Patient's Experience in Pediatric Primary Immunodeficiency Disorders: Computerized Classification of Questionnaires.

Ap il 2017 | Volume 8 | A icle 3841 O iginal esea ch published: 05 Ap il 2017 doi: 10.3389/ immu.2017.00384 F on ie s in Immunology | www. on ie sin.o g Edi ed by: Isabelle Mey s, KU Leu en, Belgium Re iewed by: Es he De V ies, Tilbu g Uni e si y, Ne he lands Filomeen Hae ynck, Ghen Uni e si y, Belgium Isabella Quin i, Sapienza Uni e si y o Rome, I aly *Co espondence: Lo enz G igull g igull.lo enz@mh-hanno e .de Special y sec ion: This a icle was submi ed o P ima y Immunode iciencies, a sec ion o he jou nal F on ie s in Immunology Recei ed: 16No embe 2016 Accep ed: 17Ma ch2017 Published: 05Ap il2017 Ci a ion: MückeU, KlemannC, BaumannU, Meye -Bahlbu gA, Ko umX, KlawonnF, Lechne WM and G igullL (2017) Pa ien ’s Expe ience in Pedia ic P ima y Immunode iciency Diso de s: Compu e ized Classi ica ion o Ques ionnai es. F on . Immunol. 8:384. doi: 10.3389/ immu.2017.00384 Pa ien ’s expe ience in Pedia ic P ima y immunode iciency Diso de s: compu e ized classi ica ion o Ques ionnai es U s Mücke1, Ch is ian Klemann2, Ul ich Baumann3, Almu Meye -Bahlbu g4, Xiaowei Ko um5, F ank Klawonn5,6, We ne M. Lechne 7 and Lo enz G igull1* 1 Depa men o Pedia ic Hema ology and Oncology, Hanno e Medical School, Hanno e , Ge many, 2 Depa men o Pedia ic Su ge y, Hanno e Medical School, Hanno e , Ge many, 3 Depa men o Pedia ic Pulmonology, Hanno e Medical School, Hanno e , Ge many, 4 Depa men o Pedia ics, Uni e si y Medicine G ei swald, G ei swald, Ge many, 5 Helmhol z Cen e o In ec ion Resea ch, B aunschweig, Ge many, 6 Os alia Uni e si y o Applied Sciences, Wol enbue el, Ge many, 7 Imp o ed Medical Diagnos ics, IMD GmbH, Hanno e , Ge many in oduc ion: P ima y immunode iciency diso de s (PIDs) a e a he e ogeneous g oup o mo e han 200 a e diseases. Timely diagnosis is o u e mos impo ance. The e o e, we aimed o de elop a diagnos ic ques ionnai e wi h compu e ized pa e n- ecogni ion in o de o suppo physicians o iden i y suspicious pa ien his o ies. Ma e ials and me hods: S anda dized in e iews we e conduc ed wi h gua dians o child en wi h PID. The ques ionnai e based on pa en al obse a ions was de eloped using Colaizzis’ amewo k o con en analysis. Answe s om 64 PID pa ien s and 62 con ols we e analyzed by da a mining me hods in o de o make a diagnos ic p edic ion. Pe o mance was e alua ed by k- old s a i ied c oss- alida ion. esul s: The diagnos ic suppo ool achie ed a diagnos ic sensi i i y o up o 98%. The analysis o 12 in e iews e ealed 26 main phenomena obse ed by pa en s in he p e-diagnos ic pe iod. The ques ions we e sys ema ically ph ased and selec ed esul ing in a 36-i em ques ionnai e. This was answe ed by 126 pa ien s wi h o wi hou PID o e alua e p edic ion. I em analysis e ealed signi ican ques ions. Discussion: Ou app oach p o ed sui able o ecognizing pa e ns and hus di e en- ia es be ween obse a ions o PID pa ien s and con ol g oups. These indings p o ide he basis o de eloping a ool suppo ing physicians o conside a PID wi h a ques ion- nai e. These da a suppo he no ion ha pa ien ’s expe ience is a co ne s one in he diagnos ic p ocess. Keywo ds: p ima y immunode iciency disease, da a mining, diagnos ic suppo , ques ionnai e, colaizzi Abb e ia ions: PID, p ima y immunode iciency diso de ; SVMs, suppo ec o machines, RFs, andom o es s; LR, logis ic eg ession; NB, nai e Bayes classi