Challenges, facilitators and barriers to screening study participants in early disease stages-experience from the MACUSTAR study

RESEARCH ARTICLE Open Access Challenges, acili a o s and ba ie s o sc eening s udy pa icipan s in ea ly disease s ages-expe ience om he MACUSTAR s udy Jan Hen ik Te heyden 1* , Cha lo e Behning 2 , Anna Lüning 1 , Ludmila Win e ge s 1 , Pie G. Basile 3 , Diana Ta a es 3 , Bea iz A. Melício 3 , Se gio Leal 4 , Geo ge Weissge be 5 , Ul ich F. O. Luhmann 6 , Da id P. C abb 7 , Adnan Tu ail 8 , Ca el Hoyng 9 , Mo i z Be ge 2 , Ma hias Schmid 2 , Ru ino Sil a 3,10,11 , Cecília V. Ma inho 3 , José Cunha-Vaz 3 , F ank G. Holz 1 , Robe P. Finge 1* and on behal o he MACUSTAR conso ium Abs ac Backg ound: Rec ui ing asymp oma ic pa icipan s wi h ea ly disease s ages in o s udies is challenging and only li le is known abou acili a o s and ba ie s o sc eening and ec ui men o s udy pa icipan s. Thus we assessed ac o s associa ed wi h sc eening a es in he MACUSTAR s udy, a mul i-cen e, low-in e en ional coho s udy o ea ly s ages o age- ela ed macula degene a ion (AMD). Me hods: Sc eening a es pe clinical si e and pe week we e compiled and applicable ec ui men ac o s we e assigned o espec i e ime pe iods. A gene alized linea mixed-e ec s model including he mos ele an ec ui men ac o s iden i ied ia in-dep h in e iews wi h s udy pe sonnel was i ed o he sc eening da a. Only pa icipan s wi h in e media e AMD we e conside ed. Resul s: A o al o 766 indi idual sc eenings wi hin 87 weeks we e a ailable o analysis. The mean sc eening a e was 0.6 ± 0.9 sc eenings pe week among all si es. The pa icipa ion a in es iga o elecon e ences ( ela i e isk inc ease 1.466, 95% CI [1.018–2.112]), public holidays ( ela i e isk dec ease 0.466, 95% CI [0.367–0.591]) and eaching 80% o he si e’s ec ui men a ge ( ela i e isk dec ease 0.699, 95% CI [0.367–0.591]) we e associa ed wi h he numbe o sc eenings a an indi idual si e le el. Conclusions: Ca e ul planning o sc eening ac i i ies is necessa y when ec ui ing ea ly disease s ages in mul i- cen e obse a ional o low-in e en ional s udies. Conduc ing elecon e ences wi h local in es iga o s can inc ease sc eening a es. When planning ec ui men , seasonal and sa u a ion e ec s a clinical si e le el need o be aken in o accoun . T ial egis a ion: ClinicalT ials.go NCT03349801. Regis e ed on 22 No embe 2017. Keywo ds: Ea ly disease s ages, Age- ela ed macula degene a ion, Coho s udy, Sc eening, Rec ui men © The Au ho (s). 2021 Open Access This a icle is licensed unde a C ea i e Commons A ibu ion 4.0 In e na ional License, which pe mi s use, sha ing, adap a ion, dis ibu ion and ep oduc ion in any medium o o ma , as long as you gi e app op ia e c edi o he o iginal au ho (s) and he sou ce, p o ide a link o he C ea i e Commons licence, and indica e i changes we e made. 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BMC Medical Resea ch Me hodology (2021) 21:54 h ps://doi.o g/10.1186/s12874-021-01243-8 Backg ound Rec ui ing asymp oma ic pa icipan s wi h ea ly disease s ages in o clinical o epidemiological s udies is challen- ging because hese indi iduals migh no be awa e o hei disease and hei pe cei ed disease bu den is o en low. In o de o o e come hese challenges, ca e ul plan- ning o sc eening and ec ui men ac i i ies is c ucial. This includes ca e ul e alua ion o sc eening and ec ui - men acili a o s as well as ba ie s. A numbe o s udies ha e epo ed ac o s ha impac ec ui men a di e - en le els [1–7], bu knowledge abou how o bes iden- i y he speci ic a ge popula ion o asymp oma ic pa icipan s wi h ea ly disease s ages in o s udies e- mains limi ed. Agains his backg ound we assessed he ec ui men p ocess and any measu es which impac ed sc eening numbe s in a s udy o ea ly, la gely asymp- oma ic s ages o age- ela ed macula degene a ion (AMD). Ou goal was o e ospec