REVIEW
Da a managemen and da a analysis echniques in
pha macoepidemiological s udies using a p e-planned
mul i-da abase app oach: a sys ema ic li e a u e e iew
†
Ma loes T. Bazelie
1
*, I ene E iksson
2
, F ank de V ies
1,3
, Ma janka K. Schmid
4
, Jani Rai anen
5,6
, Ja i Haukka
7
,
Jakob S a up-Linde
8,9
, Ma ie L. De B uin
1
and Mo en Ande sen
2
1
Di ision o Pha macoepidemiology and Clinical Pha macology, U ech Ins i u e o Pha maceu ical Sciences, U ech Uni e si y, Ne he lands
2
Cen e o Pha macoepidemiology, Ka olinska Ins i u e , S ockholm, Sweden
3
Depa men o Clinical Pha macy and Toxicology, Maas ich Uni e si y Medical Cen e, Maas ich , Ne he lands
4
Di ision o Molecula Pa hology, Ne he lands Cance Ins i u e, Ne he lands
5
School o Heal h Sciences, Uni e si y o Tampe e, Finland
6
UKK Ins i u e o Heal h P omo ion, Tampe e, Finland
7
Uni e si y o Helsinki, Helsinki, Finland
8
Aalbo g Uni e si y, Aalbo g, Denma k
9
Depa men o Endoc inology and In e nal Medicine, Aa hus Uni e si y Hospi al, Aa hus, Denma k
ABSTRACT
Pu pose To iden i y pha macoepidemiological mul i-da abase s udies and o desc ibe da a managemen and da a analysis echniques used
o combining da a.
Me hods Sys ema ic li e a u e sea ches we e conduc ed in PubMed and Embase complemen ed by a manual li e a u e sea ch. We included
pha macoepidemiological mul i-da abase s udies published om 2007 onwa ds ha combined da a o a p e-planned common analysis o
quan i a i e syn hesis. In o ma ion was e ie ed abou s udy cha ac e is ics, me hods used o indi idual-le el analyses and me a-
analyses, da a managemen and mo i a ions o pe o ming he s udy.
Resul s We ound 3083 a icles by he sys ema ic sea ches and an addi ional 176 by he manual sea ch. A e ull- ex sc eening o 75 a icles, 22
we e selec ed o final inclusion. The numbe o da abases used pe s udy anged om 2 o 17 (median = 4.0). Mos s udies used a coho design
(82%) ins ead o a case–con ol design (18%). Logis ic eg ession was mos o en used o indi idual-le el analyses (41%), ollowed by Cox eg es-
sion (23%) and Poisson eg ession (14%). As me a-analysis me hod, a majo i y o he s udies combined indi idual pa ien da a (73%). Six s udies
pe o med an agg ega e me a-analysis (27%), while a semi-agg ega e app oach was applied in h ee s udies (14%). In o ma ion on cen al p og am-
ming o he e ogenei y assessmen was missing in app oxima ely hal o he publica ions. Mos s udies we e mo i a ed by imp o ing powe (86%).
Conclusions Pha macoepidemiological mul i-da abase s udies a e a well-powe ed s a egy o add ess sa e y issues and ha e inc eased
in popula i y. To be able o co ec ly in e p e he esul s o hese s udies, i is impo an o sys ema ically epo on da abase managemen
and analysis echniques, including cen al p og amming and he e ogenei y es ing. © 2015 The Au ho s. Pha macoepidemiology and
D ug Sa e y published by John Wiley & Sons, L d.
key wo ds—pha macoepidemiology; mul i-da abase; sys ema ic e iew; da a managemen ; analysis echniques
Recei ed 18 Decembe 2014; Re ised 29 May 2015; Accep ed 08 June 2015
INTRODUCTION
The need o pos -app o al su eillance o d ug sa e y
has been widely ecognized o mo e han ou decades.
F om he ea ly days o pha macoepidemiology, ini ia-
i es ha e been unde aken o s udy sa e y and, mos e-
cen ly, e ec i eness o medica ions using ou inely
collec ed heal hca e da a. O e he pas decade, an
inc easing numbe o s udies ha e been pe o med using
heal hca e da abases om mul iple coun ies, egions o
*Co espondence o: M. T. Bazelie , Depa men o Pha macoepidemiology and
Clinical Pha macology, U ech Ins i u e o Pha maceu ical Sciences,
U ech Uni e si y, Uni e si ei sweg 99, 3584 CG U ech , Ne he lands. E-mail:
[email p o ec ed]
†
P io pos ings and p esen a ions: Some findings om his s udy we e p esen ed
a he ICPE con e ence 2014 du ing he wo kshop ‘The Common Da a Model:
Lessons om Pas P ojec s and Ongoing Ini ia i es’(Pha macoepidemiol D ug
Sa . 2014 Oc ; 23 Suppl 1: 361).
