Deep phenotyping of women with endometriosis-associated pain and bladder pain syndrome: the TRiPP (Translational Research in Pelvic Pain) study protocol

Chronic p elv ic pa in is co mmon, po orly un der s to od, and man y wome n s u f f er f or y e ars w it hout p rope r d i a g n o s i s a n d e f f e c t i v e t r e a t m e n t . T h e T r a n s l a t i o n a l R e s e a r c h i n P e l v i c P a i n ( T R i P P ) p r o j e c t t a k e s a pheno t y ping app roa ch, wi t h a p a r tic ula r focu s on endom e t ri osi s -a ssoci a ted pain (EA P) and bl add e r pai n syndr ome ( IC /B PS ) , to improv e o ur fund am enta l under standi ng o f chro nic pelv ic pain. W e beli eve tha t rec once pt u ali sing th e se c on dition s in the c ont ext of the mul t i s y st em dy s func t i on know n for othe r chron ic pain c ondi tion s r a t h er tha n a s e nd -organ path ol ogie s ha s t h e p oten tial to improv e our und er s ta nd ing o f th e c ondi tion s. O ur appr oach c ombin es clini cal, bi o logic a l, physio log ical a n d psych ologic al da ta to e s tabl i s h p er t u r b a t io n s in th e func tion s o f pa in -rel eva n t s y s t ems that ar e speci fi c t o EAP and I C /BP S, and tho se t hat overlap bo th condi t io ns an d chroni c pe lvic pa in mor e gen erally and a s socia ted qu anti tat ive bio marker pro file s. Dis c us sion: We bel i eve th at T Ri PP ’ s novel me tho dologic al a ppr oach w ill prod uc e c linic a l data to a id ou r under st anding o f p elv ic pain a nd i de n t i f y und e r ly ing pa thway s for the deve l opment of r e fin e d ani mal mode l s a nd t arge ted th erap e utic trea tmen t s. Keyw ords : c hr onic pelvic pa in, e ndo m etr io si s, b la dde r pain s y ndr o m e, int er s t itia l c y s ti tis , de e p pheno t y ping . 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 (which was not certified by peer review) The copyright holder for this preprint this version posted April 10, 2023. ; https://doi.org/10.1101/2022.05.16.22274828doi: medRxiv preprint

Chronic pelvi c pai n (C P P ) i s c ommon, a f f e cting 5 -26 .6% o f w omen (1 –4) . It h a s si gnific ant impac t o n qual ity of li fe and hig h a ssoc iat ed c o s t s f or i ndividu al s, s oc ie ty a nd heal thc ar e pr ovide rs (5) . Ye t, C P P is neg lec ted a n d under fund ed in both p a i n and w omen’ s hea l th re sea r c h field s. The Tran sla tional R e sea rch in Pel vic P ain (TRi PP ) pr ojec t (ht t p s: // w ww.i mi- pai ncare .eu / P RO JECT/TR IP P/ ) i s a colla b orati on betw ee n aca d emic s in the UK, E urope a nd the US A , Europea n Pha rma c ompani e s , a small -mediu m s i zed e nte r pri s e (S ME) a n d p atien t pa r tn er s. I t focu s se s o n end om etrio si s-a s s oci at ed pai n (EA P ) and int er s ti tial cy s ti ti s/ bl a d der pai n s y ndr o m e (I C/B PS ) in wo men, two co ndition s w her e CP P is highl y preval e nt and for w hich c urr e n t tre atmen t s predomin an tly t arge t t he p eriph e r y (ec topic t issu e for en d omet r i o s i s and t h e bla dder f or IC / B P S ) and ar e of t e n ine ff ec tive (6) . Ou r hy po t h e s i s i s th at the p ain s y mpt o m s in th es e condi tion s ar e gen era ted and main taine d b y mecha nisms s i mila r t o tho s e foun d in ot h er c hro nic pain c ondition s but occ ur in combi nation with spec i fic patholog ica l le s io n s an d s y mpt o m s (8,9 ). W e bel i eve tha t recon cep tual i s ing the se co ndition s in th e co nt e xt of t he multi sys tem dysfun cti o n know n for othe r ch r oni c pai n cond it i o ns r ath er th an a s so lel y end-o rga n pat hologi e s ha s t h e pot en tial to imp r ov e o u r under st anding of the con d ition s , all ow us t o id enti fy mea ning ful s ub group s o f pa t i e nt s, devel o p bett er pre clin ical m odel s an d thu s ultim a t e ly f ac ilita te r e s e arch and drug d evelo p ment in thi s fie ld . The pr e s e nt p rojec t t a ke s a d eep -ph eno typing approach , combin ing c linic al, bi ol o gica l, physiol og ica l and ps y cholog ica l da ta, to i mprove ou r u nde rst anding of CP P i n women . Aims/Objectives The primary obje ctive i s to e st a b lish p e rturba tion s i n th e function of pain -rel ev an t sys t e m s/mecha ni sm s th at a r e spec i fic t o E A P an d IC /B PS, an d tho se t h a t ov erl ap both c ondi tion s (EAB P) an d C PP mo re ge n erally. Th e sec ond ary objec tive s are to: a) e stabli s h bi o marker pro fil es tha t are speci fic to E AP a nd I C/BPS a nd tho se tha t overla p bo t h c ondi tion s and CP P more gener al ly; b ) d e t e r m i n e w h e t h e r w o m e n w i t h p e l v i c p a i n c a n b e s t r a t i f i e d b a s e d o n c l i n i c a l d a t a , t h e f u n c t i o n o f pai n-rel evan t s y