i ely iden i y acili a- o s and ba ie s o sc eenings om a sponso ’s pe spec- i e in a mul i-cen e coho s udy o ea ly disease s ages. The eason o add essing ea ly AMD s ages in clinical esea ch oday is o educe he signic ican bu den o la e-s age AMD by de eloping no el in e en ions ha s op o delay p og ession om ea ly AMD s ages o la e AMD and p e en po en ially i e e sible loss o ision which make la e AMD a leading cause o isual loss in indus ialised coun ies [8,9]. Ea ly s ages o AMD p o- g ess slowly a an es ima ed a e o 5–20 pe 100 pe son-yea s o la e AMD [10] and equen ly cause no o only li le symp oms [11,12]. Simila o o he ea ly disease s ages such as ea ly Alzheime ’s disease, p edia- be es o p e-clinical cance [13–15], indi iduals wi h ea ly s ages o AMD a e equen ly no awa e o hei disease [16]. This makes i impo an o in es iga e which measu es acili a e o impede sc eening ac i i ies o clinical s udies o ea ly AMD as iden i ied ac o s a e o po en ial ele ance o o he s udies ec ui ing asymp- oma ic pa icipan s. We he ein epo he impac o bo h acili a o s and ba ie s o sc eening pa icipan s o he MACUSTAR s udy, a mul i-na ional coho s udy ocusing on he mos high- isk ea ly s age o AMD (“in e media e AMD”) om a sponso ’s pe spec i e [17]. Me hods The MACUSTAR s udy The MACUSTAR s udy is a mul i-cen e coho s udy ocusing mainly on “in e media e AMD”, a high- isk ype wi hin he ea ly AMD s ages. The main s udy ob- jec i e is he de elopmen o new candida e endpoin s o in e media e AMD clinical ials. Fo his pu pose, pa icipan s a all AMD disease s ages (no, ea ly, in e - media e and la e AMD) unde go a ba e y o unc ional es s and imaging p ocedu es and se e al pa ien - epo ed ou come measu es a e adminis e ed. The ma- jo i y o pa icipan s o he MACUSTAR s udy has in e - media e AMD and was ec ui ed a 20 s udy si es while he o he g oups (ea ly AMD, la e AMD, no AMD) we e ec ui ed only a i e s udy si es. Mo e de ails on he s udy p o ocol including he eligibili y c i e ia, isi schedule, ou come measu es and hei assessmen , con- ounde s, sou ces o bias and sample size conside a ions ha e been published p e iously [18]. Rec ui men o he MACUSTAR s udy s a ed in Ma ch 2018 and las ed o 87 weeks. Pa ien s we e sc eened and ec ui ed a 20 oph halmological clinical si es in se en Eu opean coun ies (Denma k, F ance, Ge many, I aly, Ne he lands, Po ugal and Uni ed King- dom). Fi e o hem we e academic co e pa ne s wi hin he MACUSTAR conso ium, he o he si es we e a ili- a ed wi h he conso ium and membe s o he Eu opean Vision Clinical Resea ch Ne wo k (EVICR.ne ). To acili- a e planning o sc eenings, all si es con i med hei abil- i y o ec ui a minimum o 20 indi iduals in o he MACUSTAR s udy be o e s udy ini ia ion; he co e pa - ne s ag eed o a highe a ge o 40–70 ec ui ed pa ici- pan s. He ein we e ospec i ely analyse and epo he impac o sc eening measu es, and o he ac o s ound o be ei he acili a o s o ba ie s o sc eening pa icipan s. All ins i u ional e hic commi ees app o ed he s udy and pa icipan s ga e w i en in o med consen p io o pa icipa ion. The MACUSTAR p ojec ecei es unding om he Eu opean Union Inno a i e Medicines Ini ia- i e (IMI2) Ho izon 2020 p og amme. I has been egis- e ed a he websi e clinical ials.go wi h he iden i ie NCT03349801. Inclusion c i e ia o his analysis we e indi iduals sc eened o he MACUSTAR s udy wi h he sc eening diagnosis in e media e AMD, a high- isk ype o he ea ly AMD s ages (de e mined a he clinical si e). S udy inclusion a all s udy si es was based on he e alu- a ion and con i ma ion o AMD diagnosis by a cen al eading cen e, as desc ibed p e iously [17]. Exclusion c i e ia we e missing in o med consen , pa icipa ion in any o he o he MACUSTAR s udy g oups (ea ly, o la e AMD o con ol g oup) o eloca ion o ano he clinical si e wi hin he ime o he s udy. The MACUSTAR clin- ical s