© 2015 The Au ho s. Pha macoepidemiology and D ug Sa e y published by John Wiley & Sons, L d.
pha macoepidemiology and d ug sa e y 2015; 24: 897–905
Published online 14 July 2015 in Wiley Online Lib a y (wileyonlinelib a y.com) DOI: 10.1002/pds.3828
This is an open access a icle unde he e ms o he C ea i e Commons A ibu ion-NonComme cial-NoDe i s License, which pe mi s use
and dis ibu ion in any medium, p o ided he o iginal wo k is p ope ly ci ed, he use is non-comme cial and no modifica ions o adap a ions
a e made.
heal hca e o ganiza ions. Using da a om mul iple da a-
bases o e s a numbe o po en ial ad an ages such as in-
c eased sample size (da ase s become la ge enough o
gi e p ecise es ima es o medica ion isks and benefi s
e en o a e ou comes and exposu es) and gene aliz-
abili y (when simila esul s a e ound in s udies u ilizing
he same me hodology in he e ogeneous popula ions).
Fu he mo e, i o e s a po en ial o using a s anda d-
ized me hodological app oach ac oss da a sou ces.
A numbe o la ge ini ia i es ha e been launched o
de elop me hods o combining da a om mul iple
da abases and egis e s. In he Uni ed S a es (U.S.),
he Obse a ional Medical Ou comes Pa ne ship
(OMOP)
1
and he Mini-Sen inel p og am
2
ha e been
un since 2007 and 2008, espec i ely. Da a a e o en
combined using he heal h main enance o ganiza ion
(HMO) Resea ch Ne wo k, a conso ium o 19 la ge
heal hca e deli e y o ganiza ions in he U.S.
3
The Ca-
nadian Ne wo k o Obse a ional D ug E ec S udies
(CNODES), a dis ibu ed ne wo k o Canadian e-
sea che s and da a cen e s, was launched in 2011.
4,5
Eu opean ini ia i es ha add ess logis ical and me h-
odological p oblems o conduc ing mul i-da abase
s udies include EU-ADR
6
and IMI-PROTECT.
7
Recen ly, he Asian Pha macoepidemiology Ne wo k
(AsPEN),
8
a collabo a ion including Asian coun ies,
was also s a ed. Besides hese la ge p og ams, a hand-
ul o smalle esea ch p ojec s ha e also combined da a
om se e al heal hca e da abases.
9–13
The e a e a ious ways o combine da a om se -
e al independen da abases, which all ha e di e en
ad an ages and disad an ages. A combina ion o ag-
g ega e esul s does no equi e sha ing o indi idual
pa ien da a and makes op imal use o locally a ailable
da a (e.g. in o ma ion on con ounde s). Howe e ,
co ec ing o he e ogenei y be ween he da abases
may no be ully possible when combining summa y
es ima es. A combina ion o indi idual pa ien da a
opens mo e space o explo ing and co ec ing o he -
e ogenei y; i o e s an oppo uni y o use exac ly he
same defini ions o exposu es, ou comes, co a ia es,
and ime windows. This app oach may, howe e , e-
sul in a comp omise when ele an in o ma ion is los
i no a ailable in all da abases (possibly leading o
la ge esidual con ounding).
To ou knowledge, no sys ema ic e iew has been
pe o med ye o selec mul i-da abase s udies and o
illumina e which me hods ha e mos equen ly been
used o combine da a. Ou aim was he e o e o iden-
i y pha macoepidemiological s udies using a p e-
planned mul i-da abase app oach and o desc ibe da a
managemen and da a analysis echniques used o
combining da a.
METHODS
Li e a u e sea ch
We conduc ed sys ema ic li e a u e sea ches in
PubMed and Embase, as well as a manual li e a u e
sea ch, o iden i y ele an mul i-da abase obse a-
ional s udies. We ollowed he PRISMA guideline
(www.p isma-s a emen .o g).
The ollowing inclusion c i e ia we e applied: (i)
pee - e iewed pha macoepidemiological s udy (de-
fined as an obse a ional s udy abou he sa e y o e -
ec i eness o medica ion); (ii) published om 2007
onwa ds; (iii) s udy subjec s we e selec ed om wo
o mo e independen heal hca e da abases (i.e. da a-
bases co e ing a di e en s udy popula ion); (i ) all
da abases wi hin he s udy we e analyzed o answe
he same esea ch ques ion; and ( ) da a we e com-
bined o a p e-planned common analysis o quan i a-
i e syn hesis (i.e. da a we e combined ei he a
indi idual pa ien -le el o he es ima es ob ained om
indi idual da abases we e combined in analyses). We
excluded d ug u iliza ion s udies, a icles ha ocused
on he de ec ion o ad e se d ug eac ions (ADRs)
and o he pha maco igilance s udies, s udies ha only
epo ed esul s om sepa a e da abases wi hou p o-
iding any combined es ima es, pu ely me hodological
pape s (e.g. desc ibing me hods o combine da a, bu
no ac ually doing so in he pape ), as well as s udies
published in languages o he han English (exclusion
c i e ia we e applied sequen ially).