stem s and t heir b iom arker pr ofil e and ide nti fy any key pathw ays / p roc e sse s underly ing pain in the se s ubg r o up s t h a t may point t o nove l th erap eutic t arg et s; a nd c ) ex plor e whe t h er any subgro up s ide n t i f i ed during the study r e l ate to r es pon s e t o previou s trea tmen t. Study Design TRiP P is an ob s e rv ation al coho rt st ud y bei ng c on ducted in pha s e s an d inc lu des f ive group s o f partic ipan t s : EAP : endome trio si s-a ssocia t e d pain; EA BP : en dom e t rio si s -a ssoci at e d and bladde r p a in ; BPS : in te r st i tia l c ys titi s/bladd e r p ain syndrome; P P: p elvi c pain with n o end o metrio si s o r bla dd e r symptom s; and C ON: c ont r ols with no p e lvic pain or bladde r symptom s; (Figu re 1). T he study build s upon two ex i s ting e n domet rio s i s cohor t s tu die s in O x f or d a n d Bo st on (End O X : A study to id en t i fy pos s i bl e bioma rk ers in w omen with en d ometr i o s i s , Oxf ord RE C r ef 09/H 06 04 / 5 8 ; Bo s t on Cent er fo r Endom etr io si s ( BC E ): A C ro ss-In sti t uti on a l Biorep osi tor y a nd D a ta ba se , IRB - P000 042 67). G i ven th a t neithe r coh ort has a spec i fic focu s on bladder pain we pl ann ed to rec ru it ad d itional wome n w it h I C/ B P S fr o m I nst i t ut o de B i o lo gi a M o le cul a r e C elu l a r ( IB M C) P o rt o . O ve ra l l we a im e d t o id e nt i f y 800 wom en with compl ete b a se line qu e stio nnaire s a nd avai l able bio sp ec imen s ( c ol lec ted acc or ding t o . 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) The copyright holder for this preprint this version posted April 10, 2023. ; https://doi.org/10.1101/2022.05.16.22274828doi: medRxiv preprint Endom etr io si s Ph enome a nd Biob ank ing Harmoni sa tion Projec t ( E PH e ct ) re com men dation s) (10, 11 ) who meet our inc lu sion /exc lu s i on cri teri a to fo rm the TRi PP c oho rt. From thi s coh ort w e aimed t o r e c ruit 20 0 pa r t ic ipant s t o u nde rgo p sych ophy siol ogic al te s ting a nd o f the se , 100 who w ould a ls o und ergo a ne uroimagi ng scan . Dat a from e ach study ph as e w ill be a nal ys e d sep ara tely ini tial ly, w it h sub s e quent multi -moda l a n al y s is i nt e g r at i n g t h e d iff e re n t d at ase ts . Dat a coll ecti on i s c onduct ed at t h e Uni ve r si ty of Oxford , Bo ston Chil d r e n s H o spital , Br i g h am and Women's H o spit al an d I BMC Po rto . Th e study c ommenc ed in April 20 18 a nd is s t i ll ongoi ng , w it h TRiP P s pe ci fic recr uitmen t ha ving commen ced i n Sep tembe r 2 019 af ter a l l regula t ory approval s w e r e ga ined. All re crui tment i s now comple t e . Figu re 1. T RiPP Stud y De si gn. P hase I in Oxford and Boston c o nducte d p rior to T Ri P P c omm enc emen t. Pa rti cipants from Oxford an d Bo s ton s electe d ba se d o n inc lu s i o n cr it eria from a v a i labl e coho rts (E n d OX an d B C E ). P h as e I recruitment a t Po rto (I BMC) c o m menced with stud y. P h a s e II in c l ud e d a d d it ional question naire s c o m p lete d o n li ne or on paper fo r all site s. Ph ase II I c arri e d o u t by tr ain e d res e a rc h e r s a t eac h site . Ph ase I V carried ou t at Oxford b y tra i ned re search ers. Study P opulation and sample s ize Par tic ipant s f o r mi ng th e TRi P P coh ort w e re se lec ted acc ordi ng to th e fol l owing criteria : All g r ou p s : • Aged 18 – 50 y ea r s ( ac knowl edging som e wi ll have be e n younge r whe n the y firs t co nt ribu ted da ta t o END O x / B CE ) • Not pre gnant , l acta ting or planni ng preg nan cy d ur i ng the c our se o f the s tudy EAP: • sur g ica l diag n os i s o f e nd omet r i o s i s; • at le a st one pelv ic pa in scor e of > 4/ 10 on numeric al ra ting s sca l es (N RS ) • no urina r y s y mptom s ( e .g. urge , fre quen cy ) • pai n not pe rcei ved a s a r i sing fr om t h e bl adde r. Additional Questionnaires P hy s iol ogi c al T esti ng fMRI ( onl y c on ducted a t Ox for d ) Addi tio nal Q u estio nnaires EAP , EABP , BPS, PP , Con ( sel ec te d f r om EndO X a n d BCE) BPS ( r ecr u ited a t IBMC) Ba s eli ne Q u esti onn a i r es, Blo od, Saliva , U rine (p r eviou sly co l l e c t e d ) Ph ase II Ph ase I I I Ph ase IV Ph ase I Ph ase I and II Base lin e Q u estio nnaires + B l ood , S a li v a , U r in 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) The copyright holder for this preprint this version posted April 10, 2023. ; https://doi.org/10.1101/2022.05.16.22274828doi: medRxiv preprint EABP: • sur g ica l diag n os i s o f e nd omet r i o s i s; • at le a st one pelv ic pa in scor e of > 4/ 10 on NRS • urinary s y mp t om s • pai n percei ved a s a r i sing from t he bla dd e r a nd f rom oth er ar