

1031

1032

1033

1034

1035

1036

1037

1038

1039

1040

1041

1042

1043

1044

1045

1046

1047

1048

1049

1050

1051

1052

1053

1054

1055

1056

1057

1058

1059

1060

1061

1062

1063

1064

1065

1066

1067

1068

1069

1070


ARTICLE IN PRESS

EC












UNCO

R


TEDPR

OOF















R


744

745

746

747

748

749

750

751

752

753Q15754

755

756

757

758

759

760

761

762

763

764

765

766

767

768

769

770

771

772

773

774

775

776

777

778

779

780Q16781

782

783

784

785

786

787

788

789

790

791

792

793

794

795

796

797

798

799

800

801

802

803

804

805

806

807

808

809

810

811

812

813

814

815

816

817

818

819

820

821

822

823

824

825

826

827

828

829

830

831

832

833

834

835

836

837

838

839

840

841

842

843

844

845

846

847

848

849

850

851

852

853

854

855

856

857

858

859

860

861

862

863

864

865

866


ARTICLE IN PRESS

UNCO

RREC

^References



















TEDPR

OOF


















867

868

869

870

871

872

873

874

875

876

877

878

879

880

881

882

883

884

885

886

887

888

889

890

891

892

893

894

895

896

897

898

899

900

901

902

903

904

905

906

907

908

909

910

911

912

913

914

915

916

917

918

919

920

921

922

923

924

925

926

927

928

929

930

931

932

933

934

935

936 Q17937

938

939

940

941

942

943

944

945

946

947

948

949

950

951

952

953

954

955

956

957

958

959

960

961

962 Q18963

964

965

966

967

968

969

970

971

972

973

974

975

976

977

978

979

980

981

982

983

984

985

986

987

988

989

990


ARTICLE IN PRESS

UNCO

RREC




















TEDPR

OOF






















107 187ndash192


991

992

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Cognitive endophenotypes of bipolar disorder: A meta-analysis of neuropsychological deficits in euthymic patients and their first-degree relatives

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