ie s; LD, linea disc iminan ; NNs, analysis and nea es neighbo classi ie s. Table 1 | spec um o diseases in he in e iews: 12 in e iews wi h pa en s o child en su e ing om di e en diseases we e conduc ed. in e iew ca ego y Disease A P edominan ly an ibody de iciencies CVID B P edominan ly an ibody de iciencies CVID C Well-de ined synd omes wi h immunode iciency A axia eleangiec asia D P edominan ly an ibody de iciencies CVID E Complemen de iciencies C2 de iciency F Combined immunode iciencies Ce nunnos G Unde ined immunode iciency Combined immunode iciency wi h di e en cy openia H Well-de ined synd omes wi h immunode iciency Nijmegen b eakage synd ome I Congeni al de ec s o phagocy e numbe , unc ion, o bo h X-linked ch onic g anuloma ous disease J Unde ined immunode iciency Unde ined se e e immunode iciency K P edominan ly an ibody de iciencies CVID L Well-de ined synd omes wi h immunode iciency Nijmegen b eakage synd ome Mos common diagnosis was common a iable immunode iciency (CVID, n=4). 2 Mücke e al. Compu e ized Classi ica ion o Ques ionnai es F on ie s in Immunology | www. on ie sin.o g Ap il 2017 | Volume 8 | A icle 384 inT ODUcTiOn P ima y immunode iciency diso de s (PIDs) in child en a e a g oup o mo e han 200 a e diseases p esen ing a wide spec um o symp oms (1, 2). Al hough p og ess in gene ic de ini ion has been made, clinical diagnos ics emains a challenging ask o he gene al p ac i ione (GP) o pedia ician. Ea ly diagnosis is o pa amoun impo ance because he delay leads o inc eased mo ali y, mo bidi y, and educed quali y o li e (3, 4). Al hough he ime o diagnosis a ies, diagnos ic delay is common (5–8). Hence, se e al e o s ha e been made o suppo pa ien – p o ide communica ion and ea ly e e al o specialis s. Diagnos ic wa ning signs, educa ion campaigns, and guidelines ha e been in oduced in o de o aise awa eness and o sho en diagnos ic delay (9, 10). Howe e , Subba ayan e al. (11) s a e ha exis ing ools do no wo k su icien ly and new app oaches a e eques ed (12). In his ega d, pa ien ’s medical his o ies o e clues o conside ing a PID. P e ious s udies ha e emphasized he impo ance o medical his o y aking as app oxima ely 80% o he diagnoses could be es ablished by ca e ul his o y aking only (13, 14). Howe e , hese s udies do no ocus on PID. Due o he mul i ude o di e en immune de ec s and he highly a iable clinical p esen a ion, es ablishing he diagnosis o PID is pa icu- la ly challenging. In some cases, he unde lying a e condi ion mimics common diseases. In all cases, physician’s expe ience and backg ound de e mine whe he a e e al and u he es ing a e o de ed (15). Be o e es ablishing a diagnosis, pa en s o en ecognize peculia i ies. Ye , wi hou an immunological expe a hand, i is di icul o pu hese obse a ions in o he con ex o a pa icula disease. The e o e, he ques ion o how o decide which pa ien should ecei e u he in es iga ion gains sup eme signi icance. P io o es ablishing a co ec diagnosis, diagnos ic e o s occu in all medical ields (16, 17) and migh be caused by a i- ous ac o s such as unusual o silen p esen a ion o he disease, una ailabili y o expe ise, o inadequa e knowledge (18). Key indings sugges ha pa ien s should be enabled o ell hei s o y app op ia ely, and doc o s ha e o compensa e an una oidable lack o expe ience conce ning a e diseases (19, 20). The e o e, we in oduce compu e ized analysis o pa en al obse a ions collec ed in a no el ques ionnai e o p o ide