ea ( s) o f th e pel vis . BPS : • no hi story of e ndome trio s i s ; • at le a st one pelv ic pa in scor e of > 4/ 10 on NRS • urinary s y mp t om s • p a in p e r c e iv e d as ar is i n g f r o m t h e b l ad der . PP: • no hi story of e ndome trio s i s ; • at le a st one pelv ic pa in scor e of > 4/ 10 on NRS • no urina r y s y mptom s • pai n not pe rcei ved a s a r i sing fr om t h e bl adde r. CON: • no hi story of e ndome trio s i s ; • no pe lvic pain, all sco r e s <3 /10 on NRS • no urina r y s y mptom s Reg r e tfull y, du e to the CO VI D-19 p ande mi c rec r uitme n t of n e w IC /B PS pa rtic ipa nts h ad to b e ha lt e d in March 2 020 and ther ef ore t he m ajori ty of t ho s e in t he B PS g roup w er e al so i denti fied fr om th e ex is ting s tudi es . Th e full TRi PP c oho rt t here for e comp ris e s 7 86 women div ide d into th e f i ve study groups . Par t i cipa nts who agr ee d to p art icip ate in T RiP P s pe ci fic p ha se s o f the s tudy coul d c hoo s e whi ch part( s ) o f the s tudy th ey w ished to be i nvolv ed in as l ong as th ey are ab le to give i nfor m e d co ns e nt for t he i r pa rtic ipati on. Fo r phas e I V ( fMRI ) they n e ed to me et a p propri at e inc lusion / e xcl u s io n crit eria rega r d i ng MRI ma gnet sa fe ty. T h e s a m p l e s i z e o f t h e o m i c s b i o m a r k e r d i s c o v e r y a n a l y s e s i n t h e m a i n c o h o r t w a s c h o s e n t o m a x i m i s e p o w e r o f d i s c o v e r y w i t h i n t h e m o s t e a s i l y b a c k t r a n s l a t a b le b i o s p e c i m e n ( b l o o d ) , a l l o w i n g sel ec t i on of p romi sing, r ob u st signa l s tha t can be t arge ted f o r f u rther an aly si s a s pe r ex isting litera tur e (12 ). T he s amp le siz e f o r the sub sequ ent ph a se s o f t h e st udy were dete rmined on th e basi s o f pr eviou s li t e r a t u re, h owev er , a p ragm atic de ci sion a b out clo sing rec ruitm ent wa s req uired i n the li ght o f th e CO V ID -1 9 pand em ic to a ll ow time to comp le te all an aly se s. Our f u ll co hort c ompri s e s 7 86 p artici p ant s , with 158 h avin g com plete d add i t i onal que s tionn a ire s a n d 85 the physi ologi cal t e sting parad igm. f M RI dat a c ollec ti on is o ngoi ng. . 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) The copyright holder for this preprint this version posted April 10, 2023. ; https://doi.org/10.1101/2022.05.16.22274828doi: medRxiv preprint Table 1. TRiPP Study Measures and Outcomes. Outcome Measures Baseline Questionnaires All women id enti fied fr om E N D Ox and BC E had al r e ady com plete d the ba se lin e que stion naire (10) and the se da ta ha ve bee n harmoni se d in a RE D C a p data ba se . Th is que s ti onna ire pro vide s a comprehe n s iv e pro file o f th e pa r tic ipa nt s by inc luding gynae colog ical , obstet ric and medic al hi s t ory ; detail ed a sse s s men t of t heir p elv ic pai n now and prev iou s l y; and imp ortant d emog r a phic v ariable s . P ar ticipa nts rec r ui ted a t IB MC co mple te d the ba sel ine and additio na l que s t i onna ire s once con se nt e d a n d t h e s e d a t a w e r e e n t e r e d i n t h e d a t a b a s e . W o m e n r e c r u i t e d t o p h a s e I I f r o m O x f o r d a n d B C H compl eted addit ional q u e s tio nna ir e s on pap er or di rectly in to the d a t a b a s e . D a t a e n t e r e d b y ha n d fr om p aper ve rsion s wa s do ubl e ent ered to r educ e err or f o r a minimum o f ~20% of t h e qu e stio ns fo r eac h pa rtic ipant . All qu e st i on nair es w e re a vaila ble in Engli s h and P or tugue se . F or the P or tugue s e versio n, vali da ted tran sla tion s we re u s e d where av ailabl e, ot h e r w ise forwa r d a n d b ack t ran sla tio n was u sed . Additional Questionnaire Development The ques tionn ai r e s for P h a se I I of t h e st udy w ere s el ecte d by the T RiP P con so rti um with addi t i ona l input from membe rs o f IMI -P ain C a r e (E PZ, RDT) . T h ey w ere cho se n t o a ll ow a wide und er s t an ding o f C PP in the c ont ext o f w hat is known abo ut ot her chronic p ain condi tion s (e .g.m o od, ca ta s tr ophizing , s le ep di s tur ba nce s) (13–15 ) . Some o f t h e se do main s h ave b een a s s e ssed prev iou s ly in endom etri os i s and/o r I C/BPS (e.g . ga st r oin t e stin al sy mptoms) b ut not in combin a t i o n w ith the va rie ty o f o the r m e a s ur es co l l e c t ed h er e , w h ils t ot h er a r e as h a v e n ot b ee n as se ss ed b ef o r e ( e. g . a d et ai l ed charac te ri s a t i o n of fl are s i n endome trio s is ) . T able 2 i llus t ra te s the domai n s be ing as s e ssed and t o ol s that a re u sed for ph a se I 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) The