{"paper_id":"c1f4d5ac-4d96-4ab1-98bf-850cfc647077","body_text":"Title \nDeep phenotyping of women with endometriosis-associated pain and bladder pain \nsyndrome: the TRiPP (Translational Research in Pelvic Pain) study protocol \n \n \nLysia D emetri ou* 1 , L ydia  Cox on* 1 , M ich a l K rasso w s k i* 1 , Ni lufer Ra hm i o g l u 1,2 ,  Lars Ar en dt-N ie ls en 3, 4 , Q a s i m  \nAziz 5 , C hris tia n  M . B ecker 1 , J udy Birch 6 , F r a n s cis c o  C r u z 7 , A n ja  H o ff m a n 8 , A n dre w W . H orn e 9 , Lon e  \nHu mmels h oj 10 , Ste phe n McMa ho n §11 , Ja ne  Mei jl i n k 12 ,  E st h e r  P og at zk i -Z ahn 13 ,  C hri st ine  B. S ie be r g 14abc , Irene  \nTra c ey 15 ,  R o lf -De t le f  T r e e de 16 , S tace y  A. M is s m er 17abc , Kri n a  T . Z ond erva n 1 ,  Je n s N agel 18 ,  Ka ty  V in ce nt 1  \n  \n \n1.  Ox fo r d  E ndo me trio s i s  Centre , Nuffiel d D e p a rtment o f Wome n’s  a n d Repro d u c ti v e He a lt h, U niversi t y  \nof Oxf or d, U K \n2.  W el lc o m e C e ntre for H uman  Gene tics, U ni v e rsity  of Ox f o rd , Oxf ord , U K  \n3.  Center f o r Ne uropla sticit y and Pai n  (CN A P ) , S MI, De p a rtm en t of Hea l t h  S c i e nce a n d Te c h n ol og y , \nSch o ol  o f  Me di c ine,  A al borg  U niversi t y , Aa lb org, De nmark \n4.  De nmark  a n d De pa r t m e n t of M ed i c a l Ga s t roenter ol og y , Mech-Sens e, A al borg U ni v ers i t y Ho s pita l,  \nAa l b or g,  De n m ar k \n5.  Centre f or Neuro sc i e nce, S u r gery an d  Trau ma , Bl izard  Ins ti t u t e, W in gate  I n s t it ut e  of  \nNeur ogas troe n t e rol o gy. Bart s a nd T h e  Lo n d o n S c ho ol of Me d ici ne a n d De nti str y, Q uee n  Mar y  \nU n iv e r s i ty o f L ond o n UK \n6.\n P e lv i c P a in  Su ppo r t  Ne tw o rk ,  P oo le ,  UK   \n7.  IBMC/ I 3 S a n d Fa c ul t y  o f  M edic i n e o f Port o/ Hos pital  S J oão,  Porto,  Port u  \n8.  Res e arc h & De vel opme nt, Ph a rmace u t ic l s  Ex p eri ment al  Me d ic ine,  Ba y er AG,  Berli n , G erm a n y \n9.  MR C  Ce n t re for R e pr o du c t ive He a lt h,  U ni v er sit y o f E d i n b u r gh,  Ed inb ur gh, U K  \n10 .  E ndo metrios is. org,  U K  \n11 .  Fo rm erl y  of W o lfs o n CA R D Centre,  K i n g ’s  C olleg e  Lo n d on, U K  \n12 .  Int e r n a ti onal  Pa i nf u l Bla dder  Fo un dati on  \n13 .  De p art me nt  of A nest h es io log y ,  In tens iv e  Ca r e  a nd Pa i n Me dici n e , U niv e r sit y H os pit a l M u e ns ter, \nMu enst er, Germa ny \n14 .  a.  B io b e h a v i ora l P edia tric Pa i n La b,  D ep artmen t of Ps y c hi a try & Beha v i oral Scie nces, B o s to n  \nChil dren ’ s  H os p i ta l, B o s t on, M A; b. Pai n  and  Affecti v e  Ne uro scie nce C e n ter, De p art me n t  of \nA ne s t he s iol og y,  Critical Care, & P a i n M edicin e , B os t on C hildre n’ s  H o s p it al, B os to n, M A; c. Depart men t \nof P s y chi atry, H arvard  Med ical  Sch ool, Bos t on, M A \n15 .\n Wel lc o m e C e n tre f o r I nt eg ra ti v e Ne u r o i m a gi ng, F M RI B,  Wo lfs on B ui ldin g , Nuf fie l d Depart men t \nClinical  N eurosc ience s, Un iversit y of  Oxf o rd,  Joh n R a dcliff e  H os pi ta l , Ox f o rd , U K  \n16 .\n De p art me nt  of N e uro p h y si olog y , M a n n heim  Cent er fo r Trans la tion al Ne ur oscie nc e  (MC T N), \nHeidel berg  U n i ve r si t y , Man n he i m,  G erman y  \n17 .  a.  De pa rt m e nt  of O bs te trics , G yn e c olo g y , a n d R e pr oduc ti ve Bi ol og y ; Colle g e  of  H u man M e dici ne, \nM i c h ig a n  St a te  U niv e r s it y,  G ra nd  R ap i d s,  M I ,  U SA .  b .  De pa r t me n t  o f E pi d e mi o l og y , Ha rv a r d  T .H .  Cha n \nSch o ol  o f  P u blic He al t h,  B o s t o n , M A, U S A. c . Di vis ion  of  A do le s ce n t  a nd Y oun g Ad u l t  Me dic i ne,  \nDe p art me nt  of Pediatr i c s, Bos t on Chil dren' s Hos pi t a l  a nd Har v ar d Me di c a l  Sch ool,  Bos t on , MA,  US A  \n18 .\n Pharmace u t ic a ls Div isi on, Re sea r ch  a nd Earl y  D e ve l o pmen t, T h er ape utic Ar e a  En docr i no log y, \nM e ta bo l i s m  an d  Re p r od u c tiv e  H e a l th ,  E xp lo ra t o ry  P at hob io lo g y ,  B a y e r A G ,  W upp e r ta l ,  G er m a ny .  \n \n*Joint first authors \n§Deceased \n \n \n  \n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 10, 2023. ; https://doi.org/10.1101/2022.05.16.22274828doi: medRxiv preprint \nNOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.