udy is managed by he academic clinical esea ch o ganiza ion AIBILI (Associa ion o Inno a ion and Bio- medical Resea ch on Ligh and Image, www.aibili.p )and moni o ed by he Eu opean dis ibu ed in as uc u e ne - wo k ECRIN-ERIC (www.ec in.o g). Quali a i e e alua ion o sc eening measu es Sc eening s a egies and measu es we e planned cen- ally by a coo dina ion eam and hen implemen ed h ough AIBILI and ECRIN-ERIC ac oss all si es. In o de o be able o sys ema ically assess he impac o Te heyden e al. BMC Medical Resea ch Me hodology (2021) 21:54 Page 2 o 8 any o hese on sc eening numbe s, we ex ac ed all ele- an in o ma ion e ospec i ely om he s udy p o ocol, p o ocol amendmen s, clinical si e communica ions such as newsle e s and b ie ings, s a us epo s, mee ing mi- nu es and emails om Ma ch 2018 o Ma ch 2020. All ac o s ha may ha e con ibu ed o sc eening a es we e compiled and assigned o ime pe iods and clinical si es wi hin he ec ui men phase o he s udy whe e hey had been implemen ed. Time is measu ed in weeks since he i s si e opened. Fu he mo e, we conduc ed ou in-dep h in e iews wi h pe sonnel ac i ely in ol ed in he s udy (clinical p ojec manage s, s udy si e coo di- na o s and esea ch pe sonnel) o iden i y he mos ele- an sc eening ac o s based on he a ailable sc eening numbe s and ac o s p e iously iden i ied. The in e - iews consis ed o wo pa s o iden i y addi ionally ele- an ac o s: Fi s ly, all in e iewed pe sons we e asked o name which ac o s (a) acili a ed sc eenings o (b) impeded sc eenings. Secondly, he ac o s we e anked by he pe cei ed impac on sc eening numbe s by each pe son in e iewed. All pe sons we e in e iewed once and only quali a i e me hods we e applied du ing his s ep. Sc eening da a compila ion Due o he a ailabili y o de ices, e hics app o als, con- ac ing and he necessi y o implemen he upcoming Eu opean Union Gene al Da a P o ec ion Regula ion in 2018, he i s pa icipan s we e sc eened a di e en ime poin s a he pa icipa ing s udy si es. A e com- ple ion o ec ui men , da a om he elec onic case e- po o m and imaging da a we e collec ed and cleaned as epo ed in he s udy p o ocol [18]. Sc eening num- be s and ec ui men numbe s we e compiled pe clin- ical si e and pe week. We assigned week 1 o he i s week o ec ui men a he i s si e and used a global consecu i e numbe ing o weeks o all si es. Fac o s ha we e conside ed ele an in he quali a i e e alu- a ion (lis ed ch onologically and p eceded by a # sign in he esul s) we e assigned o speci ic clinical si es and o speci ic ime pe iods wi hin he sc eening numbe da a- base based on whe e and when hey we e implemen ed o occu ed. S a is ical modelling We explo ed he ela ionship be ween di e en sc een- ing ac o s and sc eening numbe s pe week a each clin- ical si e. The in e -co ela ion o ec ui men ac o s was assessed using Pea son co ela ion coe icien s. When wo a iables co ela ed wi h > 0.8, only he ac o mo e s ongly associa ed wi h sc eening numbe s in quali a i e e alua ion was used o u he analyses. To accoun o epea ed measu emen s wi hin he s udy si es, a gene alized mixed-e ec s model was buil o in es iga e he e ec o sc eening ac o s on he sc een- ing numbe s pe si e. As he o icial s a o he ec ui - men phase was scheduled a di e en ime poin s o each clinical si e, a andom in e cep depending on he si e’s ac i i y s a us was included. Each selec ed sc een- ing ac o en e ed he model as a ixed e ec . To cap u e a possible ime- end, he week numbe (measu ed in weeks since i s si e has opened) was also conside ed as a ixed linea e ec . Since he sc eening numbe s can be ea ed as coun da a, we used he Poisson amily wi h a loga i hmic link unc ion. Associa ions be ween sc een- ing numbe s and ac o s con ibu ing o sc eening num- be s a e p esen ed in e ms o ela i e isk inc eases (exp(β)) wi h 95% con idence in e als, whe e βdeno es he coe