Sys ema ic sea ch s a egies o PubMed and
Embase we e de eloped unde he supe ision o a e-
sea ch lib a ian and included ex wo ds and ele an
indexing o cap u e pha macoepidemiological s udies
sa is ying he inclusion c i e ia. The s a egies we e
adap ed o ma ch he s uc u e o each da abase and
we e based on sea ch e ms ha included ‘d ugs’,‘da-
abases’, and ‘epidemiology’/‘obse a ional s udies’
(using MeSH, Em ee, and ee ex e ms); bo h da a-
bases we e sea ched om 2007 o Oc obe 2013 (see
e- ables 1 and 2 o he ull sea ch s a egy in Pubmed
and Embase, espec i ely). The da e fil e om 2007
onwa ds was applied as ou pilo sea ches did no
iden i y any ele an publica ions be o e 2007. We
he e o e belie ed ha i would help imp o e he p e-
cision o he sea ch wi hou nega i e impac on i s sen-
si i i y. One au ho (IE) sc eened he i les and
abs ac s o he iden ified a icles using ou inclusion
and exclusion c i e ia o selec a icles eligible o
ull- ex sc eening.
The elec onic li e a u e sea ch was supplemen ed
wi h a manual sea ch (2007 o Decembe 2013). We
iden ified publica ions lis ed on he ollowing esea ch
m. . bazelie
e al.
898
© 2015 The Au ho s. Pha macoepidemiology and D ug Sa e y
published by John Wiley & Sons, L d.
Pha macoepidemiology and D ug Sa e y, 2015; 24: 897–905
DOI: 10.1002/pds
p ojec s’websi es: (i) OMOP (h p://omop. nih.o g
and www.omop.o g); (ii) Mini-Sen inel (www.mini-
sen inel.o g); (iii) he HMO Resea ch Ne wo k
(www.hmo esea chne wo k.o g); (i ) EU-ADR (www.
euad -p ojec .o g); ( ) IMI-PROTECT (www.imi-p o-
ec .eu); ( i) AsPEN (www.aspenne .asia); and ( ii)
CNODES (www.cnodes.ca). In addi ion, esea che s
wi hin ou eam we e consul ed o add mul i-
da abase p ojec s ha hey we e awa e o (and ha
we e no iden ified in he au oma ic and websi e
sea ches). The i les and abs ac s we e sc eened o
de e mine which a icles we e eligible o ull- ex
sc eening.
Two au ho s (IE and MB) e iewed he ull- ex o
all po en ially ele an s udies o de e mine final
inclusion.
Da a ex ac ion p ocess
A da a ex ac ion o m was designed o ex ac ele-
an da a om he selec ed s udies. Da a ex ac ion
was fi s pe o med by one e iewe (MB) wi h subse-
quen quali y assu ance pe o med by he second e-
iewe (IE). Disag eemen s we e esol ed h ough
discussion wi h a hi d e iewe (MA).
Analysis o s udy cha ac e is ics
We e ie ed in o ma ion abou he objec i e o he
s udies, he exposu e, he ou come, he s udy design,
and he numbe o di e en da abases and coun ies.
Fu he , we classified s udies acco ding o he me hods
ha we e used o indi idual-le el analyses and me a-
analyses. Rega ding he me a-analyses, we defined
h ee di e en le els o combining da a:
(1) An agg ega e le el app oach, in which sepa a e
analyses a e pe o med on da ase s om each
da abase and o e all esul s (adjus ed e ec
es ima es wi h confidence in e als) a e collec ed
o me a-analysis. The analyses a e usually
‘da abase-op imized’in he sense ha he bes
a ailable da a o each da abase a e being used.
This app oach allows using he no mal s a is ical
echniques o me a-analysis, including andom-
e ec s models, o accoun o he e ogenei y o
s udy esul s. Fu he , me a- eg ession can be used
o assessing a ia ion in e ec s ela ed o co a i-
a es, which may explain some o he o e all
he e ogenei y.
(2) A semi-agg ega e le el app oach, in which s a i-
fied da ase s wi h e en coun s (and o coho
s udies pe son ime) a e collec ed om all da a-
bases o one common analysis (e.g. a dis ibu ed
da a ne wo k). Da ase s can be s a ified on ou -
come, exposu e, and co a ia e pa e ns (age, sex,
ime since ini ia ion, and selec ed con ounde s).
Fo a coho s udy, his app oach employs a
Poisson eg ession model on ables o e en num-
be s and pe son ime s a ified by exposu e and
co a ia e pa e ns. Fo a case–con ol s udy, a lo-
gis ic eg ession model can simila ly be used o
analyze equency ables o cases and con ols
s a ified by di e en co a ia es.