\n\nAbs trac t \n \nObjectives:  \n \nChronic  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  \nd 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  \npheno 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  \npai 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  \nbeli 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  \nfor 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  \nour 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  \npsych 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  \nspeci 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  \ngen erally and a s socia ted  qu anti tat ive bio marker pro file s.  \n \nDis c us sion:  \n \nWe 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  \nunder 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  \nani mal mode l s  a nd t arge ted th erap e utic trea tmen t s.  \n \n \nKeyw 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  \npheno t y ping  \n  \n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 10, 2023. ; https://doi.org/10.1101/2022.05.16.22274828doi: medRxiv preprint \n\nIntroduction \n \nChronic  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  \nqual 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  \nis 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.  \n \nThe  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-\npai 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 ,  \nEuropea 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  \nfocu 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  \n(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  \npredomin 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 )  \nand 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  \ngen 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  \nbut 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  \nrecon 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  \nch 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  \nunder 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  \nbett 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 .  \nThe  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  \nand ps y cholog ica l da ta, to i mprove ou r u nde rst anding  of CP P i n women .  \n \n \nAims/Objectives \nThe  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  \nsys 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  \n(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  \nare 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 )  \nd 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  \npai 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  \nunderly 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  \nwhe 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.  \n \n \nStudy Design \nTRiP 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  \npartic 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 ;  \nBPS : 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  \nsymptom 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  \nupon 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  \npos 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  \nEndom 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  \nneithe 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  \nI 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 \nwom 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  \n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 10, 2023. ; https://doi.org/10.1101/2022.05.16.22274828doi: medRxiv preprint \n\nEndom 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 )   \nwho  meet our inc lu sion /exc lu s i on cri teri a to fo rm the TRi PP c oho rt.   \n \nFrom 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  \nthe se , 100  who w ould a ls o und ergo a ne uroimagi ng scan .  \n \nDat 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  \na 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 . \n \nDat 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 \nWomen'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  \nTRiP 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  \nga ined. All  re crui tment i s now comple t e .  \n \n  \nFigu 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 \nOxford  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  \nPo 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. \nPh 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.\n \n \nStudy P opulation and sample s ize \nPar 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 :  \nAll g r ou p s :  \n• 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  \nco nt ribu ted  da ta t o END O x / B CE ) \n• 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   \n \nEAP:  \n• sur g ica l diag n os i s o f e nd omet r i o s i s;  \n• 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 )  \n• no urina r y  s y mptom s  ( e .g. urge ,  fre quen cy ) \n• pai n not pe rcei ved a s  a r i sing  fr om  t h e  bl adde r.  \n \nAdditional Questionnaires\nP hy s iol ogi c al T esti ng\nfMRI ( onl y  c on ducted a t Ox for d )\nAddi tio nal Q u estio nnaires\nEAP , EABP , BPS, PP , Con\n( sel ec te d f r om EndO X a n d BCE)\nBPS\n( r ecr u ited  a t  IBMC)\nBa s eli ne Q u esti onn a i r es,  Blo od, \nSaliva , U rine  (p r eviou sly \nco l l e c t e d )\nPh\nase II\nPh\nase I\nI\nI\nPh\nase IV\nPh\nase I\nPh\nase I\n and II\nBase lin e Q u estio nnaires + B l ood , \nS a li v a ,  U r in e\n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 10, 2023. ; https://doi.org/10.1101/2022.05.16.22274828doi: medRxiv preprint \n\nEABP:  \n• sur g ica l diag n os i s o f e nd omet r i o s i s;  \n• at le a st one  pelv ic pa in scor e of > 4/ 10  on  NRS  \n• urinary s y mp t om s   \n• 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 .  \n \nBPS : \n• no hi story of e ndome trio s i s ;  \n• at le a st one  pelv ic pa in scor e of > 4/ 10  on  NRS  \n• urinary s y mp t om s   \n• 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 . \n \nPP:  \n• no hi story of e ndome trio s i s ;  \n• at le a st one  pelv ic pa in scor e of > 4/ 10  on  NRS  \n• no urina r y  s y mptom s   \n• pai n not pe rcei ved a s  a r i sing  fr om  t h e  bl adde r.  \n \nCON:  \n• no hi story of e ndome trio s i s ;  \n• no pe lvic  pain,  all sco r e s <3 /10 on NRS  \n• no urina r y  s y mptom s   \n \n \nReg 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  \nin 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  \nex 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  \ngroups . 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  \nwhi 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  \nco 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  \ninc lusion / e xcl u s io n crit eria rega r d i ng MRI ma gnet sa fe ty.  \n \nT 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  \nm 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 \nsel 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  \nlitera 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  \nbasi 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  \nthe 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.  \n \nOur  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  \n85 the  physi ologi cal  t e sting parad igm.  f M RI  dat a c ollec ti on is o ngoi ng.  \n \n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 10, 2023. ; https://doi.org/10.1101/2022.05.16.22274828doi: medRxiv preprint \n\n \nTable 1. TRiPP Study Measures and Outcomes. \n \nOutcome Measures \n \nBaseline Questionnaires \nAll 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)  \nand 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  \ncomprehe 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 ;  \ndetail 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 .  \nP 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  \na 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  \ncompl 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  \nfr 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  \neac 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  \nversio 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  \nwas u sed .  \n \nAdditional Questionnaire Development \nThe 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  \ninput 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  \nC 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 ,  \ns 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 \nand/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  \nm 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 \ncharac 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  \nthat a re u sed for ph a se I I.  \n \n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 10, 2023. ; https://doi.org/10.1101/2022.05.16.22274828doi: medRxiv preprint \n\nPhysiologi cal a s ses s ments \nVery 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  \nto 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  \nwi 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  \ntheir  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\n). Dat a from thi s  \ngroup 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  \nother 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  \nby 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  \nendom 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  \nT 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  \nrelev 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  \nproce 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  \nens 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  \nco 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  \nsub 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  \nTab 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  \nof 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? ”  \nque stionn ai r e ).  \n \nOmics  \nEDTA 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  \nuse 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  \nmetabo 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  \nneurolog 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  \nch 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.  \n \nfMRI  \nNeuroim 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  \nthe 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  \nco 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  \n(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  \nst 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  \na 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  \n(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) .  \n \n \n \n \n \n \n \n \n \n \n \n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 10, 2023. ; https://doi.org/10.1101/2022.05.16.22274828doi: medRxiv preprint \n\n \n \nDomain Tool Study Componen t  S t u d y  \nPhase \nPa i n:     \n• Clinical  \nhis tor y  of  \npe l v i c  pai n \nEPHect  c linica l c ovari a t es q u e st io n na ire  \n(2 3 )  \nB as eline  ques ti onn aire \nF ol l o w -up  quest io n n a ire  \nI \nII \n• Int e n sit y  NRS B as eline  ques ti onn aire \nF ol l o w -up  quest io n n a ire  \nHo w  a re  y o u t o d a y?  \nI \nII \nIII \n• Nat ure i) pai nD E T E C T (2 4)  \nii) Sh o r t-f o r m McGill  Pa in Qu est io nna i r e  2 \n( S F M PQ 2)  (25 ) \nP a in  C ha r a c te r i sti cs I I  \n• Loc a ti on  i) Fibr omy a l gi a  s urve y s ca l e (26)  \nii) B od y m ap  \nOth e r s y mpt o ms  a nd \nex pe r i e nc es  \nHo w  a re  y o u t o d a y?  \nII \n \nIII \n• Co m or bi d  \npa i n  \nc o nd i t i ons \ni) D i a gn ose s give n \nii) C o mplex  m e d ical  s ym p t oms in vent o ry  \n(2 7 )  \niii ) T MD -pai n  s cree n in g t oo l  ( 2 8)  \nB as eline  ques ti onn aire \nF ol l o w -up  quest io n n a ire  \nOth e r s y mpt o ms  a nd \nex pe r i e nc es  \nI \nII \n \nII \nGastro in te s tina l \nsy mpt om s  \ni )  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  \n(2 3 )  \nii) T he Gas troi nt e s ti n al  S ymp t om R atin g  \nScal e (29)  \nB as eline  ques ti onn aire \nF ol l o w -up  quest io n n a ire  \nOth e r s y mpt o ms  a nd \nex pe r i e nc es  \nI \nII \nMo od  Hos pi ta l  A nxiet y an d D e pre ss io n S cale  \n(HA D S) ( 3 0)  \nOth e r s y mpt o ms  a nd \nex pe r i e nc es  \nII \n 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 \nPa 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 \nF ol l o w -up  quest io n n a ire  \nHo w  a re  y o u t o d a y \nI \nII \n \nIII \nPe 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 \nex pe r i e nc es  \nII \nSoma tos ens ory   \nproces si n g \ni) Q ST ( 34)  o n t he  l ower abd o m e n (tes t \nsite)  an d d ors um  o f  t he  f oo t (c on trol  s ite)  \nii) f M RI wi t h p u nctat e  s timu li  o n t he t hig h  \nP hy si o log i ca l te s ti n g \nfM RI  \nIII \nIV \nVisceral  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 \nA u t o no m i c  ne r v ou s  \ns y st em  fun c t ion \ni) heart  ra t e mon it oring  bef ore a n d aft er \np a in s ti m u li \n \nP h ys io l o g ic a l  t est ing  III \nHP 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)  \nii) c ort is ol  bef o re  an d a fter p a i n s ti m u li \n(saliv a) \nP h ys io l o g ic a l  t est ing  III \nEn d og enou s pa in  \nm o du la t ion \nCo ndit ion ed  pain m odu la t io n  paradi gm \n(3 6 )  \nP h ys io l o g ic a l  t est ing  III \nFl ares  i n  sy mpt o ms \nand tri g g ers  \nCh a racterist ic s o f fl are s  i n s ym pt oms  an d  \nass ociat ed tri g g ers  ( 37)  \nF la r e s  qu es tion na i re  II \nSl 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 \n(3 8 )  \nii) N eur o-Q OL  v1  F a t ig ue ( 3 9 )  \nOth e r s y mpt o ms  a nd \nex pe r i e nc es  \nII \nM 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  \nii) All e r gies  \nB as eline  ques ti onn aire \nF ol l o w -up  quest io n n a ire  \nOth e r s y