icien es ima e ob ained om he mixed-e ec s Poisson model. The analyses we e pe o med wi h he so wa e R, e - sion 3.6.1 (R Co e Team 2020, Vienna, Aus ia), using he packages lme4 and MuMIn [19,20]. Resul s The o e all numbe o sc eenings o he in e media e AMD g oup was 767 in 87 weeks. One pa icipan was excluded om he analysis due o eloca ing a e he sc eening isi . The las si e was opened o ec ui men 37 weeks a e he i s si e (Fig. 1). The mean sc eening a e was 0.6 ± 0.9 sc eenings pe week among all si es. A o al o 584 pa icipan s o he 766 indi iduals wi h in e media e AMD included in he analysis (76%) we e included in he MACUSTAR s udy. Quali a i e e alua ion Twen y ac o s wi h a possible impac on pa ien sc een- ings we e iden i ied a global s udy le el (Table 1). While some o hem occu ed con inuously, o he s we e linked o speci ic pe iods o ime. Sc eenings in he MACUSTAR s udy p oceeded in h ee phases. Du ing an ini ia ion pe iod (weeks 1–25), he o e all sc eening end inc eased and mos pa ici- pa ing clinical si es we e successi ely opened o ec ui - men ( ac o #1). The weekly sc eening numbe s inc eased no iceably a e he summe holiday season o 2018 (#2). Se e al sc eening / ec ui men measu es im- plemen ed con inuously h oughou he MACUSTAR s udy we e ini ia ed in his pe iod, including he ec ui - men o pa ien s om p e-sc eening lis s, use o dissem- ina ion ma e ial and a s udy newsle e as well as indi idual con ac s wi h in es iga o s (i.e. phone calls and emails o he p incipal in es iga o ). In he ensuing execu ion pe iod (weeks 26–60) weekly sc eening numbe s a ied mo e ( ange: 0–25 o al sc eenings pe week). The implemen ed measu es a he beginning o he execu ion pe iod included an inc ease o pa icipan a el expenses eimbu semen om ini ial Te heyden e al. BMC Medical Resea ch Me hodology (2021) 21:54 Page 3 o 8 EUR 50 pe isi o EUR 75 pe isi (#3), an inc eased MACUSTAR newsle e dis ibu ion equency om mon hly o biweekly (#4) and he ini ia ion o egula coo dina ion elecon e ences wi h he p ojec manage- men and moni o s (#5). Th ee elecon e ences wi h he p incipal in es iga o s (#6) we e conduc ed du ing he execu ion pe iod and sc eening numbe s inc eased a e hese elecon e ences. The elecon e ences we e used o p o ide da a om ecen in e im analyses o he s udy s a (p inciple in es iga o s, s udy coo dina o s, s udy echnicians) as well as o allow anyone o ask ques ions and sha e app oaches on common o ganiza ional hu - dles, such as he o ganiza ion o he s udy schedule, eedback on why sc eenings ailed o pi alls in he e- c ui men . Two in pe son in es iga o mee ings (#7) we e also ollowed by an inc ease in weekly sc eenings. The ec ui men pe iod was ex ended beyond he ini ial end in week 48 un il week 87 in o de o mee ec ui - men a ge s. The wo lowes weekly sc eening a es in he execu ion pe iod (weeks 39 and 56) coincided wi h Ch is mas 2018 and he planned end o ec ui men be- o e being ex ended. The hi d phase o sc eenings was a ansi ion pe iod (weeks 61–87). I was cha ac e ized by mo e s eady sc eening a es. The numbe o weekly sc eenings de- c eased in he summe holiday season 2019 bu in- c eased no iceably a e wa ds. A change in he inclusion c i e ia (#8), which opened up ec ui men o indi id- uals wi h unila e al in e media e AMD, was associa ed wi h an inc ease o he sc eenings a he end o he e- c ui men pe iod be o e he ansi ion o he ollow-up phase o he s udy. A he single clinical si e le el, he cumula i e sc een- ings ollowed wo di e en pa e ns. A eigh si es, his de elopmen inc eased con inuously while a 12 si es, a sa u a ion o he sc eening a es owa ds he end o he ec ui men pe iod was obse ed (#9). The co e pa ne si es eached highe ec ui men a es (o e all median ec ui men pe si e: 66 people) han he o he clinical si es (o e all median ec ui men pe si e: 29 people; #10). Va iable selec ion p ocess