copyright holder for this preprint this version posted April 10, 2023. ; https://doi.org/10.1101/2022.05.16.22274828doi: medRxiv preprint Physiologi cal a s ses s ments Very li t tle i s k nown ab ou t th e neu rophy s iology of women with C PP . T he Mul tidi s cipl inary Appro ac h to t h e S tudy of C h r oni c Pe lv ic Pain (MA PP ) N e t w ork ha s und ertak en many of t hes e te s t s in tho s e wi t h Ur o logic Ch ronic P elvic P ain Synd rome (an ove r a r c hing term that incl u de s I C/ BPS ), howe ve r their c ohor ts c ompri se bo th m en a n d wom en ( ht tp s :/ / w ww .mappne two r k .o rg ). Dat a from thi s group and o ther s l oo king at wome n on l y do s uppo rt the id ea th at the se c o ndit ions are simila r t o other chr onic pain condition s (16,1 7 ); ho wev er, to dat e thi s ha s not been c ompre hen sively as s e s s e d by c ombini ng multiple a ss es s m en ts in a d ee ply p heno typed c oh ort and in c ombination w i t h endom e t rio si s. Th e par adig m fo r TRiP P wa s de sign ed w ith i npu t from pai n re s e archer s w ithi n th e T R i P P c o n s o r t i u m ( L A N , Q A , S M , C S , K V ) a n d I M I -P a i n C a r e p r o j e c t ( E P Z , R D T ) . W e a i m t o a s s e s s a l l relev an t sy st ems whi l s t keepi ng th e paradi gm a n a cce pt a bl e length and avoid ing invasiv e proce dure s . Pa t i en t par t n e rs ( JB, LH, JM ) were k ey to d e signin g an ac ce p t a bl e pa radi gm. In ord er t o ens ure r epro ducib ility be tw een the c e ntr e s , a ll re se arch er s involv ed in th e p hysiologic al d a ta co llec t io n a tten d ed a coordina t e d t raini n g s e ss ion in H e idelb erg, Ge rmany i n Septemb er 2019 a nd sub s e quen t po st -C O V ID vir tual r e f r e she r se s s io ns. The compo nen t s of the pa r adig m a r e lis ted i n Tab le 2. A q ue st i onnair e a s se ssing s t a t e m ea sures con s ide r ed i mp orta nt c ovaria te s for th e a n alysi s of t he se p hysiol ogi cal da ta i s c omple ted prior to e ach e xperim enta l se s s i on (“How are yo u toda y? ” que stionn ai r e ). Omics EDTA pla sma f rom bi ob anks ( stor ed for a max imum o f 8 y e ar s ) and new ly recr uited pati en ts w a s use d to ob ta in gen o t y pe s of pa rtici pa nts a nd qua nti fy the rel a tive abunda n c e of p r o tein s a n d metabo li te s. 1 82 p rote in s w e re mea sur e d u sing Oli nk’ s pr oxi mity exten si on a ssa y i nflamma tion a n d neurolog y pa nel s (18) and ~1200 met a bo lite s w e r e qua n t i fi ed u s in g ul tr a -hi gh per for ma nc e liqu i d ch r oma t o gr aphy-tande m ma s s spec trom etry run i n four di ff er ent mode s by M e t a bolon. fMRI Neuroim agi ng wi ll be used t o furthe r un de rsta nd th e c ent ral proc e s s e s unde rlyin g obse rvation s fro m the phy siolog ica l t e s ting an d e xplore whe t h e r MR I marke rs ob s e r v ed in other c hronic p a i n co ndition s a r e pr e sen t in C PP . Th e s c an nin g pr o toc ol incl u de s s tr uc t ur a l and fu nctiona l s eque nce s (s ee Ta bl e 1 ) and is a ligned t o the fMRI pr otoc ol of th e Bio P ain su bprojec t o f IM I -P ai nC are . P unc ta t e st i muli will b e u sed for t he “ pai n ta sk” a s they h av e be en pr evi ou s ly demon s t r ated to give robu s t a c t i v a t i o n o f k e y p a i n -r e l a t e d a r e a s i n h y p e r a l g e s i c s t a t e s ( b o t h e x p e r i m e n t a l ( 1 9 – 2 1 ) a n d c l i n i c a l (22) ) an d in w omen wi t h endom etri o si s -as socia ted p ain w ithou t hype r a lge si a (KV unp ublish ed da ta) . . 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) The copyright holder for this preprint this version posted April 10, 2023. ; https://doi.org/10.1101/2022.05.16.22274828doi: medRxiv preprint Domain Tool Study Componen t S t u d y Phase Pa i n: • Clinical his tor y of pe l v i c pai n EPHect c linica l c ovari a t es q u e st io n na ire (2 3 ) B as eline ques ti onn aire F ol l o w -up quest io n n a ire I II • Int e n sit y NRS B as eline ques ti onn aire F ol l o w -up quest io n n a ire Ho w a re y o u t o d a y? I II III • Nat ure i) pai nD E T E C T (2 4) ii) Sh o r t-f o r m McGill Pa in Qu est io nna i r e 2 ( S F M PQ 2) (25 ) P a in C ha r a c te r i sti cs I I • Loc a ti on i) Fibr omy a l gi a s urve y s ca l e (26) ii) B od y m ap Oth e r s y mpt o ms a nd ex pe r i e nc es Ho w a re y o u t o d a y? II III • Co m or bi d pa i n c o nd i t i ons i) D i a gn ose s give n ii) C o mplex m e d ical s ym p t oms in vent o ry (2 7 ) iii ) T MD -pai n s cree n in g t oo l ( 2 8) B as eline ques ti onn aire F ol l o w -up quest io n n a ire Oth e r s y mpt o ms a nd ex pe r i e nc es I II II Gastro in te s tina l sy mpt om s i ) E P He c t c l in i ca l c ov a r ia t e s qu e st ion na i re (2 3 ) ii) T he Gas troi nt e s ti n al S ymp t om R atin g Scal e (29) B as eline ques ti onn aire F ol l o w -up quest io n n a ire Oth e r s y mpt o ms a nd ex pe r i e nc es I II Mo od Hos pi ta l A nxiet y an d D e pre ss io n S cale (HA D S) ( 3 0) Oth e r s y mpt o ms a nd ex pe r i e nc es II State anx i e ty i n v e nt or y ( 3 1 ) Ho w a re y o u t o d a y? III Pa i n C o g n i ti on s Pa i n C at astr o ph i s in g Scale ( 3 2) B as eline ques ti onn aire F ol l o w -up quest io n n a ire Ho w a re y o u t o d a y I II III Pe r so n a lit y Pe r so n a lit y I n v e n t ory ( 3 3 ) Oth e r s y mpt o ms a nd ex pe r i e nc es II Soma tos ens ory proces si n g i) Q ST ( 34) o n t he l ower abd o m e n (tes t site) an d d ors um o f t he f oo t (c on trol s ite) ii) f M RI wi t h p u nctat e s timu li o n t he t hig h P hy si o log i ca l te s ti n g fM RI III IV Visceral s ens iti vit y Blad de r Sens iti vit y pa ra dig m (3 5) P h ys io l o g ic a l t est ing III A u t o no m i c ne r v ou s s y st em fun c t ion i) heart ra t e mon it oring bef ore a n d aft er p a in s ti m u li P h ys io l o g ic a l t est ing III HP A a x i s f u ncti o n i) 2 4 hour c ortis ol p r o fil e ( s a li va) ii) c ort is ol bef o re an d a fter p a i n s ti m u li (saliv a) P h ys io l o g ic a l t est ing III En d og enou s pa in m o du la t ion Co ndit ion ed pain m odu la t io n paradi gm (3 6 ) P h ys io l o g ic a l t est ing III Fl ares i n sy mpt o ms and tri g g ers Ch a racterist ic s o f fl are s i n s ym pt oms an d ass ociat ed tri g g ers ( 37) F la r e s qu es tion na i re II Sl ee p a nd f atig ue i) AS CQ-Me v 2 Slee p I m pa c t S h o r t For m (3 8 ) ii) N eur o-Q OL v1 F a t ig ue ( 3 9 ) Oth e r s y mpt o ms a nd ex pe r i e nc es II M e d i c a l h i s to r y i ) E P He c t c l in i ca l c ov a r ia t e s qu e st ion na i re ii) All e r gies B as eline ques ti onn aire F ol l o w -up quest io n n a ire Oth e r s y mpt o ms a nd ex pe r i e nc es I II II . 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) The copyright holder for this preprint this version posted April 10, 2023. ; https://doi.org/10.1101/2022.05.16.22274828doi: medRxiv preprint T r a u ma C h i ld ho od t r a um a ti c e ve nt s sc a l e (4 0 ) Rece n t tra u m at ic e v e nt s sc ale (4 0) Oth e r s y mpt o ms a nd ex pe r i e nc es II Tre a tm ents Tre a tm ents t ri e d qu esti o n s wi th s cori ng of ou t c om e T rea tme nts trie d ques ti onn aire II Ove r a ll h ea l t h EPHect c linica l c ovari a t es q u e st io n na ire B as eline ques ti onn aire F ol l o w -up quest io n n a ire I II Tabl e 2 . S tudy P ar a di g m . Asses s m e n t-too ls employ ed at ea c h stud y ph ase ba se d o n t h e domains o f interest. Data Manag e ment and Analy s is Par tic ipant s a re only iden tifi e d by s t u dy s pe cific pa rtici pa nt numbe r i n any databa s e. Per s on a l informa tion i s store d s e p ara tely fr om t h ese da t a ba se s and re taine d a t th e indi vidual sit es . Phy s iol ogica l dat a was t r a n sfer red t o the Univ ers i ty of O x for d pr i or t o analy s i s . Derived va r i abl es w ill be calc ul ate d f r o m all v alidat ed scale s and phy siologi cal te st i n g pa r a digm s ac cording t o pu bli shed me thod olog y. Re g ular mee ting s of the pa in da ta a n d t h e omics da ta a n alysi s groups r evie w all analy s i s pla ns b e f or e c ommen cing analy s i s and t h e overall TRi P P s tati stic al a naly si s pla n i s main ta ined a s a live doc ument . Appropri at e stati s tical s of tware wi ll be us e d to ana ly se th e large volume s o f d ata c olle ct ed. Omic s modell ing w ill be p e rforme d u sing b a se R, r m s and e a s y s ta t s pac kag es, Stan or Py MC3, a nd multipl e Pytho n pac ka ge s incl uding p ingouin . Q S T da ta w ill b e ana lys ed in MATL AB . fM RI da ta w il l be ana lys ed wi th F SL ( F MR IB’ s S of t w are Li br a r y ; ww w.fmrib.ox .ac . uk/ f sl ) . O t h e r s t a t i s t i c a l a n a l y s i s w i l l b e c a r r i e d o u t i n S P S S . A n i n t e g r a t i o n a n a l y s i s w i l l b e u n d e r t a k e n t o c o m b i n e a l l t h e d i f f e r e n t m o d a l i t i e s , a l l o w i n g c o m p a r i s o n s o f t h e b i o m a r k e r profil e s b e t w e en pa tien t g roup s a nd c ontro l s and an e xplora tion o f di f fer ent p hen otypic pre sen tati on s. Dis c us sion The TRi P P c o nso r ti um ben efi t s from gl oba l in terd isci pli nary co -op e r a t i on s bet wee n c linic ian s a n d basic sci enti s ts from a w ide vari ety of bac kground s w o rking both in a c ademia an d th e pharma ceu tic al indu s tr y , a s well a s t hre e ac tive pa tie n t orga nisa t i o ns w ho h ave been inv olved w it h the s t udy s in ce inc ep