(3) An indi idual le el app oach, in which indi idual
pa ien da a a e collec ed om all da abases o
one common analysis. In his scena io, he in o -
ma ion om di e en da abases has o be made
compa ible wi h ega d o defini ions o expo-
su es, ou comes, co a ia es, and ime windows.
He e ogenei y o s udy popula ions and a ia ion
in he e ec s bo h o exposu e and co a ia es be-
ween da abases may a ec he esul s. This may
be accoun ed o using s a is ical echniques
co ec ing o o e all a ia ion wi hin and be-
ween da abases.
Wi h ega d o da a managemen , we we e in e es ed
in which da a we e collec ed cen ally and whe he
cen al p og amming o he use o dis ibu ed common
p og ams was men ioned in he a icle. Mo eo e ,
mo i a ions o conduc ing he s udy (as s a ed in
he a icle) we e classified. Fo all ques ions he e
was a ca ego y ‘no specified’ ha could be icked.
This ca ego y is only shown in he esul ables i he e
was a leas one s udy wi h missing da a. F equen-
cies we e calcula ed o desc ibe he s udy cha ac e -
is ics, da a analysis echniques, da a managemen ,
and mo i a ions.
RESULTS
The PubMed and Embase sea ches iden ified 3083
publica ions (see Figu e 1). A e he sc eening o i-
les and abs ac s, 44 a icles we e selec ed o a ull-
ex sc eening. The manual sea ch iden ified an addi-
ional 176 publica ions; 22 om OMOP, 64 om
Mini-Sen inel, 34 om he HMO Resea ch Ne wo k
(based on a Pubmed sea ch, because no a icles we e
ound on he p ojec ’s websi e), 36 om EU-ADR,
11 om IMI-PROTECT, 2 om AsPEN, 2 om
CNODES, and 5 om indi idual p ojec s (da a no
shown in he flowcha ). A e e iew o i les and ab-
s ac s we selec ed 31 a icles o a ull- ex sc eening.
Figu e 1 shows ha om he 75 a icles selec ed o
ull- ex sc eening, 22 we e finally selec ed o
inclusion.
mul i-da abase s udies: a sys ema ic li e a u e e iew 899
© 2015 The Au ho s. Pha macoepidemiology and D ug Sa e y
published by John Wiley & Sons, L d.
Pha macoepidemiology and D ug Sa e y, 2015; 24: 897–905
DOI: 10.1002/pds
E- able 3 gi es an o e iew o he 22 s udies in-
cluded in ou e iew.
9–30
Six s udies we e published
be ween 2007 and 2010, while a majo i y o 16 s udies
was published be ween 2011 and 2013. Fo se en
s udies, he e was a me hod objec i e in addi ion o
an o e all (mos ly clinical) objec i e.
10,13,15,17,18,23,27
Figu e 2 shows which coun ies con ibu ed o he
mul i-da abase p ojec s. F om he 22 s udies, he e
we e 14 (64%) ha used a leas one da abase om
he U.S. o Canada. Hal o he s udies (50%) used a
leas one Eu opean da abase. Wi hin Eu ope, da a
om G ea B i ain we e mos o en used: he e we e
nine s udies (41%) ha used a B i ish da abase (wi h
he Clinical P ac ice Resea ch Da alink (CPRD) being
he mos equen ly used one, i.e. fi e imes). Fu he ,
he e we e fi e s udies ha used a leas one
Scandina ian da abase (23%), fi e s udies ha used a
da abase om he Ne he lands (23%), and fi e s udies
ha used an I alian da abase (23%).
Table 1 shows ha mos s udies add essed sa e y
(82%) a he han e ec i eness issues (23%). The de-
sign ha was mos o en used was he coho s udy de-
sign (82%) as opposed o he case–con ol design
(18%). The numbe o da abases used pe s udy anged
om 2 o 17 (median = 4.0), while he numbe o coun-
ies in ol ed anged om 1 o 6 (median = 2.5). The
ype o exposu e ha was mos equen ly s udied
was medica ion ela ed o he ne ous sys em (41%),
o example an idep essan s and dopamine agonis s.
In e ms o ou comes, ca diac diso de s we e mos e-
quen ly ep esen ed (36%), ollowed by all-cause mo -
ali y (23%) and ne ous sys em diso de s (18%). The
Figu e 1. Flowcha o he selec ion o a icles. * No pape s we e excluded because hey we e non-English ( he e we e 122 non-English pape s bu hey we e
excluded because o o he exclusion c i e ia)
m. . bazelie
e al.
900
© 2015 The Au ho s. Pha macoepidemiology and D ug Sa e y
published by John Wiley & Sons, L d.
Pha macoepidemiology and D ug Sa e y, 2015; 24: 897–905
DOI: 10.1002/pds
code sys em used o iden i y exposu e was o en no
specified (82%), while o he ou come his was less
o en he case (18%).