Th ee o he 10 global a iables iden i ied (Table 1) we e highly co ela ed (#3 –#5; inc ease o a el expenses eimbu semen , inc ease o newsle e equency, ini i- a ion o egula coo dina ion elecon e ences wi h he p ojec managemen and moni o s). In he in-dep h Fig. 1 Pa icipan s sc eened and pa icipan s eligible o he MACUSTAR s udy wi h in e media e age- ela ed macula degene a ion as well as numbe o ac i e si es and ac o s impac ing sc eenings, displayed pe week since s a o ec ui men a he i s s udy si e (80% a ge eached e e s o indi idual clinical si es; all o he ac o s a e global). The blue cu es ep esen cumula i e numbe s; he g ey cu e ep esen s numbe s pe week Te heyden e al. BMC Medical Resea ch Me hodology (2021) 21:54 Page 4 o 8 in e iews (see abo e), highe a el expenses eimbu se- men s we e conside ed o ha e he la ges impac on he o e all sc eening numbe s and we he e o e included his ac o in he mul i a iable model only. Thus, we iden i ied he ollowing eigh pa ame e s o u he s a - is ical e alua ion in a mul i a iable model: Modi ica ion o inclusion c i e ia, inc ease o pa icipan a el ex- penses eimbu semen , o ganiza ion o in es iga o ele- con e ences and mee ings in pe son, public holidays, sa u a ion o sc eening numbe s (80% o o e all ec ui - men pe si e), week and being a co e pa ne in he MACUSTAR conso ium. Mul i a iable sc eening numbe model A mixed-e ec s model including he a iables iden i ied quali a i ely, excluding highly co ela ed a iables ( ac- o s #1 –#3, #6 –#10, Table 1) was i ed o he sc een- ing da a. The pa icipa ion a in es iga o elecon e ences, public holidays and eaching a high p o- po ion (80%) o he si e ec ui men a ge showed s ong associa ions wi h sc eening a es a an indi idual si e le el (Table 2). The condi ional R 2 alue o he model was 0.95 [19,20]. Acco ding o his modelling ap- p oach, expec ed sc eening numbe s inc eased by he ac o exp.(β) = 1.466 (95% CI [1.018–2.112]) a e in es- iga o elecon e ences we e implemen ed, dec eased by he ac o exp.(β) = 0.446 (95% CI [0.367–0.591]) du ing public holidays and dec eased wi h a ac o o exp.(β)= 0.669 (95% CI [0.367–0.591]) a e a si e eached 80% o hei ec ui men a ge (a e adjus ing o he o he ac o s included in he model). This is in line wi h he a e age sc eenings pe week, which inc eased om 0.56 o 0.97 a he ime o in es iga o elecon e ences. They dec eased om 0.65 o 0.29 du ing holiday pe iods and om 0.67 o 0.40 when indi idual si es eached 80% o hei ec ui men a ge . Discussion In he MACUSTAR s udy, we success ully ec ui ed a la ge coho o pa icipan s wi h ea ly, mos ly asymp- oma ic AMD s ages and ound ha cons an in e ac ion wi h clinical si es including newsle e s, in es iga o mee ings, elecon e ences, indi idual con ac s and ou- bleshoo ing imp o e o e all ec ui men pe o mance. Ou o his lu y o ac i i ies, howe e , egula in es i- ga o elecon e ences we e he only measu e which was signi ican ly associa ed wi h inc eased sc eenings a si e le el. As was o be expec ed, public holidays we e associ- a ed wi h dec eased sc eening pe o mance. Si es slowed down sc eenings when hey eached 80% o hei ec ui - men a ge . In summa y, egula in e ac ions wi h he si e in es iga o s a e c ucial o a smoo h ec ui men , and his should likely be inc eased once si es need o e- c ui he las 20% as his was when sc eenings slowed down again. Table 1 Rele an global sc eening ac o s iden i ied o he MACUSTAR s udy in quali a i e e alua ion o de ed by es ima ed magni ude o impac on sc eening numbe s Sc eening measu es Fac o s p io i ized in quali a i e in e iews* O he ac o s All si es Change o inclusion c i e ia (opening o indi iduals wi h unila e al in e media e disease) (#8) Dissemina ion ma e ial (pa ien lye , e e al le e , s udy p ocedu e lye s, sample isi schedules) Inc ease o pa icipan a el expenses eimbu semen (#3) Dis ibu ion o s udy newsle e In