Phenotype Execution and Modelling Architecture (PhEMA) to support disease surveillance and real-world evidence studies: English sentinel network evaluation

P h e not yp e Sys tem a t i zed Nomen cl atur e o f Med icin e Routine l y Coll ec ted He al t h D a ta Medic al rec o rd s ystem s, c omput er i zed Clin ical codin g . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted November 22, 2023. ; https://doi.org/10.1101/2023.11.21.23298758doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

Objective To ev aluate Phen otype Exec uti on an d Modellin g A rc hi tec ture (PhE MA) , t o ex pr e s s sh arabl e p h e n ot ype s us i n g C l i n i ca l Q u er y La n g u ag e ( CQ L) a n d i nt e ns io na l S N OM E D C T F a st H e al t h ca r e Inte rope rabil i t y Re sou rce s (F H I R) val u e s e ts, for e xempl a r chro nic di s e a se, soc iodemo graphic ri s k fac t o r a nd sur v eilla nce ph en otype s .

We c ur a t e d t hr e e phen otyp e s : Type 2 di abet e s (T2D M), ex ces sive a lcoh ol u s e an d inc ident i n fluenz a- l i k e i l l n e s s ( I L I ) u s i n g C Q L t o d e f i n e c l i n i c a l a n d a d m i n i s t r a t i v e l o g i c . W e d e f i n e d o u r p h e n o t yp e s wi t h value s e t s, u sing S N OME D’ s hi era rchy and ex pre ssi on c on strain t langua ge (ECL ), and C Q L , co mbining va luese ts and a dding tempo ral eleme n ts w here n e eded . We compa r e d th e count o f ca s e s found u s ing PhE MA w ith our exi s t i ng a pproach u s in g con venie nce d a t a set s.

The T 2D M ph e no t ype coul d b e d efin ed as two int en siona ll y de fined S NO MED v alue se ts a nd a C Q L scrip t. I t inc r e a s ed the pre vale nce fr o m 7.2% to 7.3% . Ex ces s al coh ol phen ot yp e w as de fin e d by v a l u e s e t s t h a t a d d e d q u a l i t a t i v e c l i n i c a l t e r m s t o t h e q u a n t i t a t i v e c o n c e p t u a l d e f i n i t i o n s w e c u r r e n t l y u s e ; t h i s c h a n g e i n c r e a s e d p r e v a l e n c e b y 5 8 % , f r o m 1 . 2 % t o 1 . 9 % . W e c r e a t e d a n I L I va lues et with S NOM E D c onc e pts, a ddi ng a tem por a l el eme nt u s ing C Q L t o dif fer enti at e new epis ode s. T hi s inc rea se d the w e ekly i nciden ce in our c onve nienc e sampl e (w e eks 26 to 38) from 0.95 cas es to 1.11 ca se s p er 100,0 00 peo pl e. . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted November 22, 2023. ; https://doi.org/10.1101/2023.11.21.23298758doi: medRxiv preprint

P h e not yp es f o r s u r ve i l lan c e an d r e s e a r c h c a n be de s cr i b e d f u l l y a n d c om pr ehe ns ib l y us i n g CQ L and inten sion al F H IR v alu es et s. O ur u s e c a s e pheno type s iden tif ied a g rea te r numb e r of c as e s, whil st antic ipa ted f rom exc e s siv e a lcoho l t hi s was not for ou r oth er v ariabl e . T hi s ma y have be en due to our us e o f S N O MED CT hie r a r c hy. . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted November 22, 2023. ; https://doi.org/10.1101/2023.11.21.23298758doi: medRxiv preprint

Moving towards shareable phenotypes A digital ph enotyp e re fer s to th e r ul e s t hat are appli ed t o c omput eri s e d medica l r e cord s (C MR) t o iden t i fy cohor t s o f pa t i en t s o r epi so d es of int ere st. [ 1] The r ul e s a r e conve rted to c ompu ter alg orit h m s that typic ally in clud e bo th lo g ical e xpre s s ion s a nd da ta el emen t s suc h a s li st s of cli nica l co des. Th es e al gorithm s a re appli ed t hrough c ompu teri se d qu erie s to a c o mputeri s ed me dica l record (CM R) sys tem or o the r heal t h dat a repo sit or y to r etu r n t h e d e sired d ata o ut p ut.[ 2] Phen o t ype s s hould be t ran s f e ra ble be t wee n o r g ani sa tion s a nd e nvironm ent s, to suppo rt t h e g oal s of op en sci en ce .[ 3] To en su re in terp r e t a bility and f ac ilita te el ectr onic s haring o f alg orit h m s wi t hi n data pipelin e s phe no type s sho uld be rep res ent ed i n human a nd mac hine- r eada bl e forma t s. A numbe r o f publi c ph eno typ e lib rari e s h a ve bee n devel oped to s uppo rt the s ha r i n g and di s tr i bu t i o n o f a lg o r it h ms . Fou r t ee n des i d e ra t a h av e b e en i de n t if i e d f or t h e i d e a l p hen ot y p e lib r ar y, t ho u g h t he y are ra rely eve n pa rtially met . [ 4] Digital phenotyping at the Oxford-Royal College of General Practitioners (RCGP)-Research and Surveillance Centre (RSC) The RSC co llec t s CMR d ata from ove r 1, 8 00 Eng lis h pr i mary ca re pr a ctic e s fo r su rv eilla nce, re s earc h , qual ity improve men t, a nd educ a tion al p ur po se s. [ 5] Thi s p s e ud onymise d dat a i s s ecurely s to red in a tru s t ed re se arch envi r o nme nt (TRE). [ 6] The RS C ha s i s s ued w e ekly di s e a se s ur v e illa nce repo rt s t o the UK He alth S ecurity Ag ency (U KHSA ) and it s pr ede ce s s o r s fo r o ver 50 yea r s , a nd co nduct s chronic dise a se C MR r e se arc h. D e velopm e nt o f dig it a l pheno type s, or ph enotypin g, i s p iv otal for the w or k undert ak en by t he RS C. [ 7] . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted November 22, 2023. ; https://doi.org/10.1101/2023.11.21.23298758doi: medRxiv preprint At t he RS C, we u se a th ree -la y e red app roa ch to phen o t yping shown in Fig ure 1. [ 8] On t ol ogic al layer : a huma n-rea dabl e de scrip tio n o f the ke y conc epts and r ela t i on s hip s of a phe no ty pe . C o ding layer: w h er e t he c o n c e p t u al r ea s o n i ng is us ed t o g e ne r at e l i s ts o f c l i n ic a l c o d es. O ur c od e lis ts ar e t yp i ca l l y bas ed on Systema ti sed Nome n clatu re of M edici ne (S NOM E D ) Clinic al Te r m s (CT ) a s thi s i s t h e m a n d a t e d t e r m i n o l o g y u s e d i n U K p r i m a r y c a r e. [ 9 ] S N O M E D C T c o d e l i s t s a r e t yp ic a l l y f o r m a t t e d a s r e fs et s . We d e v elo p r e f se ts us i n g our i n h ous e so ft w a r e t oo l , t h e “ SN OM E D he lp e r t o o l ” , s ho w n in S u pp l e m e nt a r y Fi g u r e S1. L o gi c al d a t a ext r ac t l a y er : w h e re St ru ct ur e d Q u er y L a n gu a g e ( S Q L) q ue r i es are ma nually writ ten u sing log ica l expre s sion s combine d with the r ef se t s to e xt r a ct the de sir ed da ta . The data i s sub s e qu ently t e ste d fo r fac e val idity a nd comp ared with o t he r d at a s o ur c e s. We h av e pr evio u s ly de fin ed i mpo r ta n t p h enotype s s u ch a s pr egna ncy, chr onic ki dney di sea s e, s ocia l pre scribing in terve n t i on s , and lon g CO V ID w ith Web On tology L angua ge (O WL ) us i ng t he Pro tégé so ft w ar e. [ 10,11, 1 2] Thes e pheno type s we r e then u ploa ded to the publi c phen oty pe librari e s Biopor tal and Phen oFl ow. [13 ] . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted November 22, 2023. ; https://doi.org/10.1101/2023.11.21.23298758doi: medRxiv preprint Figure 1 : Existin g t hree-la yer ed a p p roa c h fo r defining pheno types a t t he R S C . Ontological layer: hum a n -reada bl e ph e notype spec i ficat i o n , may uti lise diagn o stic cri teria, sy m pto m e xa min at i o n fi ndi n g s, te st result a n d t h e ra pi e s. Coding layer: Creati o n of c ode lists typi c all y usi n g S NOM E D CT. Logical extract model: S truct ured Q u e ry Language (SQL ) sc ri pts a re m anua l ly d e ve l op e d ba se d o n o n t ological a nd c od in g la y er. Test extract: Ass essed f or ve ra city mo di f icatio ns are fed b ack to o n t ol o g i c a l a nd c odi n g layer s . T h e p h e notype sc h e m a c a n t hen b e fi nali s ed. Case for changing our approach to developing phenotypes W e a r e c hanging our app roac h to deve loping pheno t y pe s a s, f i rstly, we fo und O WL ex cel lent fo r s e man tic pr ec i sion, bu t some time s cha ll engi ng to al ign w i t h clini cal a nd projec t re a s on ing. S econ dly , in t he c oding laye r we ha d pr eviously defin e d r ef s et s ‘exten si onal ly’. Thi s is w here each co d e i s . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted November 22, 2023. ; https://doi.org/10.1101/2023.11.21.23298758doi: medRxiv preprint ex plici t l y list ed a s a m ember o f t he se t s . W e now pl an to mak e b et ter u s e of the S NOME D expre s s i o n c o n s t r a i n t l a n g u a g e ( E C L ) . [ 1 4 , 1 5 , 1 6 ] S N O M E D C T i s d e s i g n e d t o b e m a c h i n e p r o c e s s a b l e a n d i t s E C L all ows a r ule -ba sed or ‘in ten sion al ’ ap pr oa ch t o dev elo ping re f set s t ha t utilis e SN O MED ’ s poly hierarchi cal sub type s an d s up e rtype s . [ 17, 18] The l ogic u s ed t o de fine in ten si ona l r e f set s i s mor e ex plici t . Evaluation of Phenotype Execution and Modelling Architecture (PhEMA) Phen o t ype Ex ecution and Mo de lling Arc hitect ure ( PhEM A) i s a standa rds -ba sed , modul ar arch itec tur e for d evel oping phen otyp e al gorithm s , inc luding th eir v alida t i o n, ex ec ut i on a n d dis s e min ation d ev eloped for r eal world stu die s u s ing CM R da t a . [ 19] PhEM A u s e s a spec t s of H e a lth Le vel 7’s