Table 2 shows ha logis ic eg ession was mos e-
quen ly used o indi idual-le el analyses (41%),
ollowed by Cox eg ession (23%) and Poisson eg es-
sion (14%). As me a-analysis me hod, a majo i y o
he s udies used an indi idual le el app oach (73%)
(see e- able 4 o he exac ca ego iza ion). The e we e
h ee s udies wi h a semi-agg ega e app oach (14%),
and six s udies pe o med an agg ega e me a-analysis
(27%). Fo wo s udies, he agg ega e me a-analysis
was he only me a-analysis ha was conduc ed (be-
cause da a we e collec ed on an agg ega e le el). The
o he ou agg ega e me a-analyses we e conduc ed in
addi ion o an indi idual pa ien da a me a-analysis ( h ee
s udies) o a semi-agg ega e me a-analysis (one s udy).
The e we e ou s udies ha collec ed semi-agg ega e
da ase s (18%), bu one o hem did no use his
in o ma ion in a me a-analysis ( eflec edin heca ego y
‘me a-analysis: none’). A quan i a i e he e ogenei y as-
sessmen was conduc ed in almos hal o he s udies
(45%) wi hou one specific es being mos popula .
Fo 12 s udies, cen al p og amming was men ioned
in he publica ion. The use o dis ibu ed common
p og ams was men ioned o fi e s udies; in h ee
cases hese common p og ams we e used in a semi-
agg ega e le el app oach, and he o he wo cases we e
ela ed o an agg ega e le el app oach.
A majo i y o he a icles mo i a ed hei mul i-da abase
s udy by powe o men ioned powe as a s eng h o hei
s udy (86%) (da a no shown in a able). Only one a icle
explici ly men ioned a e exposu e as an a gumen , and
h ee a icles made men ion o a a e ou come. Ex e nal
alidi y was s essed in six publica ions (27%), while only
h ee a icles men ioned compa ing di e en popula ions
o da abases as an a gumen o pe o m a mul i-da abase
p ojec (14%).
Figu e 2. Map o coun ies in ol ed in mul i-da abase s udies. Legend: - he numbe s eflec how many imes he coun y (a leas one da abase) was in-
ol ed in a mul i-da abase s udy ( he da ke he colo , he highe he numbe o s udies) - s ipes: coun y no in ol ed in any mul i-da abase s udy
mul i-da abase s udies: a sys ema ic li e a u e e iew 901
© 2015 The Au ho s. Pha macoepidemiology and D ug Sa e y
published by John Wiley & Sons, L d.
Pha macoepidemiology and D ug Sa e y, 2015; 24: 897–905
DOI: 10.1002/pds

DISCUSSION
Ou sys ema ic li e a u e sea ch iden ified 22
pha macoepidemiological mul i-da abase s udies, in
which da a we e combined o a p e-planned common
analysis o quan i a i e syn hesis. Fo indi idual-le el
analyses, logis ic eg ession was mos equen ly used,
ollowed by Cox and Poisson eg ession. Fo me a-
analyses, 16 s udies combined indi idual pa ien da a,
while a semi-agg ega e le el analysis was conduc ed
in h ee s udies and an agg ega e le el analysis in six.
I was a challenge o cap u e mul i-da abase obse -
a ional s udies in a sys ema ic li e a u e sea ch. Usu-
ally, he clinical opic was well ep esen ed in sea ch
e ms o keywo ds, bu he use o mo e han one inde-
penden da abase was much ha de o cap u e. The e is
a Mesh e m called ‘Mul icen e s udy’, bu his was
on he one hand oo b oad (e.g. also in ol ing s udies
ha selec ed hei pa ien s om wo di e en hospi als,
which was no he defini ion o mul i-da abase s udy
we we e looking o ) and on he o he hand missing
ou on ele an a icles. Among s udies ha used mo e
han one da abase, i was almos impossible o dis in-
guish s udies wi h pooled es ima es om s udies ha
only showed esul s om he sepa a e da abases, using
sea ch e ms. Because o hese issues, we we e qui e
libe al in defining he sea ch s a egy and manually
sc eened o e 3000 a icles, which only esul ed in
44 a icles ha we e selec ed o a ull- ex sc eening.
S ill, we missed ou on 31 a icles ha we e ound in
he addi ional manual sea ch.
Among he s udies finally selec ed o inclusion, he
ange o di e en exposu es and ou comes was qui e
b oad. This indica es ha he upcoming end o
pe o ming mul i-da abase obse a ional s udies s e ches
ou o e he en i e field o pha macoepidemiology.
App oxima ely hal o ou selec ed s udies used a
leas one da abase om he U.S. o Canada, and his
pe cen age was simila o Eu opean da abases. This
indica es ha No he n Ame ica and Eu ope cu en ly
ake an almos equal pa in con ibu ing o his ela-
i ely new field o mul i-da abase esea ch.