es iga o elecon e ences (#6) In es iga o mee ings (con e ences) (#7) Le e o app ecia ion o clinical si es a ec ui men s a Inc ease o s udy newsle e equency (mon hly o biweekly) (#4) Implemen a ion o a clinical si e ques ionnai e o iden i y unsol ed issues Regula coo dina ion elecon e ences wi h he p ojec managemen and moni o s (#5) Single si es P e-sc eening lis s Indi idual con ac s wi h in es iga o s (e-mail, phone, in pe son) Indi idual con ac s wi h si e coo dina o s Appea ing in he newsle e as a “ op ec ui e ” In e ac ing ac o s Public holiday (#2) Compe i i e ec ui men Reaching a high p opo ion o he ini ial “ ec ui men a ge ”o exceeding his a ge (#9) Communica ion o ec ui ing p oblems by indi idual si es Successi e ini ia ion o sc eening ac i i y (#1) P oblems wi h s udy de ices a indi idual si es Conso ium co e membe ship (#10) * only global ac o s ha could be assigned o speci ic ime pe iods we e allowed Fac o s p eceded by a # sign we e conside ed ele an in he quali a i e e alua ion and a e displayed in he anking o de ob ained in he quali a i e e alua ion Te heyden e al. BMC Medical Resea ch Me hodology (2021) 21:54 Page 5 o 8 Failu e o ec ui a su icien numbe o pa icipan s in any s udy can ha e di e consequences. In an e alua ion o wo unding agencies, 36% o 195 ials eached less han 80% o hei ec ui men a ge s, esul ing in a e- duced powe which had medical, scien i ic, inancial and e hical implica ions [21,22]. In addi ion, low ec ui - men is a equen cause o ea ly e mina ion o clinical s udies [23]. Ca e ul ec ui men planning is he e o e an absolu e necessi y in all clinical s udies. In MACUS- TAR, no single measu e esul ed in success ul comple- ion o ec ui men alone. This is in keeping wi h a ailable li e a u e whe e i has p e iously been no ed ha only a combina ion o ec ui men measu es can lead o success ul comple ion o s udy ec ui men [24]. A e iew and me a-analysis o ec ui men acili a o s iden i ied elephone eminde s o non- esponding candi- da e pa icipan s as a signi ican acili a o o ec ui - men o andomized con olled ials [1]. We assume ha one o he media o s o his e ec was ha pa ici- pan s we e encou aged o alloca e hei esou ces in ways ha suppo ed he s udies. Simila ly, elecon e - ences wi h he in es iga o s had a signi ican posi i e impac on he MACUSTAR sc eenings in a mul i-si e se ing. In ou expe ience, elecon e ences as well as in- di idual calls allow o a pe sonal ela ionship and mul i- o bidi ec ional con e sa ions wi h he si e s a on e.g. goals and si e-speci ic di icul ies. I also suppo s pee g oup lea ning and c ea es a common sense o esponsi- bili y o he s udy. In con as o ou indings, Caldwell e al. did no ind signi ican ly inc eased ec ui men when keeping inc eased con ac wi h in es iga o s [2]. Sc eening a es o he MACUSTAR s udy d opped signi ican ly du ing public holidays. This esul has no been epo ed in he a ailable li e a u e [1–3,5,21,25– 29] bu seems sel -e iden as acili ies a e closed du ing holidays. Gkioni and colleagues e iewed models o he p edic ion o ec ui men when ials a e designed [6]. They desc ibed ha seasonal a ia ions we e conside ed by only 17% o he p edic i e models ound in he li e a- u e. We obse ed high absolu e inc eases in weekly sc eenings sho ly a e he end o holiday pe iods. This inding could be o s a egic alue o he ini ia ion o e- c ui men measu es in o he clinical s udies. We assume ha acili a ing ec ui men wi h new measu es could be pa icula ly e ec i e a e public holidays. Besides he assumed in luence o elecon e ences and public holidays, we obse ed signi ican sa u a ion e ec s o sc eening numbe s in he MACUSTAR s udy. These would be expec ed in a s udy wi h commi ed ec ui - men goals o each clinical si e. Howe e , wi h compe i- i e ec ui men in he MACUSTAR s udy his was an unexpec ed inding and u u e esea ch is needed o u - he assess his