Fa st H eal t h c are I nte rope rabili t y Resourc e s (FHI R) frame wo rk inc luding the us e o f Cli nical Qua lity L anguag e (C Q L ). C QL is a struc t ured way of ex pre ssing phe no t ype logic and code li sts a n d a l lo w s e x p r ess io n a n d s h a r i n g o f ph en o typ e lo g i c , it is d es i gn e d t o b e h u ma n a n d m ac h i n e r ea da b l e . [ 20,21 ] . This st u dy aimed to eva luat e P hEMA's C Q L -ba s e d logic m odel and c rea ti on o f H ea lth L eve l 7 (HL 7) Fa st He althc a re Int erop erabil i t y Re sou rc es (FH IR) va lu e s e t s , in to th e RS C's thre e -l ay e r ed appro ac h to pheno t yping, r eplac ing OW L or un s tr uc tur e d ph e no t ype de finitio ns . W e a d apt ed our ap proa ch t o inc orpor a t e PhEM A el eme nts and t hen a imed to d ev elop p he no t ype s for thr ee p urpo sive ly s elec t e d use ca s e s : type 2 di abet e s mellitu s (T2 D M), incid en t influ enza -like illne s s (IL I), a nd e xce ssive a lcoho l co ns ump tion . . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted November 22, 2023. ; https://doi.org/10.1101/2023.11.21.23298758doi: medRxiv preprint

The three phenotype use cases We sel ec t e d thre e di s s im ilar us e ca s e s th at we an tici pat ed w ould r equir e di f f e r en t l ogic model s. Th e thre e w e sele c ted wer e: (1 ) Type 2 di abe te s mellitu s (T2 D M ), (2 ) Ex ces s i ve a lc ohol us e, and (3) Inc ident ca se s of i nflu enza -lik e illn e s s (IL I). We c ompa red t he new ph enotyp es w ith tho s e produc e d using ou r c ur r e n t pr oc e s s , a nd whe r e a v a r i able i s ne w look ed fo r ex t e rna l val idati on. Use case 1: Type 2 diabetes mellitus We c ho se the T2DM phen otype d ue to o ur ext en sive expe r ie nc e w ith C MR- ba s e d T2DM studi e s a n d its fr eque n t us e a s a c ova r ia t e i n o the r re sea rch. [ 22, 23,24] Ou r inv olveme nt ex t end s t o ex amining misdiag no s i s, mi s c oding, and miscla s si fica t io n wi t hi n CMR s. [ 25,26, 27] Pheno typ in g T 2DM is ch alleng ing bec au se th e diag no s i s ca n be der ive d t h roug h nume rou s c linic ally coded e ven t s, inc luding di agno stic co d e s , la bor a t o r y r esul t s o r th e pre s c r i bing o f medic ation . Additi onall y , T2D M may r e s olv e th rough li fe s tyle i nte r v en tion s and baria tric su rgery, bu t t her e is p ote ntial lat er relap se . [ 28,2 9,30] The RS C ha s a wel l -e s t abl i s he d but comple x phe notyp ing alg o r i t h m b ase d on ou r ex is ting th re e-la yered ap proac h .[ 31] T o e v aluate PhE MA's po t e n tial int egra tion, howe ver, we will use a simpl i fied ve rsi on of o ur curre nt T2 DM phen otype . Use case 2: Excessive alcohol use The a lcohol use c a s e phen otype i s an e x emplar of a s oc iodem ogr aphic ri sk fac tor. We ide nti fied a va r i ety of d efi n it i on s o f exc e ssive a lcoh ol use and cho se on e ba sed on con su mption leve l s ra the r than qu e stionna i re s a bou t the e ff ect s o f drinkin g. The N HS de fi ne s exc essiv e con s umption of a lcoh ol as mor e than 14 uni t s of alc o hol pe r we e k .[3 2] . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted November 22, 2023. ; https://doi.org/10.1101/2023.11.21.23298758doi: medRxiv preprint Use case 3: Incident influenza like illness The W orld H ea l th Orga niz a t i on (WHO ) re commen d s su rveil lance o f th e re s pi ra t o ry clini cal s yn dr om e IL I as a marker o f comm unity spre ad of re s pi r a tory inf ec t i on s. Trac king the in ciden ce of ILI is importan t b ec au s e i n r es pira tory s u rv eillan ce system s around hal f o f ILI c linic al ca se s hav e lab or a t ory con firmed i n flu enza. [ 33] Al ongsi de o t h e r surveil l anc e indic a tors IL I s u r v ei llan ce should b e part of the mo saic o f me as ure s u sed to f la g an e m ergen t pand e mic. [ 34, 35] The RS C p r ovides w e ekly IL I inc idence figure s t o U K H S A in it s week ly report . Modifying our three-step ontological process for defining a phenotype in real- world data Our modi fie d thr ee - ste p a p pr o ach to e mb r a ce PhEMA p r i nciple s i s sh own in Figure 2. T he logic model a nd codi n g laye r u s e th e PhEM A pr o ce s s e s with l og ic mode l expr e s s ed in C QL. Th e PhEM A log ic mode l inc lude s op era tion al fa ctor s i n additio n to c linic a l c once p t s . O pera tio nal f a c tor s d e s c r ib e non-c linic al f a c tor s that i nfl u ence CMR c oding and may rel a t e to t he d ata en try environme n t o r sys t e m s o f prac t i ce . For i n s ta nc e, varia tion s i n the u s e o f sp ec ific cod e s might be i nflu enc ed by co nt rac tual requi remen ts an d in cen tive s; thi s cont ex t i s e s sen tial for our app roa c h. Addi tional ly, we a l t e r t h e c r i t e r i a t o a d j u s t t h e s e n s i t i v i t y o r s p e c i f i c i t y o f t h e e x t r a c t i o n a c c o r d i n g t o t h e a i m s o f t h e st u d y.