addi ional suppo . Ou aim was no o de ine a co ec and speci ic diagnosis bu o iden i y he need o imely e e al o a PID specialis . Some s udies al eady indica e he po en ial use o pa ien -cen e ed ques ionnai es and da a mining in diseases wi h a a he na ow spec um o symp oms (21–23). To aid he disco e y o unknown co ela ions o o de i e ecommenda- ions o u he ac ion, compu e -assis ed analysis o huge amoun s o da a is use ul (24). This a ge ed pa e n analysis has al eady been es ablished in in e ne sea ch engines, bank- ing, insu ance, and ma ke ing. I is used o make a p edic ion o o se e as an immedia e ale unc ion. In medicine such algo i hms ha e been applied success ully in di e en con ex s (25, 26). We hypo hesized ha p e-diagnos ic expe iences o PID pa ien s could be used o de elop a ques ionnai e. Such a ques- ionnai e should dis inguish di e en pa ien coho s using da a mining classi ie s. This in es iga ion could es ablish a basis o de elop a compu e ized diagnos ic suppo ool. MaTe ials anD MeThODs A i s , pa ien -cen e ed semi-s uc u ed in e iews wi h gua d- ians o child en wi h a con i med PID we e conduc ed. The s udy p o ocol was app o ed by he e hics commi ee o Hanno e Medical School and w i en in o med consen was ob ained om each gua dian. An o e iew o he diseases included in he in e iew p ocess is p o ided in Table1. The selec ion o in e iew pa ne s ollowed p ede ined p inciples: su icien speech comp ehension, w i en consen , con i med PID, child en’s age 0–18yea s, majo i y o he eigh IUIS-ca ego ies (27) should be ep esen ed by a leas one in e - iew, inclusion o u he in e iewees un il heo e ical sa u a ion (28). In e iewe s used a guideline o s anda dized p ocedu e and a uni o m beginning (wha did you obse e ega ding you child’s heal h and gene al de elopmen be o e he doc o s could inally ell you ha you child su e s om a PID?). Each in e - iew was analyzed using Colaizzi’s amewo k wi h espec o phenomena expe ienced by pa en s in he p e-diagnos ic pe iod (see Figu e 1). This s anda dized p ocedu e con ains se en de ined s eps and is well es ablished in social sciences o con en analysis (29). The esul s o he analysis we e documen ed in a able con aining a sepa a e column o each s ep. The phenomena we e so ed depending on occu ence in he in e iews in o de o in eg a e ele an obse a ions in he ques ionnai e. Fo s udy pu pose, we added a s ep o ques ion gene a ion (see Figu e1). Membe s o he s udy g oup used he esul s o d a ques- ions. The pa en al poin o iew and he choice o wo ds we e in eg a ed in he de elopmen o he ques ionnai e. All ques ions we e summa ized in a ques ion pool o u he selec ion. Each ques ion ecei ed an iden i ica ion numbe o e aceabili y o i s o igin. The o al numbe o ques ions was sys ema ically FigU e 1 | colaizzi’s amewo k con ains de ined s eps o s anda dized con en analysis. Modi ica ion: “ph asing o ques ions” was inse ed o s udy pu pose. 3 Mücke e al. Compu e ized Classi ica ion o Ques ionnai es F on ie s in Immunology | www. on ie sin.o g Ap il 2017 | Volume 8 | A icle 384 educed ollowing p ede ined equi emen s: each phenomenon ele an o he p e-diagnos ic pe iod was ep esen ed by a leas one i em, and he mos ele an phenomena we e inco po a ed by addi ional ques ions. Duplica es we e canceled, a p e es o com- p ehensibili y, consensus in he s udy g oup, and expe opinion we e in eg a ed. The ull esul ing ques ionnai e consequen ly e lec s he p