Rega ding he me hods o pe o ming such a s udy,
we ound ha he combina ion o indi idual pa ien
da a was he mos equen ly used echnique. I should
howe e be no ed ha one o ou inclusion c i e ia was
ha da a we e combined o a p e-planned common
analysis. The eby we excluded all ‘s anda d’me a-
analyses ha pool es ima es om di e en s udies o-
ge he on a pos -hoc basis, i.e. he app oach o com-
bining esul s om published li e a u e. This la e
ype o me a-analysis is equen ly used in he field
o clinical ials and is p obably also qui e common
Table 1. Objec i e, design, exposu e, and ou come
Numbe o s udies
( o al: n = 22) %
Objec i e ca ego y
E idence gene a ion 20 91%
Me hod / easibili y s udy 15%
Dual pu pose (combina ion o he abo e)15%
S udy ype (a)
Sa e y 18 82%
E ec i eness 5 23%
Design ca ego y
Coho s udy 18 82%
Case–con ol s udy 4 18%
Numbe o da abases
Range [2,17]
Mean 5.9
Median 4.0
Numbe o coun ies
Range [1,6]
Mean 2.4
Median 2.5
D ug exposu e: ATC ca ego y
N—Ne ous sys em 9 41%
A—Alimen a y ac and me abolism 4 18%
C—Ca dio ascula sys em 3 14%
M—Musculo-skele al sys em 3 14%
B—Blood and blood o ming o gans 15%
R—Respi a o y sys em 15%
S—Senso y o gans 15%
Ou come: All-cause mo ali y/MedDRA SOC (a)
Ca diac diso de s 8 36%
All-cause mo ali y 5 23%
Ne ous sys em diso de s 4 18%
Congeni al, amilial and gene ic diso de s 3 14%
Gas oin es inal diso de s 29%
Musculoskele al and connec i e issue
diso de s
29%
Blood and lympha ic sys em diso de s 15%
Eye diso de s 15%
In ec ions and in es a ions 15%
P egnancy,pue pe ium,and pe ina al
condi ions
15%
Renal and u ina y diso de s 15%
Respi a o y, ho acic and medias inal
diso de s
15%
Skin and subcu aneous issue diso de s 15%
D ug code sys ems (a)
ATC 4 18%
BNF 29%
No specified 18 82%
Ou come code sys ems (a)
ICD-9 13 59%
ICD-10 8 36%
ICPC 29%
RCD 29%
CCP 15%
CPT 15%
mRS 15%
No specified 4 18%
(a) One s udy could con ibu e o mo e han one ca ego y.
Abb e ia ions: ATC, Ana omical The apeu ic Chemical; BNF, B i ish Na-
ional Fo mula y; CCP, Canadian Classifica ion o Diagnos ic, The apeu ic
and Su gical P ocedu es; CPT, Cu en P ocedu al Te minology; ICD-9,
In e na ional Classifica ion o Diseases—9 h e ision; ICD-10, In e na-
ional Classifica ion o Diseases—10 h e ision; ICPC, In e na ional Clas-
sifica ion o P ima y Ca e; mRS, modified Rankin Scale; RCD, READ
CODE Classifica ion; SOC, sys em o gan class.
m. . bazelie
e al.
902
© 2015 The Au ho s. Pha macoepidemiology and D ug Sa e y
published by John Wiley & Sons, L d.
Pha macoepidemiology and D ug Sa e y, 2015; 24: 897–905
DOI: 10.1002/pds
in he field o obse a ional s udies, as i can be done
ela i ely quickly wi hou he need o ge ing access
o pa ien -le el heal hca e da a. I his ype o me a-
analysis would ha e been included in ou e iew, he
p opo ion o agg ega e me a-analyses would he e o e
ha e been much highe .
The e we e h ee s udies ha compa ed an indi id-
ual le el me a-analysis o an agg ega e le el (fixed o
andom e ec ) me a-analysis, using he same
da a.
10,13,18
In all h ee cases, he esul s we e simila
be ween he wo app oaches. Impo an ly, hese
agg ega e le el analyses we e designed wi h a p e-
specified common analysis plan, i.e. he same plan as
was used o he indi idual le el analyses, bu now
wi hou combining he indi idual pa ien da a bu
pooling da abase-specific es ima es oge he . F om a
logis ic poin o iew, his ype o agg ega e me a-
analysis could be an in e es ing al e na i e o an indi-
idual le el app oach, as no indi idual pa ien da a
ha e o be ans e ed. O he me hods ha do no e-
qui e sha ing o indi idual pa ien da a in ol e a dis-
ibu ed ne wo k app oach such as he EU-ADR
15
o
a case-cen e ed logis ic eg ession app oach as de-
sc ibed by Toh and cowo ke s.