tion. We beli e ve th at ou r novel ap p r oa ch, bot h in te rms o f dee p phen otyping and th e u s e o f m ethod ol ogie s not u s ua ll y app lied to th ese con dition s , ha s th e p oten tial to improv e our und er sta nding o f p el vic pa in. W e ho pe t o be a ble t o pro duce n ov el c linic ally rele van t d ata ( e.g . an un derst anding of t h e pre vale nce a n d impac t o f bo t h w ide spre ad pai n and flar es in C P P), id e nt i fy underly ing pa in pathwa y s a nd thu s pot e ntia l new the rap eu tic targe t s or o pportu ni t i e s to re purpo s e trea tmen t s fr o m o the r c ondi tion s. Mo r eove r , oth er wo rk -pa ck age s w it h in the pr o ject w ill bac k- tran s l a te ou r findi ng s to r e fin e e xis t i ng r od en t mode l s (41 ) of e ndome trio s i s a nd IC /BP S with t h e hope o f improving the drug de vel opm en t capa biliti e s. L i m i ta ti o n s The u se of ex is t i ng bio re s ou rc e s , wh il st allow ing thi s projec t t o pr oceed rel ati v ely rapidl y, me an s that th e time be twe en bio sp ecim en coll ection an d analy s i s varie d f o r ea ch par ti ci pant and re sul te d in sampl e agi ng o f r elev ance to th e o mi cs da ta . C ommon to mo s t rec en t st udie s, t h e C OV ID -1 9 pand emic and r elat ed res tric tion s sever e ly delay ed rec r ui tme n t and da ta coll e ctio n for ph a se s I II a n d IV. Addi t i on ally, it limit ed our ability t o re cruit a n e w IC /BP S c ohor t of ad eq ua te si z e. W hi l st w e cou l d mitiga te a gai ns t thi s t o an ex t ent by u s ing partic ipan t s w it h in th e bio re source s who met t he B P 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) The copyright holder for this preprint this version posted April 10, 2023. ; https://doi.org/10.1101/2022.05.16.22274828doi: medRxiv preprint recruitm ent cri teri a, thi s grou p is no t of t h e si z e w e ha d o rigin ally plan ned a nd the majori ty o f partic ipan t s were id e nt i f i e d fr om gy naeco logy r a t he r tha n u rology clin ics. D e c l ar at i o n s Ethic s approv al and c o ns e nt t o pa r tic ipate The s tudy ha s rec eiv ed e thic al approva l f rom York shire & T he H um b er – S ou th Y or k s h ire R e s ea r c h Ethic s Com mi t te e (19/ Y H/0030) w ith l oc a l s i te ap proval s and i s bei ng c on duct ed in a cc or da nce w it h the princ ipl e s of the D ec lar ation o f Hel si nk i and with relev an t regula t i on s a nd Go od Clini cal P r a ctic e. Info rmed con s en t is ob t a ine d fr o m a ll the pa r tic ip ant s a t e a ch pha se o f t he st udy, and they w er e inform ed tha t th e y are f re e to w ithd raw from th e study at a ny t i me. Availa bility of data and material Direc t ac ce s s will be gran ted to a u thor i sed rep re sen ta tive s fr om the S p on s or a n d host i n s ti tutio n fo r monitoring a nd/or audi t of th e s tu dy to en sur e compl ianc e with r e gula tion s. All s t udy da ta wil l b e stored fo r 10 year s a ft er t he en d of the s t udy . Once th e study an d a ll f oll o w up anal yse s ar e co mplete de -id enti fie d d ata will be dep osi ted in a public ly a cce s si ble rep o sito ry as req ui r e d by th e funde r s. Fundi ng This p rojec t ha s r ec eiv ed fu nding fr om the Inn ova t iv e Medic in es Ini tia tiv e 2 Join t Unde rtaking u nde r grant agre e ment No [77750 0 ]. This J oin t Under taking rec eive s suppor t fr om th e European Unio n’ s Horiz on 20 20 r e s earc h and inn ova t i o n p r og r a mme and EFP IA. F ur t he r in f ormation i s f o un d under w ww. imi-painc a re .eu a nd ww w.i mi .europ a.e u . Di sclai mer: T he s ta tem ent s and opinion s pr e s e n t e d h e r e re fle ct t he a ut h o r ’ s vi ew and nei ther IM I nor th e Europe an U nio n , EFPI A, or any Associa t e d Pa rtn ers ar e re spo ns i ble for any use tha t may b e made of the in forma tion cont aine d ther e in. Ack nowledge ment s The a ut ho rs wi sh to ac know ledge Alli s o n Vitoni s and Kur t i s Ga r b utt fo r thei r work in ha r mon i s ing datab a se s betw een Bo s ton and Oxford a nd identi fy ing pa r tic ip ant s s ui ta ble for th e TRi PP co h or t . Consent for publication All a utho rs read a nd appr ov ed the fina l manuscrip t. Competing int e r e s ts LD, LC an d MK dec lar e no c ompe ting inte re s t s. NR: No comp e t i ng int ere s ts LAN: No c ompe ting i nte r e s t s QA: N o compe ting int ere st s CMB: R e s e arch G ran t s from Baye r H e al thcare , MD N A Life Sc ienc es, Roc he Di a g nos tic s , Eur opea n Commis sio n, NIH. Hi s empl oyer h a s rec eived c on s u lancy fe e s from M y ovan t an d Ob s E va fo r w ork out side o f thi s pr ojec t . JB: N o com peting int er es t s FC: C on s ul t a nt and /or inve s tigato r fo r All erga n ( Abbvie) , A stel la s, Ba ye r, Ip se n an d Recorda ti AWH : r epor t s grant fun ding fr om t he MRC, NIHR, CSO, Wellb e ing o f Women , Roc he D i agno s t i c s, Astra Z enec a, Fe rring, Charl e s Wol f s on C harita ble T r u s t and S ta ndard Li fe . Hi s employe r ha s r ec eiv e d co ns ul tan cy fe e s from Roc h e Diag no stic s, AbbVi e, Nordi c Pha r ma and F er ring , ou ts i d e th e submi tte d work . In add iti on, A WH ha s a pat ent for a s e rum bi omarke r fo r endome t rio si s p e nding . . 