e-diagnos ic expe ience o pa en s wi h a child a ec ed by PID (Table S1 in Supplemen a y Ma e ial). Dis ibu ion o he Ques ionnai e To gene a e a da a se , he ques ionnai e was dis ibu ed o pa ien s who isi ed he Immunological Ou pa ien Clinic o he Hanno e Medical School in 2013 and 2014 o egula appoin - men . All pa ien s had an es ablished diagnosis o PID. An addi- ional online e sion was accessible o membe s o he pa ien g oup o PID in Ge many [Deu sche Selbs hil e Angebo ene Immunde ek e (DSAI)] wi h a special access code. As a con ol g oup, we andomly collec ed ques ionnai es om gua dians o heal hy child en and child en who we e hospi alized due o a disease o he han PID. Da a Mining Me hods S a is ical so wa e lib a ies o e di e en compu e -based me hods o analyze and classi y da a. Mos o hese me hods a e a ia ions o main s a is ical concep s like ec o space me hods o a i icial neu al ne wo ks. The ool unde discussion uses sup- po ec o machines, andom o es s, logis ic eg ession (LR), nai e Bayes classi ie s, linea disc iminan analysis and nea es neighbo classi ie s (30). Classi ie s we e ained and es ed wi h ques ionnai es p ocessed in nume ic able o ma . A usion algo- i hm combined he di e en p edic ions made by each single classi ie o one inal decision (31). Valida ion o he sys em was pe o med in wo s eps. Fi s , he diagnos ic accu acy was chal- lenged using wo se s o ques ionnai es: child en wi h PID and heal hy child en. In a second s ep, he sys em had o dis inguish be ween ques ionnai es o PID child en and a combina ion o andomly chosen heal hy and sick child en wi h di e en diseases, e.g., se e e b onchi is, b ain umo , cys ic ib osis, and ulce a i e coli is ( ull spec um, see Table S2 in Supplemen a y Ma e ial). On bo h le els, alida ion was pe o med by k- old s a i ied c oss- alida ion. In addi ion, we analyzed ques ions conce ning hei con ibu ion o he co ec classi ica ion based on he p-Value o he coe icien s in LR, i.e., wi h he null hypo h- esis ha he coe icien o he ques ion is 0, meaning ha he co esponding ques ion does no con ibu e signi ican ly o he p edic ion based on LR. esUlTs co e Phenomena We e e ealed h ough F equen Pa en al Obse a ions in s anda dized, semi-s uc u ed in e iews The analysis o he in e iews using Colaizzi’s amewo k e ealed majo hemes such as ch onological cha ac e is ics o in ec ions, pa en al pe cep ion o in ec ions, suscep ibili y o in ec ions in e e yday li e, in ec ions o he espi a o y ac , and e ec i eness o an ibio ic ea men (Table S3 in Supplemen a y Ma e ial). These we e exp essed in wo ds and concep s by he a ge g oup. gene a ion o a 36-i em Ques ionnai e by s anda dized con en analysis Based on majo hemes and quo a ions, 186 p elimina y ques- ions we e ph ased o ep esen he pa en al pe spec i e (no shown). Fo he inal e sion, he ques ions we e sys ema ically educed (Table S1 in Supplemen a y Ma e ial). Reasons o exclu- sion we e: duplica ions in o m and con en , i ele ance o he p e-diagnos ic pe iod, and incomp ehensibili y. Modi ica ions we e discussed wi h expe ienced immunologis s and app o ed by consensus o he s udy g oup. The inal ques ionnai e was sub- sequen ly comple ed by 126 pa en s. A low cha o he p ocess is shown in Figu e2. He e, he inal ques ionnai e was comple ed by pa en s om di e en pa ien collec i es. The esul ing aw da a se consis ed o 64 ques ionnai es om child en wi h PID and 62 ques ionnai es wi hou PID (35 heal