e ec . In e ms o p ac ical implica ions, sponso con ac should be inc eased o clinical si es which ha e almos eached hei ec ui men a ge . Besides hese global ac o s which we e p esen o im- plemen ed ac oss all clinical si es in his s udy, si e spe- ci ic ac o s such as exis ing e e al ne wo ks o a his o y o clinical esea ch p ojec s a e likely o impac sc eenings numbe s and ec ui men as well. Un o u- na ely, i is impossible o assess he impac o any si e- speci ic ac o s in a sys ema ic ashion as hey canno be quan i ied ac oss si es. The main s eng hs o ou analysis include i s quali a- i e and quan i a i e esea ch me hodology, i s ocus on mul i-cen e epidemiological esea ch and i s inclusion o ec ui men ac o s also iden i ied by p e ious s udies ollowing a ho ough e iew o he li e a u e. We o- cused ou analysis on sc eening numbe s on a si e le el. Rec ui men was no di ec ly assessed in ou model since ec ui ed pa icipan s ou o he pool o sc eenings we e de e mined by a cen al eading cen e, no by he local in es iga o . The main limi a ion o ou s udy is i s e ospec i e cha ac e and hus limi ed gene alizabili y o o he s udies. As he e y ew p e ious s udies on e- c ui men acili a o s we e done in con olled Table 2 Model pa ame e s o he sc eening numbe s pe week in a mul i a iable gene alized mixed-e ec s model (Poisson amily wi h loga i hmic link unc ion) P edic o βcoe icien * exp (β)* 95% in e al o exp(β)* p alue Re ision o inclusion c i e ia 0.186 1.204 (0.881–1.647) 0.243 Inc ease o a el expenses eimbu semen 0.149 1.161 (0.859–1.570) 0.331 In es iga o elecon e ences 0.382 1.466 (1.018–2.112) 0.0398 In es iga o mee ings −0.084 0.919 (0.705–1.199) 0.534 Co e pa ne si e 0.379 1.460 (0.254–8.392) 0.671 Reaching 80% o si e ec ui men a ge −0.357 0.699 (0.542–0.903) < 0.001 Public holidays −0.763 0.466 (0.367–0.591) < 0.001 Week −0.006 0.994 (0.986–1.003) 0.202 In e cep −4.19 0.015 (0.005–0.045) * adjus ed alues. No e idence o o e dispe sion was ound (dispe sion pa ame e : 1.0098, p= 0.3820 [19]). Only a sha ed ixed in e cep is added when he si e is inac i e (β 0 =−4.19, exp.(β 0 ) = 0.015, 95% CI [0.005–0.045]). Random in e cep s α o ac i e clinical si es anged om 3.42 o 4.35 Te heyden e al. BMC Medical Resea ch Me hodology (2021) 21:54 Page 6 o 8 in e en ional ials, ou esul s om his obse a ional s udy ha e o be in e p e ed wi h cau ion bu add o he exis ing li e a u e. In addi ion, ou analyses p o ide alu- able in o ma ion in pa icula ele an o s udies ec ui - ing di icul o ec ui popula ions such as ea ly and asymp oma ic disease s ages [30]. In conclusion, many di e en acili a o s and ba ie s likely in e ac ed du ing he ec ui men phase o he MACUSTAR s udy, a mul i-si e coho s udy o ea ly s ages o AMD. Regula elecon e ences wi h si e in es i- ga o s inc eased while public holidays and sc eening ac- i i y sa u a ion a indi idual clinical si es dec eased sc eening pe o mance. These ac o s should be gi en special a en ion in he design and conduc ion o u u e s udies as well as selec ion o clinical si es in pa icula when ec ui ing pa icipan s wi h ea ly and la gely asymp oma ic disease s ages. Abb e ia ions AIBILI: Associa ion o Inno a ion and Biomedical Resea ch on Ligh and Image; AMD: Age- ela ed macula degene a ion; CI: Con idence in e al; EVIC R.ne : Eu opean Vision Clinical Resea ch Ne wo k Acknowledgmen s We a e e y g a e ul o he con inuous suppo p o ided by Na halie Seigneu e a he IMI O ice in B ussels. We also g a e ully acknowledge he wo k pu in o his p ojec by conso ium membe s who ha e since mo ed on o wo k elsewhe e. Disclaime The communica ion e lec s he au ho ’s iew and nei he IMI no he Eu opean Union, EFPIA, o any associa ed pa ne s a e esponsible o any use ha may be made o he in o ma ion con ained he ein. Au ho s’con ibu ions FGH, RPF, MS, UFOL, DPC, AT, CVM, JCV, RS and CH designed he s