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) The copyright holder for this preprint this version posted April 10, 2023. ; https://doi.org/10.1101/2022.05.16.22274828doi: medRxiv preprint LH: no compe t i ng int ere s ts in r e la tion t o this wo rk JM: no c ompe ting int er e st s EMP-Z: re ceiv ed finan cial s upp o r t from G runent hal a nd Mun dipha r ma for re sea rc h ac t i vitie s and adv is o r y and l e ctur e f ee s f rom Gr ü ne nth a l, Novar ti s and Mund iph arma . In addi tio n, s h e r ec eiv e s scien tifi c suppo rt f rom t h e Ge r ma n Re s e arch F ounda tion (DF G), the Fe dera l M i ni s t ry of E duca t i o n and Re s e a rch (BM BF) , the G e r ma n Fede ral Joint Commit tee (G -B A) and the In novativ e Medic in e s Initia t iv e (I MI ) 2 Joi n t U nde rtak ing unde r g r a nt agre eme nt N o 777500. Thi s Join t Under t a king rece ive s suppor t from the Eur opea n Uni on’ s H orizon 2020 res earc h a nd i nnovati on pr o gramme a nd EF PIA . All mone y w ent to th e ins titu t io n E.M.P . -Z. is w orking for . AH: Employ ee o f Ba yer AG, Germa ny. CS: decl a r e s no compe t in g int ere s t s IT: On the scie nti fic advi sory boa rd f o r Amgen (2017 –2019 ); h as rec eiv e d ho no r a r i a for providin g va r i ous e ducati on al t alk s a n d worksh op s; is a c ounci l member o f th e M e dic a l Re se arch Counc il of the Uni ted Kingdom; i s a tru s t ee o f M Q , a men tal heal th ch ari t y ; i s Pre s i de nt -e l ect o f FE N S ; and i s invo lved w ith I nnova tive Medi cine s Initi ativ e– Pai n Ca re (Biopai n), a p an p ha rma - ac ademia con sor tium. RDT: Ad bo a r d f or BA Y ER, IAS P t a s k fo r c e on c hronic pain c la ss i f i ca tion SAM: h a s be en an a dvi sory bo ard m e mber for Abb Vie and Roch e an d rec e ive s r ese arch fundi ng fr o m the Nati onal I n s ti tut e s o f H e a lth, th e U S D e pa rtmen t o f D e fe n se, the J . Wil la rd a nd Alic e S . M a r rio t t Fou ndati on, a nd Ab bVi e; non e are rela te d t o t h e p re s e n t e d work . KTZ : repo r t s g r a n t fun di ng fr om E U Ho ri z on 2020 , N IH U S , W e llb eing o f Wome n, Bay er AG, Roc h e Diagn o s tic s , E vot ec-L ab282 , M DNA L ife S c ienc es, outsid e t h e s ub mi tted work. JN: Employ e e and s ha reh olde r of B ay er AG , German y KV: dec lar e s re se arch fu nding from Bay e r Heal thc ar e and honor aria for c on sul ta ncy a nd ta lks a n d as s o cia ted t rav el ex pe ns e s f r om Ba yer H ealthc a re, Grun enth al GmBH, A bbVi e an d Eli Lill y. Author ’s c ont ributions LD, LC, MK a nd K V d ra fted t he ma nu s c r i pt . All othe r autho r s con tribu ted to th e o rigi nal de sign o f th e projec t and r evi ewed and e di t e d the ma nuscrip t.

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Di sclo sure o f tra uma s and p s y chos omatic pr o c e sse s. S oc S ci Med . 1988;2 6 (3) :327–32. 41. Nunez -Bad ine z P, De Leo B, La ux-Bi ehlm a nn A, Ho ffman n A, Zollner T M, Saunde rs PTK, e t al. Prec linic al m od el s of endome trio si s and i nter s t i t i al c y s ti ti s/bl adder p ai n synd rome : an In novativ e M edic ine s Ini tia tive -Pain Car e i nitiative t o improve t hei r value for t ran sl ationa l re sea rch in pel vic pain. P ain. 20 21; . 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) The copyright holder for this preprint this version posted April 10, 2023. ; https://doi.org/10.1101/2022.05.16.22274828doi: medRxiv preprint Fig ur e s a nd Tables Se e o ur ge n eral f or m at t in g guidel i ne s . Autho rs mu st limi t the n umb er of tabl e s a nd figure s i n th e manu s c r ip t to 3 in or der to be con si s t ent w ith a note a rt i cle ty pe. Addition a l ta ble s / fig ure s ca n b e pr ovide d a s add i t i onal file s or b e de po sit ed in a n ap pr op ria te d a ta depo sito ry (e .g . Fig s h a r e ). Figu re 1. S tu dy Desig n Fi g ure. Pha se I in Oxford a n d Bo s ton c o nducted p rio r to T R iP P c omme n cem e n t. P arti cipan ts from Oxford an d Bo s ton s electe d ba se d o n inc lu s i o n cr it eria from a v a i labl e coho rts (E n d OX an d B C E ). P h as e I recruitment a t Po rto (I BMC) c o m menced with stud y. P h a s e II in c l ud e d a d d it ional question naire s c o m p lete d o n li ne or on paper fo r all site s. Ph ase II I c arri e d o u t by tr ain e d res e a rc h e r s a t eac h site . Ph ase I V carried ou t at Oxford b y tra i ned re search ers. Additional Questionnaires P h y s io lo g i c a l T e s t in g fM RI ( onl y cond uct ed at O xf ord ) A d ditio nal Ques t i on naires E A P, E A B P, B P S , P P, C o n ( s e le c t e d f r om E nd O X a n d BC E ) BPS (recru it ed at I BMC) Bas el in e Q u es t i on naires , Bl oo d, Sali v a, U r in e (p r eviou s l y co l l e c te d ) Phase II Ph ase I II Phase IV Ph ase I Phase I and II Baseli ne Ques tio nnai r es + Blo od, Sali v a, Uri ne . 