hy+27 pa ien s wi h illness o he han PID, see Figu e3). The mos common diagnoses in he PID g oup we e common a iable immunode iciency diso de s (CVID) (n=11) and agammaglobulinemia (n=10) (see Table2). Diagnoses in he illness-o he - han-PID g oup we e e.g., acu e lympha ic leukemia, coli is ulce osa, cys ic ib osis, and ch onic enal ailu e (Table S2 in Supplemen a y Ma e ial). iden i ica ion o suspicious answe Pa e ns by Da a Mining shows a sensi i i y o up o 98% 99 indi iduals answe ed he ques ionnai e o s ep 1. This g oup consis ed o 64 indi iduals wi h PID and 35 heal hy child en se ing as a con ol g oup (see Figu e 2). A 11- old s a i ied FigU e 2 | Flow cha o he s udy p ocedu e. A e conduc ion o 12 in e iews wi h pa en s o p ima y immunode iciency diso de (PID) pa ien s, con en analysis was used o de elop a 36-i em ques ionnai e. The no el ques ionnai e was u ilized o collec da a o aining and es ing o da a mining echniques conce ning classi ica ion app oaches esul ing in sensi i i y up o 98%. 4 Mücke e al. Compu e ized Classi ica ion o Ques ionnai es F on ie s in Immunology | www. on ie sin.o g Ap il 2017 | Volume 8 | A icle 384 c oss alida ion showed an o e all sensi i i y o 98%. Rega ding he g oup o child en wi h PID, 63 o 64 (98%) ecei ed he co - ec diagnosis, and 34/35 o he con ols we e classi ied co ec ly. In o al, 97/99 indi iduals ecei ed he co ec diagnosis in he c oss- alida ion. Subsequen ly, 27 ques ionnai es o andomly chosen child en wi h di e en diseases we e added o he da a se (see Figu e3). A 21- old s a i ied c oss- alida ion was pe - o med o examine diagnos ic sensi i i y. In his g oup (PID pa ien s compa ed o heal hy + illness o he han PID), 113/126 (90%) o he ques ionnai es we e clas- si ied co ec ly. In de ail, 61/64 indi iduals wi h PID ecei ed he co ec diagnosis, bu only 52/62 indi iduals we e co ec ly classi ied as “no-PID.” analysis Disco e ed Ques ions signi ican o Di e en ia ion The analysis o he 36 ques ions, using p-Value compu a ion, e ealed 32 ques ions which con ibu ed o he co ec classi ica- ion signi ican ly (p<0.05). Ques ions wi h highes signi icance in s ep 2 (PID s. heal hy+illness o he han PID) we e Q1 (Did you child su e om ill heal h cons an ly?) Q31 (Is i ue ha you child’s in ec ions las ed longe han he ones o o he child en?) Q32 (Is i ue ha you child was ea ed wi h an ibio ics egula ly?) Q35 (Is i ue ha he doc o s could no ell wha you child was su e ing om?) Th ee-dimensional Visualiza ion o answe Pa e ns Di e en ia es heal hy om sick child en In e ms o a classi ica ion p oblem he answe pa e n classi i- ca ion wi h 36 i ems consis s o 36 dimensions as 36 ques ions we e answe ed. Based on Sammon mapping, a h ee-dimensional ep esen a ion o he da a was gene a ed (see Figu e4) (32). I isualizes he ques ionnai es conce ning he co ec classi ica- ion, and illus a es he gene al p inciple o dis inguishing wo g oups o pa ien s. Compa ing s ep 1 and s ep 2 o he s udy (Figu es 4A,B) mo e o e lapping o he coho s is shown in Figu e4B. O e lapping ques ionnai es can ep esen misdiag- nosed cases. DiscUssiOn The diagnosis o PID p esen s a challenge o pedia icians due o a e incidence and unspeci ic symp oms, esul ing in delayed e e al and nega i e ou come o pa ien s and pa en s (3, 4). The p e-diagnos ic expe ience o pa ien s and hei amilies is no su icien ly in eg a ed in o he diagnos ic p ocess. The s udy a hand indica es ha a no el combina ion o