27,31
I was no always clea ly s a ed in he a icles how
he da a we e combined. Especially he echnique o
combining indi idual pa ien da a (ins ead o combin-
ing semi-agg ega e o agg ega e da a) was no always
explici ly men ioned. Mos o he a icles clea ly had
a clinical ocus, and desc ip ions o da a managemen
we e o en e y sho o comple ely missing. Cen al
p og amming was men ioned o 12 s udies, bu he
ac ual numbe o s udies ha did so is p obably highe ,
because his echnique is e y likely o he s udies
ha combined indi idual pa ien da a (16 in o al).
Howe e , he use o dis ibu ed common p og ams
was equen ly men ioned o semi-agg ega e and ag-
g ega e le el app oaches. This is a good p ac ice, be-
cause di e en ways o s a is ical p og amming may
lead o he e ogenei y be ween esul s om di e en
da abases. In he indi idual le el app oach, i was o -
en no clea ly desc ibed i and how defini ions we e
kep simila be ween da a om di e en sou ces.
Powe was he mos s a ed eason o pe o ming a
mul i-da abase s udy. Compa ing di e en popula ions
o da abases was seldom men ioned. Many pape s, es-
pecially he indi idual pa ien da a s udies, did no
show any cha ac e is ics o pa ien s om he sepa a e
da abases. O e all, only hal o he s udies pe o med
a quan i a i e he e ogenei y assessmen .
The e a e impo an s eng hs and limi a ions o his
e iew. To ou knowledge, we we e he fi s o pe -
o m a sys ema ic li e a u e sea ch abou me hods used
in mul i-da abase s udies. Full- ex sc eening was pe -
o med by wo independen e iewe s, and da a ex ac-
ion was quali y checked by a second e iewe as well.
E en hough we pe o med a sys ema ic li e a u e
sea ch, we p obably missed ele an a icles, because
he o mula ion o a sui able sea ch s a egy was no
s aigh o wa d. Ou sea ches we e limi ed om
2007 onwa ds; howe e , in ou pilo sea ches wi h
no da e fil e applied we we e no able o iden i y
any s udies published p io o 2007 ha would po en-
ially fi ou inclusion and exclusion c i e ia.
Table 2. Da a analysis echniques and da a managemen
Numbe o s udies
( o al: n = 22) %
Indi idual-le el analyses
Logis ic eg ession 9 41%
Cox p opo ional haza ds model 5 23%
Poisson eg ession 3 14%
Incidence a e /incidence a e a io 29%
P e alence /p e alence a io 15%
Rela i e isk 15%
Gene alized linea model eg ession 15%
Exposu e– ime ela ion
Time-dependen exposu e 14 64%
In en ion o ea (e e /ne e ) 7 32%
Cumula i e exposu e (dose o ime)15%
Con ounde con ol
Con en ional 11 50%
P opensi y sco e 7 32%
Disease isk sco e 15%
None 3 14%
Me a-analysis me hod (a)
Indi idual 16 73%
Semi-agg ega e 3 14%
Agg ega e 6 27%
Fixed e ec 4 18%
Fixed e ec / andom e ec 29%
None 15%
He e ogenei y assessmen
Quan i a i e es 10 45%
I-squa ed 29%
Chi-squa ed 15%
Coch an’s Q s a is ic 15%
In e ac ion by da a sou ce 15%
Kaplan–Meie s a ified by da abase 15%
No specified 4 18%
Quali a i e s a emen s only 15%
No specified 11 50%
P og amming
Cen al (leading cen e ) 12 55%
Decen al 00%
No specified 10 45%
Da a collec ed cen ally
Indi idual-based egis e da a 16 73%
Semi-agg ega e da ase s 4 18%
Agg ega e esul s 29%
Dis ibu ed common p og ams
Yes 5 23%
No specified 17 77%
(a) One s udy could con ibu e o mo e han one ca ego y.
mul i-da abase s udies: a sys ema ic li e a u e e iew 903
© 2015 The Au ho s. Pha macoepidemiology and D ug Sa e y
published by John Wiley & Sons, L d.
Pha macoepidemiology and D ug Sa e y, 2015; 24: 897–905
DOI: 10.1002/pds
Classifica ion in o he di e en le els o da a combin-
ing was done o he e iewe s’bes e o , bu was
some imes based on e y li le in o ma ion. Classifica-
ion o mo i a ions o pe o m he s udy may ha e
been suscep ible o subjec i e in e p e a ion.
In conclusion, mul i-da abase s udies a e becoming
mo e popula in obse a ional esea ch. We eel ha
he e is oom o imp o emen in making clea o he
eade how da a om di e en da abases we e com-
bined; on an indi idual, semi-agg ega e, o agg ega e
le el. Fo all scena ios, i is use ul o know how defi-
ni ions o exposu es, ou comes, con ounde s, and
ime-windows we e kep consis en ac oss he da a-
bases. Fu he , i should be explained how da a man-
agemen was o ganized, which da a we e collec ed
cen ally and whe he cen al p og amming o dis ib-
u ed common p og ams we e used. I is use ul o show
cha ac e is ics o pa ien s om he sepa a e da abases
o enable he eade o e alua e whe he he e we e
impo an di e ences. When combining da a om
di e en da abases, he pe o mance o he e ogenei y
assessmen s should become common p ac ice. E en
i he objec i e o a s udy is clinical a he han me h-
odological, all his in o ma ion enables a be e in e -
p e a ion o he esul s o a mul i-da abase s udy.