[ 36] The l o gica l dat a ex t r ac tion step is ext erna l t o the PhE MA p roc e ss. H ere we gen era te t he data ou t p ut a nd c heck the in tern al and e x t e r na l va lidity o f new ph eno type s. . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted November 22, 2023. ; https://doi.org/10.1101/2023.11.21.23298758doi: medRxiv preprint Fi gure 2: R e vised th re e- st e p m o del for d e velop i ng p hen otypes a t the R S C . Logic model: De f ine cl i n ica l an d o p e ra tio n al lo g i c usi n g Cl inica l Q u a lity L a ng ua ge ( CQL). Coding layer: C re a te i n tensional refs e ts u sing in - h o use S NOMED CT h e lp e r t ool (Supp lem e n tary Figure S 1 ). SNOM E D re fs ets ar e converte d to F a st Healt h care Inte rop e ra bi l ity R esou rc es (FHIR ) val u e s ets f o r C Q L co m p a t ib i l it y . Logical extraction model: Aut o ma te d proce s sin g o f m ac h i ne read able PhEMA o u t p u t t o e xtra c t dat a from C M R . Test extract: Asses sed fo r ve ra c i ty mo dif i c a ti ons a re fe d ba ck t o PhEMA la y er s. I n te rn al and e xte rn al v a lida t io n pro c esse s. . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted November 22, 2023. ; https://doi.org/10.1101/2023.11.21.23298758doi: medRxiv preprint Step 1: Describing the logic model using Clinical Query Language (CQL) We u s e d th e PhEMA work benc h to de fine the phen otype log ic model f or eac h of our thr ee u s e ca s e s i n C QL. [ 37] S ub se quen tly w e u s e d Vi s ua l S tudio Cod e from Mic ros of t, with t he C QL ex t en s i on whi ch provide s s yn t a x highl ighting and debug ging tool s. [ 38,39] O ur C Q L c ode i s ba s ed re sou r c e s dev eloped in th e FHIR a nd P hEMA help e r l ibrarie s. [4 0, 41] The r e source s pr oduc ed un de r the P hEMA and Cl inica l Q ua li ty Frame work ( C Q F ) , inclu ding CQL, c on tain a s et o f e xampl e s t hat c an be u sed t o gen era te th e maj or ity of com monly use d phenotype s . We found th e H L 7 Conf luenc e communi t y work s pac e , th e most ac ce s sible r out e to g et star ted . [ 42] Step 2: Defining the FHIR valuesets and SNOMED CT refsets SNOM E D re f se ts were ini tia lly cre a t e d using our S NOMED Hel per Tool (Suppl e mentary Fig ure S 1) . S N O M E D ’s E C L a l lo ws s et s of c o n ce pts t o be de f in e d i nt e ns ion a l l y f r o m t h e ir r e lat i o ns h ips . [4 3 ] M ost oft en thi s i s a hi e r a r c hica l r ela tion shi p w here a high-l ev el c once p t (k nown a s a s u pe r type ) i s ex plici t l y defin ed a nd all low e r leve l con c ept s (kno wn a s s ubtyp e s ), w ho s e m e an ings ar e su bsume d by the hig h er conc ept, are includ e d by i nfer enc e .[14 ,15,1 6] Co nver s e ly, co n cept s may b e ex clude d by s pe cifyi ng a minu s s u pe rt y pe an d none o f it s s ubtype s w ill be inc lud ed. The S N OME D ECL func t i o ns we u s ed incl ud ed “Chi ld o r S el f of” (w r it ten ch il dO rS e lf Of) wh ere a cl inica l t e rm and it s ch ild c odes a re inc lud ed. [ 44] SNO ME D re f se ts w ere then c onve rted to FHI R v alue se ts. F H I R v a l u e s e t s a r e a s et o f c l i n i c a l t e r m s a n d a s s o c i a t e d m e t a d a t a t h a t a r e c o m p a t i b l e w i t h m u l t i p l e co de s ystem s, i ncludi ng int en s i onal S N O MED CT expre s sio ns o r r e fs et s. Met a da t a c an incl ude t h e co ding or c las s ific a tion s ystem us ed, t h e v alues et p r ov en anc e a nd lif ecycle man agemen t, such a s marki ng a v alue s et a s experime n t a l. [ 45] A FHIR va lue se t c an be marked a s a dra f t, or at end of li fe , be form al ly reti red w hil st pre servi ng th e c onten t. [ 46] . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted November 22, 2023. ; https://doi.org/10.1101/2023.11.21.23298758doi: medRxiv preprint Step 3: Describing the logical extract model We us ed th e devel op ed pheno type s to ex t rac t t h e a ssoci at ed cohor t of pa tien t s from the RS C S Q L - bas ed CM R. We did thi s by ma nually conv ert in g C Q L phen otyp e logic to S Q L . W e plan to a u t oma t e this st ep i n th e futu r e to t a k e full a dvan t a ge o f t he mac hin e -re adabl e na t u re of C Q L . F rom t he ex t rac t ed dat a, we th en calc ulat ed s umma r y s ta ti stic s for e ac h of t he u se c a se s. T2DM We comp a red t h e pr e val en ce o f T2 DM i n the curre nt adult (>18 year s) RS C p op ulation to tha t o f a rece n t c oho rt tha t u sed ou r p reviou s p henotype . Addi t i on ally, w e compar ed t he pr eval ence in all ag e group s to tha t o f th e e s t i mat ed U K dia be te s p rev alenc e u s in g da ta fr om Di abe te s UK and t h e Offi ce f or N ation al Sta ti st i c s ( O NS ). Excessive alcohol use We as s e ssed e xce s s ive alco hol co ns u mption preval enc e us in g qual i t a tive S N OME D cod e s , t he n co mbined th em with quan tita tiv e S N O MED cod es , s pe ci fic ally t he uni t s o f alc ohol con s umed , a n d dete rmined re lative p ercen tag e inc re a s e in preva lenc e with the ad dition o f quan ti tative cod es . Influenza like illness We comp a r e d t h e i ncide n ce o f ILI for IS O week s 26 to 38 o f 2023, th e mo s t r e c ent d ata ava ilabl e , using both th e old and new phenotype s . We used th e s e dat e s a s a conve nienc e s a mpl e. We repo rt the med ian , low er and up per qu artil e s o f t h e wee kly incide nce o f ILI by age band for thi s peri od. The ag e band s u sed ar e con si s te nt w ith t ho se pre s en ted in the w eekl y sur v eilla nc e re po r t t o UKHSA. . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted November 22, 2023. ; https://doi.org/10.1101/2023.11.21.23298758doi: medRxiv preprint Ethical considerations The varia ble s cu r at ed in thi s work ar e all r e qui red for our se ntin el s urve illanc e, appr oved und er Regula t i o n 3 of t he H e a lth S ervic e ( C on t r ol o f P a t i en t In for ma t i on ) Regula tion s 2 002, and review ed and a ppr o ved a n nually by the U KHSA C a l dicott G uardi an.[47 ]

Use case 1: Type 2 diabetes mellitus Logic model C linic al te r m s t ha t inf err ed a di agn osi s of T2DM w ere ide n t i fi ed i n t e n s ion a lly fr o m th e SN O ME D hierarchy . F or thi s s i mplifi ed dia b et es ph e not y pe , we di d n ot us e blood gl ucose lev el s or pre s c r i pt i on o f medic a tion to ind ica te a diagn o s i s o f T2DM . W e al s o iden ti fie d indi vidual s who s e diabet e s had r esol ved and ex clu ded t he m from the final c oh ort. Fo r op era tiona l logic w e inc luded proce s s of c a r e c od e s whic h imply a di agnosi s o f T2 D M, fo r exam ple, “T ype 2 D M rev iew” , (STCID : 279321 00000010 4). The CQ L cod e ca n b e s een i n Fig ur e 3 . Fi g u r e 3 Cl i n ica l qua l ity lan g uage (CQL) logic model f or our type 2 di a b e tes (T2DM ) ph e notype. Indi v id ua l is co d e d as re s o lve d if re sol v ed date i s g reate r th a n d i agn o s i s da te . . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted November 22, 2023. ; https://doi.org/10.1101/2023.11.21.23298758doi: medRxiv preprint Coding layer We crea t e d t w o SN O MED CT ref s et s , th e fir st con si s ti ng of code s implying the di agnosi s o f d iabe te s and the sec ond implying t h a t th e diag nos i s ha d r e solv e d. The firs t re f se t in cl uded th e diag no s t ic co des such a s “ D i abe te s me l litu s type 2” (SCT I D : 4405 4006 ) and all o f i t s d e sc endant code s. We addi t i on ally used single rel evant cl ini ca l t e r m s s u ch a s “Type 2 diabetic on insulin” (S CT ID : 2447 1000000 103) and o t he r c once pts a nd t he i r r e l evan t c hil d c once p ts. S u bt yp es m ake up the bu lk of the de finiti on - 97% o f the conc ep t s in th e f i nal, expan d ed, ex ten sion al set a r o se from t he “c hildOrSel fO f” de fini tion s (S upple me nta ry Tex tbox S 1). Logical extract model In i ndividua l s over 18 ye ar s o f age, t h e R SC CMR's dia b ete s pr e val en ce u sing t he new p heno type wa s 7.3% . This is sligh t ly higher than th e 7.2 % p r ev alen ce fr om a 2021 c ohort s tudy on sodium -gluc o s e co - t ran spor t e r -2 inhi bi tor p re scrip tion s i n prima r y care, whi ch utiliz ed th e o ld R SC phen oty pe a nd 2019 RSC dat a. [ 48] F or a na tion al c omp aris on, we inc or p ora ted d ata for tho s e unde r 18 . The preva lenc e acr os s all age gr oup s with th e new pheno type w a s 5. 