a ques ionnai e and da a mining echniques p o ides he means o iden i y suspicious answe pa e ns. Ou da a show ha pa ien in e iews a e a easible ool o gene a e ques ionnai es. In o de o imp o e he quali y o he ques ions, pa en al in e iews we e ob ained o collec obse a ions om he p e-diagnos ic ime. Colaizzi’s me hod is widely applied in nu sing science and quali a i e esea ch and has p o en use ul o de i e knowledge om in e iews (33, 34). I appea s o be use ul o collec pe sonal expe i- ence and o mine i o he gene a ion o a ques ionnai e (35). The da a gene a ed in his s udy suppo s he impac o quali a i e esea ch in he diagnos ic p ocess (36). Ou da a gi e impo an insigh s in o he pa en s’ pe cep ions p io o diagnosis as opposed o clinical ocus, and likewise easons o he diagnos ic delay could be exposed. An ad an age o Colaizzi’s amewo k is he s anda dized p ocedu e, which makes he connec ion be ween ci a ion and gene a ed ques ion e aceable (37). In ou app oach, we combined six classi ie s and added a usion algo i hm o inc ease sensi i i y. Ou combina ion showed a sensi i i y o 84–98%. In compa ison o s ep 1 and s ep 2, sensi i i y dec eased when adding sick child en o heal hy con ols. The o e all sensi i i y o 90% in s ep 2 s ill unde sco es he p omising pe o mance o he echniques pilo ed he e. The applica ion o a usion algo i hm imp o ed he diagnos ic quali y o he ool. Recen ly, he concep o ques ionnai es and da a mining was success ully pilo ed by Ro he e al. (23). They applied ela ed echniques on pulmona y diseases and achie ed encou aging esul s. The combina ion o a ques ionnai e and da a mining has al eady been es ed in diagnosing gas oesophageal e lux dis- ease (GERD) (21). The ool di e en ia es be ween complain s caused by GERD and o he dyspep ic diso de s. In con as o ou s udy, Ho owi z e al. used a sho e ques ionnai e (15 s. 36 i ems), did no use ex ensi e in e iews o accumula e obse a ions, and applied less da a mining echniques. I is impo an o emphasize ha he p ocess o p o essional medical his o y aking is nei he in ended no sui able o be eplaced by ques ionnai es. In ac , his o y aking migh be imp o ed because he diagnos ic ool highligh s hose ques ions, Table 2 | The ou mos equen diagnoses o child en wi h p ima y immunode iciency diso de s (PiDs): he ou mos equen diagnoses o a o al o 64 ques ionnai es ecei ed om PiD pa ien s. Diagnosis n Common a iable immune de iciency (CVID) 11 Agammaglobulinemia 10 Synd omes wi h ecu en e e (TRAPS+PFAPA) 6 Ch onic g anuloma ous disease 5 TRAPS, TNF ecep o -associa ed pe iodic synd ome; PFAPA, pe iodic e e wi h aph hous s oma i is, pha yngi is, and adeni is. FigU e 3 | Da a sou ce o ques ionnai es o de ed by ca ego y showing s epwise analysis app oach. Ques ionnai es we e dis ibu ed o h ee g oups and subsequen ly used o da a mining aining and es . Tes o classi ica ion skills was pe o med in s ep 1 [p ima y immunode iciency diso de s (PIDs) s. heal hy] and s ep 2 (PID s. no PID). No-PID con ains ques ionnai es o heal hy child en and child en wi h illness o he han PID. 5 Mücke e al. Compu e ized Classi ica ion o Ques ionnai es F on ie s in Immunology | www. on ie sin.o g Ap il 2017 | Volume 8 | A icle 384 which da a mining sugges ed o be o high diagnos ic ele ance. Physicians can cla i y he pas medical his o y and ecei e addi- ional hin s (38–40). The accep ance o diagnos ic ques ionnai es has al eady been p o en (41). Some expe s s