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) The copyright holder for this preprint this version posted April 10, 2023. ; https://doi.org/10.1101/2022.05.16.22274828doi: medRxiv preprint Table 1. TRiPP Study Measures and Outcomes. Domain Tool Study Component Study Phase Pain: • Cli n ic a l his tor y of pelv ic p a i n EP He c t cli n ic al co v ari at e s q ue sti o nnai r e (2 3) Bas e li ne q ue s tion n a ire Fo l lo w- up qu est ion na i re I II • Int ens it y N R S Bas e li ne q ue s tion n a ire Fo l lo w- up qu est ion na i re How are you t od ay ? I II III • Nat ure i) pa i n DET ECT (2 4 ) ii) S h ort-f orm M c Gil l Pai n Quest io n naire 2 ( S F M PQ 2) (2 5 ) P a in C ha r a c t e r i st i c s II • Lo ca ti o n i) Fibr om yalgia s urv ey sc ale (2 6) ii) Bod y m ap O t he r sym pto m s a nd experi ences How are you t od ay ? II III • Co mo r bi d pain c o n dit ion s i) D iag n o s es gi v e n ii) Co m pl ex m edic a l sym pt o m s in v e n t ory (2 7) iii) T M D -p a i n screen i n g t oo l ( 28) Bas e li ne q ue s tion n a ire Fo l lo w- up qu est ion na i re O t he r sym pto m s a nd experi ences I II II Gastr oin tes ti nal sy mp t o ms i) EP H ect c l i nical c ovariate s q u es t io nn a ire (2 3) ii) The G a s t roint es ti na l Sy mpt om Rati n g Scale (2 9) Bas e li ne q ue s tion n a ire Fo l lo w- up qu est ion na i re O t he r sym pto m s a nd experi ences I II Mo o d Hos p i tal Anxie ty a n d Depres si on Scal e (HADS) ( 30) O t he r sym pto m s a nd experi ences II S t at e an x i e ty in v e n to ry ( 31 ) H o w a r e y o u to da y? III . 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) The copyright holder for this preprint this version posted April 10, 2023. ; https://doi.org/10.1101/2022.05.16.22274828doi: medRxiv preprint Pa i n C o g n i ti on s Pa i n C at astr o ph i s in g Scale ( 3 2) B as eline ques ti onn aire F ol l o w -up quest io n n a ire Ho w a re y o u t o d a y I II III Pe r so n a lit y Pe r so n a lit y I n v e n t ory ( 3 3 ) Oth e r s y mpt o ms a nd ex pe r i e nc es II Soma tos ens ory proces si n g i) Q ST ( 34) o n t he l ower abd o m e n (tes t site) an d d ors um o f t he f oo t (c on trol s ite) ii) f M RI wi t h p u nctat e s timu li o n t he t hig h P hy si o log i ca l te s ti n g fM RI III IV Visceral s ens iti vit y Blad de r Sens iti vit y pa ra dig m (3 5) P h ys io l o g ic a l t est ing III A u t o no m i c ne r v ou s s y st em fun c t ion i) heart ra t e mon it oring bef ore a n d aft er p a in s ti m u li P h ys io l o g ic a l t est ing III HP A a x i s f u ncti o n i) 2 4 hour c ortis ol p r o fil e ( s a li va) ii) c ort is ol bef o re an d a fter p a i n s ti m u li (saliv a) P h ys io l o g ic a l t est ing III En d og enou s pa in m o du la t ion Co ndit ion ed pain m odu la t io n paradi gm (3 6 ) P h ys io l o g ic a l t est ing III Fl ares i n sy mpt o ms and tri g g ers Ch a racterist ic s o f fl are s i n s ym pt oms an d ass ociat ed tri g g ers ( 37) F la r e s qu es tion na i r e II Sl ee p a nd f atig ue i) AS CQ-Me v 2 Slee p I m pa c t S h o r t For m (3 8 ) ii) N eur o-Q OL v1 F a t ig ue ( 3 9 ) Oth e r s y mpt o ms a nd ex pe r i e nc es II M e d i c a l h i s to r y i ) E P He c t c l in i ca l c ov a r ia t e s qu e st ion na i re ii) All e r gies B as eline ques ti onn aire F ol l o w -up quest io n n a ire Oth e r s y mpt o ms a nd ex pe r i e nc es I II II T r a u ma C h i ld ho od t r a um a ti c e ve nt s sc a l e (4 0 ) Rece n t tra u m at ic e v e nt s sc ale (4 0) Oth e r s y mpt o ms a nd ex pe r i e nc es II Tre a tm ents Tre a tm ents t ri e d qu esti o n s wi th s cori ng of ou t c om e T rea tme nts trie d ques ti onn aire II Ove r a ll h ea l t h EPHect c linica l c ovari a t es q u e st io n na ire B as eline ques ti onn aire F ol l o w -up quest io n n a ire I II Tabl e 2 . S tudy P ar a di g m . Asses s m e n t-too ls employ ed at ea c h stud y ph ase ba se d o n t h e domains o f interest. . 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) The copyright holder for this preprint this version posted April 10, 2023. ; https://doi.org/10.1101/2022.05.16.22274828doi: medRxiv preprint