9%, i n c on tr a s t t o a n app roxima te 5.3% derive d f r o m Diab et e s UK and the O f fice f or Na t i on al S t a t i stic s da ta . [4 9] Use case 2: Excessive alcohol use Logic model Us in g o nly cl inica l logic we id enti fie d i n dividua ls w it h e videnc e o f con sumpti on of gre at er tha n 1 4 unit s o f alc ohol p er w eek . F irstly, we l oo ked for qua li tative cod e s with a ru bri c tha t in clud es t h e speci fi c numbe r o f uni t s con sumed, fo r exa mple “ modera te d rinker 3 -6u /day”, ( SCT ID: 1 6057600 6) . We the n id enti fie d c ode s allow ing inp ut o f quali fyi ng va lues , in thi s ca se the s pec ific number o f unit s . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted November 22, 2023. ; https://doi.org/10.1101/2023.11.21.23298758doi: medRxiv preprint consumed by an indi vidua l . O ur fina l logi c al mode l for exc essive alco hol u se (Figu re 4), with t he CQL logic in a s up plem enta ry fi le . Fig ure 4 C l i n ica l c on c epts u se d to define t h e exces siv e a lco h o l use valu e set. In c l uding qualit a tive c o des and quant i tat i v e cod e s that r epres e n t t he number of u nits of al c oh o l co n sum e d i n t he specified t im e p e ri od . Coding layer W e c rea ted fou r v alue se ts wh ich comb i ned to pr oduc e ou r phe no type, two contai ning quali t a t i v e code s and two cont ai ned cod e s wit h assoc ia ted qu alify ing val ue s ( quanti tativ e cod e s). Th e qualita tiv e value se t s cont ai n c oncep ts from t he “ findi ng s ” secti on o f t h e S NO MED C T hi erarc hy. W i t h one value s e t d efini ng he av y drin k ers includ ing “ He avy drinke r 7- 9 u/day ” and “V ery he av y d r i n k e r > 9 u/ d a y” co d es . T he se c o n d v a l ue se t co nt ai ns t he s i n gl e c on c e pt fo r m o de r a te d r i n k e r . Tw o valu eset s w ill con tai n “ ob s e r v abl e en tit y” c oncep t s f rom the U K S NO ME D C T Extensio n: “Alc oho l unit s co n s ume d p er d ay ” and “Alc ohol unit s con s umed p er we e k”. The CQL fo r ex ces sive alc oho l consump tion c an be s e e n in S upplem ent ary Textbox S2. . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted November 22, 2023. ; https://doi.org/10.1101/2023.11.21.23298758doi: medRxiv preprint Logical extract model The overall pr evale nce o f exc e ssive alc oh ol c ons um p t i on in th e RS C CMR u sing on l y qua litative SNOM E D code s wa s 1 .2%. T he add i t i on o f quan tita tiv e co de s to t he ph eno type in crea sed the preva lenc e to 1.9% , a 58 .3% rel a t i ve inc r ea se al thoug h thi s i s still con sid erably be low the Heal th Surve y da t a for Engla nd whic h repo rt ed 21% of adul ts drinki ng mor e than 14 uni t s wee kly. [50 ] Table 1 show s the b rea kdow n o f preval ence by ag e band . The i ncr ea se in pre valen ce a t a ge for ty is li kely due t o t h e N HS Hea lth Chec k w hich i nclude s qu e s tio ns abou t a lcoho l u se and i s o f fer ed to a ll regis te red pa tie n ts ev er y five y ea r s fr om age 40 to ag e 75. [ 51 ] Ag e ban d Q ua lit ati ve c od e s Co mbine d c odes % Ch a nge All ( > = 16 y ears ) 1. 4 5 % 2 . 3 0% + 5 8. 31% 16 -4 0 y e a r s 0. 5 4 % 0 . 3 1% + 7 7. 34% 41 -6 5 y e a r s 3. 05% 1 . 8 6% + 6 4. 54% >6 5 y ears 4. 3 7 % 2 . 9 5% + 4 8. 26% Table 1: Preva l e nc e of e xces siv e a l c oh o l co n sum p tion in t he R SC i n t hose 16 yea rs o r o lder. a : P r ev a l en c e u s in g o nl y q u al itat ive codes. b : P re va l e n c e u s i ng qua litat ive an d quan ti tative c odes. d : t he p e rc e n ta ge increa s e in preva l ence through u se o f c omb ined c od e s. Use case 3 Influenza-like Illness Logic Model A s I L I i s an a c ut e c l i n ic a l s yn d r om e t h at m a y r ec u r m u l t i p le t i mes i n th e s a m e in di v i d ua l , we a i m ed t o iden t i fy wee kly i ncide nt c a se s. Thi s contra s ts wi t h t he pr eviou s us e ca s e s in w hich w e we r e iden t i fying the preval e nce of a cond i t i o n. W e de velop ed a n a ppro ach to di st in g uish b etw een new and repe a t pr e sen tatio ns o f th e s ame I L I episo de u s ing the P hE M A f ramewo r k . We identi fie d IL I . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted November 22, 2023. ; https://doi.org/10.1101/2023.11.21.23298758doi: medRxiv preprint cl inica l t e r m s re corded mo re th an 28 d ays, fr om th e pr eviou s record ed ev en t (S upplem enta ry file IL I.cql) . A s t his re quire s u se of d at e v a lues within C QL we u s e d the PhEM AHe lper s l ibr ary whic h c on t ai ns f un c t i o ns to s i m p l if y r e pr es e nt at i o n of da te s . Coding layer W e c r e a t e d a s i n g l e v a l u e s e t f r o m t h e S N O M E D C T i d e n t i f yi n g c o n c e p t u a l l y d i f f e r e n t a r e a s w i t h i n SNOM E D CT whi ch met ou r cli nica l c ri te r ia for ILI . The se i nclud e d the follow i ng code s an d thei r sub type s: “In flu enza -lik e ill ne s s”, “In fl u enz a -like symptom s” an d “I n fluenz a”. Addi tiona l ly, we ex clude d high -lev el c on cept s w ithin th e hierarch y s uc h a s “He althc a re a ssoci at e d inf ec t io n s ” whic h ex clude s “ Heal thca re a ssoc iat ed in flu enza dis ea se” fr om w ithin the “ in fluenz a” parent co d e. Logical extract model Betwe en I SO we e k s 26 a nd 3 8 of 2023, the media n week ly inc id enc e of IL I u s i ng the n ew ph enotype defini t i on wa s 1.11 ca s e s per 100 ,000 p e ople. In cont ra s t, usi ng the old phen otyp e de finitio n, i t w a s 0.95 cas es p er 100, 000 peo p le. Ta bl e 2 s how s th e week ly inc idenc e o f IL I by age band. Ag e band New phen ot y p e Old ph e n ot ype All ag es 1 . 1 1 ( 0. 66-1. 44) 0 . 9 5 ( 0. 60-1. 25) 6 5 y ears 1 . 1 6 ( 1. 00-1. 22) 1 . 0 2 ( 0. 68-1. 16) Table 2 : Med i a n we ekly in c idence o f I L I in t he R S C CMR fo r ISO weeks 2 6 to 3 8 o f 2023 u si ng bot h t h e n e w an d old phen o ty p e s. Val ues denote m edia ns, wit h l ower a nd u p per qu a rt i le s e n c l ose d i n b r ack ets. . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted November 22, 2023. ; https://doi.org/10.1101/2023.11.21.23298758doi: medRxiv preprint

Principal Findings We h av e demo n stra ted th at we can e ff e ctive ly us e PhE M A to c ura te pheno ty pe s - cr eating value s e t s and more sh are able logic . SN OMED re fse t s cre ate d int en sionally take adva ntage o f S NO ME D’ s co ns i st ent hi erarc hy a nd ECL . U sin g C Q L to ex pr e ss c linic al an d ope r ationa l log ic w as co mpr e hen sibl e to c linic ian s and epid emi ologis t s i n our team a nd wi ll be adopted . W e have demon str ate d thi s ac ro ss t h ree d if fe r e n t use ca ses . Acro ss all the se u se ca se s the cas e ac quisi t i o n inc r e a s e d . We a nticipa t e d tha t t h e pr eva lenc e o f exc e s s iv e a lcoho l w ould i n crea se, as w e w er e addi ng qualit ativ e clini cal te rms. Howe v er, i t w a s n ot an tici pa ted for T2DM w here we a dded t h e ca pabili t y t o go i nt o r e mi ssion or in ILI w here w e added a t emporal c on st r ai nt t o h elp en su re t hat w e only count ed incid e nt c a se s. O ur int erpr eta tion is th at th e in ten sion u se of S NOME D ’ s ECL ac counted for thi s inc rea s e. Implications of the finding We wil l migra te our app roac h t o c urati n g varia ble s fr om O W L , whe re w e wer e more c hall eng ed to ex pr e s s cl in ica l logic , to PhEM A a nd C Q L . The sepa ra t i on of cli nica l logic fr om ad mini s t rative , largely hea lth s ystem con st r a in t s , wa s co n s id e r e d help ful. St an dardi s i ng our v alu e se t s u s i ng t he FH IR metada t a improv e s our a bili ty t o sha re a nd v ers ion con trol our c ur a t e d v aria bles . T his i s a ste p t o w a r d s p h e n o t yp e s t h a t a r e r e a d i l y m a c h i n e p r o c e s s a b l e . I n t e n s i o n u s e o f S N O M E D ’ s E C L m a y b e importan t in en s u r ing t hat all r e leva n t c li nic al term s withi n t hat hi erarchy ar e c ap tured . Comparison with the literature The r e ha ve b ee n s ev e ral at temp t s to all ow sharing o f phen otyp e s.[ 52, 53,54] The se ha v e us ed th eir own fo r ma ts for expr es sing th e c r i teria f or e xt racting d ata f rom the m edic al rec o r d . Log ic i s typic ally . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted November 22, 2023. ; https://doi.org/10.1101/2023.11.21.23298758doi: medRxiv preprint desc ribed in fr e e t e xt o r expre s s e d u s ing general sc r ip ting langu age s with an imp lementa tion whic h is cl o s el y tie d to th e unde rlying data st r u c ture and s torag e us ed b y the r e sea rche r. In the UK t he l e ading o r g ani sa tion s pr o moting sh ared ph e no t ype s a nd cod e li st s ha ve b ee n H e a lth Dat a Re s e a r c h UK a nd Ope nSa f e ly re spec t i vely .[ 55, 56] How ever, nei the r of the se includ e inter oper able exp res si on s of clin ical logic . The U S N a t i onal L ibr ary o f M edic ine d istr ibute s val u e s e ts thr ough t he Va lu e s e t A u thori ty C ente r, [5 7] but the NHS Engl and Termino logy S erve r lac ks the fo rmer’ s scope .[5 8] H e alt h recor ds and S NOMED CT d if f e r s ig ni fica nt l y be twe en in the U S A and the NHS. We unambi guo usly ac cept ed th e rigo r o f t h e S N OME D hie rarchy , a nd whil s t va s tly bet ter t ha n t h e inc ons i stenc ie s o f the UK’ s p r ev iou s Rea d code s , th er e are limi t a t i on s and q ue s t ions a s t o w heth e r they are su ffic iently quali ty as s u red .