ess he no ion ha mo e awa eness o PID is needed among physicians in e ia y hospi als (11). Ye , Lankisch e al. (42) sugges ocusing on p ima y ca e physicians and pedia icians wi hou p o ound expe ience in PID. Lankisch e al. p o ided a modi ied ca alog o wa ning signs and achie ed imp o ed esul s o de ec ing child en wi h PID compa ed o classic wa ning signs (12, 42). Howe e , hey unde lined he need o imp o emen s in he diagnos ic pa hway in o de o de ec p e e ably 9 ou o 10 child en su e ing om PID. The ool pilo ed he e migh help o ill his gap despi e he p elimina y cha ac e o he s udy as well as i s limi a ions. Di e en pape - based ques ionnai es a e nowadays used on occasion in ou pa- ien clinics o collec da a abou pa ien s’ medical his o y. They a e based on expe opinion, mos a e no empi ically e i ied, and hey a e in e p e ed manually de i ing hin s depending on examine s expe ise. In con as , ou ool ocuses on he pa ien s o gua dians pe spec i e, can be s a is ically e iewed, is ex end- able, imp o ed by adding mo e da a, and i wo ks independen ly om he doc o ’s expe ience. Pa s o ou ques ionnai e e lec cu en guidelines (43). Addi ionally, he ques ions wi h high impac o he diagnosis PID sha e simila i ies o he classical “wa ning signs” bu also di e ences. The usage o an ibio ics is included in bo h ools. Simple ques ions like Q1 (did you child su e om ill heal h cons an ly?) and Q36 (is i ue ha you child was absen om school/p e-school/kinde ga en due o sickness mo e o en han o he child en?) a e solely de i ed om pa en al expe ience and e ealed an impo an con ibu ion o co ec classi ica ion. In con as o an analysis by Subba ayan e al. (11), a posi i e amily his o y was no signi ican o inding he co ec diagnosis in ou coho . This esul suppo s a p esump ion by B odszki e al. (44) who s a es ha he deg ee o consanguini y in he collec i e is essen ial. Kallus (45) unde lines ha a speci ic a ibu e has o be ep esen ed in a sample o en enough o each su icien disc imina o y powe . Fo his eason, a ques ionnai e con aining mo e han 10 i ems inc eases he p obabili y o ca ch su icien obse a ions. Ne e heless, i is no a single ques ion ha makes he di e ence. I is he combina ion o se e al ques ions wi h di e en con ibu ions o he co ec classi ica ion ha makes diagnos ic hin s possible. Ou s udy has se e al limi a ions: i s o all, as i is a s udy o p oo o concep , only a na ow spec um o diagnoses was included in he in e iew phase. Likewise, only a small pa o all known PID was ep esen ed. Second, he numbe o pa ien s and con ols is limi ed. Ne e heless, c oss- alida ion suppo s he esul s which need e-e alua ion in a p ospec i e ial. Besides, diagnos ic suppo was also possible o hose diagnoses no included in he in e iews indica ing he plas ici y o he sys em. Thi d, using a w i en ques ionnai e limi s he usage o a ool. Fo example, i equi es enough language comp ehension. The ques- ionnai e was gene a ed and e alua ed in Ge man. Today, he ans e in o di e en languages and cul u es and ep oduc ion o he excellen esul s is unp o en. In he e a o mul icul u al socie ies, a uni e sal comp ehensibili y independen o language abili y would be desi able (46). Table compu e s, which ha e al eady been posi i ely e alua ed in o he a eas could be used o educe he e o o comple ion o he ques ionnai e and i s in e p e a ion (47, 48). Fu he mo e, possible online adap ions o pape e sions al eady p oo ed usabili y in