CONFLICT OF INTEREST
Ma loes T. Bazelie ’s employmen a U ech Uni e -
si y is unded by he CARING p ojec (Eu opean
Communi y’s Se en h F amewo k P og am g an
ag eemen numbe 282526).
F ank de V ies is employed by U ech Uni e si y as
a senio esea che , conduc ing esea ch coo dina ed
by The Cen e o Resea ch Me hods. The Cen e o
Resea ch Me hods has ecei ed un es ic ed unding
om he Ne he lands O ganiza ion o Heal h Re-
sea ch and De elopmen (ZonMW), he Du ch Heal h
Ca e Insu ance Boa d (CVZ), he Royal Du ch Pha -
macis s Associa ion (KNMP), he p i a e–public
unded Top Ins i u e Pha ma (www. ipha ma.nl, in-
cludes co- unding om uni e si ies, go e nmen , and
indus y), he EU Inno a i e Medicines Ini ia i e
(IMI), he EU 7 h F amewo k P og am (FP7), and
he Du ch Minis y o Heal h and indus y (including
GlaxoSmi hKline, Pfize , and o he s).
Ma ie L. De B uin is employed by U ech Uni e -
si y as a senio esea che conduc ing esea ch in col-
labo a ion wi h he WHO Collabo a ing Cen e o
pha maceu ical policy and egula ion. This Cen e e-
cei es no di ec unding o dona ions om p i a e
pa ies, including pha ma indus y. Resea ch unding
om public–p i a e pa ne ships, e.g. IMI, TI Pha ma
(www. ipha ma.nl) is accep ed unde he condi ion
ha no company-specific p oduc o company ela ed
s udy is conduc ed. The Cen e has ecei ed un e-
s ic ed esea ch unding om public sou ces, e.g.
Ne he lands O ganiza ion o Heal h Resea ch and De-
elopmen (ZonMW), he Du ch Heal h Ca e Insu -
ance Boa d (CVZ), EU 7 h F amewo k P og am
(FP7), Du ch Medicines E alua ion Boa d (MEB),
and Du ch Minis y o Heal h.
Mo en Ande sen pa icipa es/has pa icipa ed in e-
sea ch p ojec s unded by As aZeneca, Lundbeck,
Me ck Sha p & Dohme, No a is, Nycomed, and
Pfize wi h g an s ecei ed by he ins i u ions whe e
he has been employed. He has pe sonally ecei ed ees
o leading and eaching pha macoepidemiology
cou ses a anged by Medicademy, he Danish Associ-
a ion o he Pha maceu ical Indus y.
KEY POINTS
•The upcoming end o pe o ming mul i-
da abase obse a ional s udies s e ches ou o e
he en i e field o pha macoepidemiology.
•Rega ding he me hods o pe o ming such a s udy,
we ound ha he combina ion o indi idual pa ien
da a was he mos equen ly used echnique.
•The e is oom o imp o emen in making clea o
eade s how da a om di e en da abases we e
combined (on an indi idual le el o agg ega e
le el), how da a managemen was o ganized, and
whe he cen al p og amming was used.
•I is use ul o show cha ac e is ics o pa ien s
om he sepa a e da abases and he pe o mance
o he e ogenei y assessmen s should become
common p ac ice.
ETHICS STATEMENT
The au ho s confi m o ha e adhe ed o E hics p inci-
ples du ing all phases o he s udy.
ACKNOWLEDGEMENTS
The esea ch leading o he esul s o his s udy has
ecei ed unding om he Eu opean Communi y’s
Se en h F amewo k P og amme (FP-7) unde g an
ag eemen numbe 282526, he CARING p ojec .
The unding sou ce had no ole in s udy design, da a
collec ion, da a analysis, da a in e p e a ion, o w i ing
o he epo .
m. . bazelie
e al.
904
© 2015 The Au ho s. Pha macoepidemiology and D ug Sa e y
published by John Wiley & Sons, L d.
Pha macoepidemiology and D ug Sa e y, 2015; 24: 897–905
DOI: 10.1002/pds
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SUPPORTING INFORMATION
Addi ional suppo ing in o ma ion may be ound in
he online e sion o his a icle a he publishe ’s
web si e.
mul i-da abase s udies: a sys ema ic li e a u e e iew 905
© 2015 The Au ho s. Pha macoepidemiology and D ug Sa e y
published by John Wiley & Sons, L d.
Pha macoepidemiology and D ug Sa e y, 2015; 24: 897–905
DOI: 10.1002/pds