[ 59, 6 0] Strengths and imitations The re se arch g rou p h av e ha d long ex pe r i enc e o f c ura t i ng v ari able s a cro ss t he r a ng e o f cli nica l terminol og ie s u sed i n th e Engl i s h NHS . W e h a ve s how n that pheno type s can be expr es se d a n d dist r i bute d in a wa y that i s c ompreh en si ble to both huma n s a nd c ompute rs a n d t ha t i mplem enting the PhE MA Fram ewo r k is t e chnic ally and prac tica lly fe a s ib le . Whils t w e have me t th ree o f th e de s i de r a ta tha t Cha pman [4 ] expre s sed f o r th e creatio n o f a nex t gen era tion phen o t ype li br a r y, th e ma n y g aps tha t r emain are a limi ta tion o f thi s p roce s s . We demon str ate d thi s pr oc e ss u sing the hierarc hi e s of S N O MED CT, but i t would apply to l e s s ontolog ical ly c omplex t e r mi nol ogie s suc h a s I CD or OP CS. Ou r conc lu sion s about the i nte rpre tabili t y . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted November 22, 2023. ; https://doi.org/10.1101/2023.11.21.23298758doi: medRxiv preprint of C Q L a re ba s ed on t he opinion s o f th e autho rs a n d no fo rmal con sen su s bui l ding or q ualita tive as s e ssme nt wa s c onduc te d. We w ill nee d con sider abl e ef for t to conve r t ou r l arg e lib r a ry of cur ate d v ariabl e s i n t o PhE MA forma t . The lac k of an op en va lu es et auth ority in t he U K, a s exi st s i n USA , limit s o ur abil i ty to co llabo rat e a n d sha re va lue se ts.

We hav e s h ow n t ha t w e ca n e xpre s s ph enotype s u sing the princ ipl e s of t h e P hE MA fram e work for the iden ti fic ation o f pa tien t s w ith c hronic dis ea se , the a s ses sm ent o f ob s ervation s an d fo r sur v eill a nce o f communi cabl e di se as e u si ng in t e r na t io nal h ea l th dat a s tanda rd s. It wa s fea sibl e and prac tical t o di st r i bute FHIR valu e se t s u sing i nte n s io nal de fini tion s whic h ca n b e co mpiled to e xt en sional li s t s by termino l ogy serve rs . Thi s a pp roach al so incr ea s e d case findi ng. We ha ve d es c ribed the logi c un ambig uou s ly u sing C Q L , a FHIR sp eci f i ca tion, in a wa y w hich is under st andabl e fo r human s a s wel l a s po tenti all y co mputabl e.

Pati e nts who al low dat a sha ring regi s t er ed with prac tice s who ar e memb er o f t he Roya l Colleg e of Gene ral P racti tione rs (R CG P) R e s ea r c h a nd S ur v eilla nce Cen tre (RS C ). EMIS M a gentu s, T P P, a n d InPr ac tice S yste ms for fac ilit ating p s e ud o ny mised d a ta sharing . . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted November 22, 2023. ; https://doi.org/10.1101/2023.11.21.23298758doi: medRxiv preprint CONRTIBUTIONS Sde L and G J dra f t e d t he te xt and GJ a s si sted b y DK, R W a nd A F crea ted the v alu es et s . WE, RB , W H perf ormed th e da t a extrac t i on and a nalysi s. RB a nd Dr J ohn Will iam s cre at ed t h e SNO ME D CT H e lpe r Tool . All the autho rs rea d and revi ewe d t he manu scrip t. CONFLICTS OF INTEREST Sde L i s t he Dir ec to r o f the Roya l Coll eg e of G ene r a l Pr a c titio ner s (R CG P) R es earc h a nd Surveil lanc e Cen tre (RS C ). SdeL thro ugh his Unive rsity ha s rec e ived funding f rom A stra Ze nec a, Eli Lilly , GSK , Modern a, Novo Nordi sk, P fiz er, San o f i , S eqiru s, and Ta kenda and be en memb er s of a dvi sory b oard s for A straZen e ca, GS K, Sano fi and S eq ir u s . He ha s had me eting ex pen s e s f u nd ed by Ast r a Zenec a. G J has rec e ived payme n ts from A s t raZ e ni c a fo r educ ation al ta lks and h old s s ha r e s i n GSK. Oth er author s h ave no c onflic t s of in ter e st.

1 Brandt PS , Kho A, Luo Y e t al. Cha r a cte riz i ng va r ia bili ty of el ect ronic he alth r ecord -drive n pheno t yp e de fini tion s. J A m M e d I n f o r m A s s o c 202 3 Fe b 16;3 0 (3):427 -437. doi : 10.1 093/jamia/ oc ac235 . 2 Ric hes son RL , Hammond WE, Nahm M et al . E lectr onic heal th r eco r d s ba se d ph enotyping in ne xt - gen era tion clin ical tri al s: a per sp ectiv e from the NI H Hea lt h C are Sys tem s Col la borat ory. J Am Me d Inf orm A s s oc 2013 Dec;20 (e 2 ):e226 -31. d oi: 10.1 136/ amiajn l-2013 -0019 26. Epub 2013 Aug 16. . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted November 22, 2023. ; https://doi.org/10.1101/2023.11.21.23298758doi: medRxiv preprint 3 UNESCO. (2022). 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