o he a eas (49). A u he limi a ion is ela ed o he selec ion o con ols. The coho s do no e lec he egula spec um o pa ien s seen by GP o pedia icians. Ideally, his s udy should ha e inco po a ed a con ol g oup ep esen a i e o he day- o-day popula ion o GP and/o gene al pedia icians. Con ols p esen ing wi h symp oms suspicious o a PID would ha e answe ed a ques ion- nai e p io o he e e al o an immunologis . Due o limi ed esou ces, his e alua ion will be pa o a u u e ial based on his pilo p oo o concep . Thus, u he p ospec i e s udies wi h pa ien s p esen ing PID-like symp oms a e needed o e i y ou app oach. FigU e 4 | Visualiza ion o answe s indica es di e en answe pa e n. Answe pa e n can be isualized by he dimension educ ion echnique Sammon mapping. X=p ima y immunode iciency diso de (PID), O=con ol. (a) Classes PIDs s. heal hy a e easy o dis inguish. (b) Due o inc eased he e ogenei y i is mo e di icul o disc imina e classes PID s. no-PID. No-PID con ains ques ionnai es om heal hy child en and child en su e ing om illnesses o he han PID. 6 Mücke e al. Compu e ized Classi ica ion o Ques ionnai es F on ie s in Immunology | www. on ie sin.o g Ap il 2017 | Volume 8 | A icle 384 Taken oge he , we success ully pilo ed a ques ionnai e-based ool in ended o classi y di e en pa ien coho s. A diagnos ic ool o de ec ion o child en wi h PID could be used in di e en se ings: he GP o he pedia ician could hand i o pa en s wi h child en showing ecu en in ec ions o eas- su e he need o u he diagnos ics. The ques ionnai e could be answe ed on a able compu e while si ing in he wai ing a ea. A diagnos ic sugges ion would only be p esen ed o he physi- cian who could include he compu e ized diagnos ic sugges ion in o he diagnos ic wo k low and use eye-ca ching answe s o cla i ying. A se ies o i e clinical cases as an example o he p ospec- i e classi ica ion p ocess is gi en in Table S4 in Supplemen a y Ma e ial. Ex ensi e in es iga ion o use iendliness is pa o a p ospec i e e alua ion. The p inciples applied in his s udy migh also be ex ended o o he g oups o a e diseases beyond PID. aUThO cOnT ibUTiOns UM and LG concep ualized he s udy, conduc ed he in e iew, analyzed ansc ip s, and w o e he manusc ip . WL, FK, and XK pe o med all da a mining. CK, UB, and AM-B supe ised he clinical p ocess. All au ho s discussed he esul s and commen ed on he manusc ip . acKnOWleDgMenTs This s udy would no ha e been possible wi hou he help o pa en s and pa ien s who pa icipa ed in he in e iew p ocess and comple ed he ques ionnai es. 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BMJ Open (2014) 4:e005141. doi:10.1136/bmjopen-2014-005141 Con lic o In e es S a emen : WL, FK, and LG a e co- ounde s o IMD (IMD GmbH, Deu schland). The o he au ho s ha e no con lic s o in e es o disclose. The handling edi o decla ed a pas co-au ho ship wi h one o he au ho s UB and s a es ha he p ocess ne e heless me he s anda ds o a ai and objec i e e iew. Copy igh © 2017 Mücke, Klemann, Baumann, Meye -Bahlbu g, Ko um, Klawonn, Lechne and G igull. This is an open-access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion License (CC BY). The use, dis ibu ion o ep oduc ion in o he o ums is pe mi ed, p o ided he o iginal au ho (s) o licenso a e c edi ed and ha he o iginal publica ion in his jou nal is ci ed, in acco dance wi h accep ed academic p ac ice. No use, dis ibu ion o ep oduc ion is pe mi ed which does no comply wi h hese e ms.