udy. JHT, AL, LW, PGB and DT compiled he da ase . JHT, CB, MB, MS and RPF analysed he da a. JHT, CB and RPF w o e he manusc ip . All au ho s con ibu ed subs an ially o he concep ion o design o he s udy, da a acquisi ion, da a analysis o da a in e p e a ion as well as o d a ing he manusc ip o c i ically e ising i . They app o ed he inal e sion o be published. Funding This p ojec has ecei ed unding om he Inno a i e Medicines Ini ia i e 2 Join Unde aking unde g an ag eemen No 116076. This Join Unde aking ecei es suppo om he Eu opean Union’s Ho izon 2020 esea ch and inno a ion p og amme and EFPIA. Open Access unding enabled and o ganized by P ojek DEAL. A ailabili y o da a and ma e ials The da a p o ing he main indings o he s udy a e con ained wi hin he manusc ip . The o e all da ase used o analysis is a ailable om he MACUSTAR conso ium and he MACUSTAR da a access commi ee upon easonable eques ([email p o ec ed]). Decla a ions E hics app o al and consen o pa icipa e All ins i u ional e hic commi ees app o ed he s udy and pa icipan s ga e w i en in o med consen p io o pa icipa ion, as epo ed p e iously. These commi ees included Uni e si y Hospi al Bonn e hics commi ee (384/17), Pa is Oues IV (04/18_2), AIBILI (032/2017/AIBILI/CE), No a Medical School (13507/2017), London Queen Squa e Resea ch E hics Commi ee (18/LO/ 0145), Cen e o Sundhed Glos up (H-18000126), Comi a o E ico Milano (37910/2018), Ospedale San Ra aele (da ed 25/10/2018), Radboudumc echnology cen e (2017–3954) and LUMC commissie medische e hiek (L18.055/SH/sh). Consen o publica ion No applicable. Compe ing in e es s J. H. Te heyden: Heidelbe g Enginee ing, Op os, Ca l Zeiss MedicTec, Cen e Vue. C. Behning: None. A. Lüning: Heidelbe g Enginee ing, Op os, Ca l Zeiss MedicTec, Cen e Vue. L. Win e ge s : Heidelbe g Enginee ing, Op os, Ca l Zeiss MedicTec, Cen e Vue. P. G. Basile: None. D. Ta a es: None. B. A. Melício: None. S. Leal: Employee o Baye AG. G. Weissge be : Employee o No a is Pha ma AG. U. F. O. Luhmann: Employee o F. Ho mann-La Roche L d. D. P. C abb: Alle gan, Roche, San en, Cen e ue. A. Tu ail: None. C. Hoyng: Op os, Baye . M. Be ge : None. M. Schmid: Pixum Vision. R. Sil a: Alle gan, Allime a Sciences, Alcon, Baye , No a is, Thea. C. V. Ma inho: EVICR.ne J. Cunha-Vaz: Alime a Sciences, Alle gan, Baye , Gene Signal, No a is, P ize , P ecision Ocula L d., Roche, Sano i-A en is, Vi o Pha ma and Ca l Zeiss Med- i ec, EVICR.ne F. G. Holz: Acucela, Alle gan, Apellis, Baye , Boeh inge -Ingelheim, Bioeq/Fo - mycon, Cen e Vue, Ellex, Roche/Genen ech, Geude , G aybu g Vision, Heidel- be g Enginee ing, Kanghong, LinBioscience, Nigh S a X, No a is, Op os, Pixium, Vision, Oxu ion, S eal h BioThe apeu ics, Zeiss. R. P. Finge : No a is, Baye , Alle gan, Alime a, Roche/Genen ech, San he a, Op hea, Inosi ec, Ellex, Cen eVue, Zeiss, Heidelbe g Enginee ing. Au ho de ails 1 Depa men o Oph halmology, Uni e si y Hospi al Bonn, Bonn, Ge many. 2 Ins i u e o Medical Biome y, In o ma ics and Epidemiology, Uni e si y Hospi al Bonn, Bonn, Ge many. 3 Associa ion o Inno a ion and Biomedical Resea ch on Ligh and Image, Coimb a, Po ugal. 4 Baye AG, Be lin, Ge many. 5 No a is Pha ma AG, Basel, Swi ze land. 6 Roche Pha maceu ical Resea ch and Ea ly De elopmen , T ansla ional Medicine Oph halmology, Roche Pha ma Resea ch and Ea ly De elopmen , Roche Inno a ion Cen e , Basel, Swi ze land. 7 Di ision o Op ome y and Visual Sciences, School o Heal h Sciences, Ci y, Uni e si y o London, London, UK. 8 Moo ields Eye Hospi al, London, UK. 9 Radboud Uni e si y Medical Cen e , Nijmegen, Ne he lands. 10 Uni e si y o Coimb a, Coimb a Ins i u e o Clinical and Biomedical Resea ch (iCBR), Facul y o Medicine, Coimb a, Po ugal. 11 Oph halmology Depa men , Cen o Hospi ala e Uni e si á io de Coimb a (CHUC), Coimb a, Po ugal. 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