mpt o ms  a nd \nex pe r i e nc es  \nI \nII \n \nII \n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 10, 2023. ; https://doi.org/10.1101/2022.05.16.22274828doi: medRxiv preprint \n\nT 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 ) \nRece n t  tra u m at ic e v e nt s sc ale (4 0)  \nOth e r s y mpt o ms  a nd \nex pe r i e nc es  \nII \nTre a tm ents  Tre a tm ents  t ri e d  qu esti o n s  wi th  s cori ng of  \nou t c om e \nT rea tme nts  trie d \nques ti onn aire \nII \nOve 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 \nF ol l o w -up  quest io n n a ire  \nI \nII \nTabl 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. \n \nData Manag e ment and Analy s is  \nPar 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  \ninforma 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 .  \nPhy 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 .  \n \nDerived  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  \nac 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  \ngroups 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  \npla 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  \nlarge  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  \npac 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  \nana 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 ;  \nww w.fmrib.ox .ac . uk/ f sl\n) .  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  \nw 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  \nprofil 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  \npre sen tati on s.  \n \nDis c us sion  \nThe  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  \nbasic  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  \npharma 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  \nthe 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  \nand 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  \nour 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 .  \nan 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  \nunderly 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  \ntrea 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-\ntran 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  \nhope o f improving  the drug de vel opm en t capa biliti e s.  \n \nL i m i ta ti o n s  \nThe  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  \nthat 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  \nin 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  \npand 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  \nIV. 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  \nmitiga 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  \n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 10, 2023. ; https://doi.org/10.1101/2022.05.16.22274828doi: medRxiv preprint \n\nrecruitm 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  \npartic 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.  \n \nD e c l ar at i o n s  \nEthic s  approv al and c o ns e nt  t o pa r tic ipate  \nThe  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  \nEthic 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  \nthe 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.  \nInfo 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  \ninform ed tha t  th e y are f re e to w ithd raw from th e study at a ny t i me.  \n \nAvaila bility of data and material  \nDirec 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  \nmonitoring  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  \nstored 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  \nco 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  \nfunde r s.  \n \nFundi ng  \nThis 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  \ngrant 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  \nHoriz 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  \nunder w ww. imi-painc a re .eu\n a nd ww w.i mi .europ a.e u .  \n \nDi 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  \nnor 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  \nmade  of the in forma tion cont aine d ther e in.  \n \nAck nowledge ment s \nThe  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  \ndatab 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 . \n \n \n \nConsent for  publication  \nAll a utho rs read a nd appr ov ed the fina l manuscrip t.  \n \nCompeting int e r e s ts \n \nLD, LC an d MK dec lar e no c ompe ting  inte re s t s.  \nNR: No comp e t i ng int ere s ts  \nLAN: No c ompe ting i nte r e s t s \nQA:  N o compe ting  int ere st s  \nCMB: 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  \nCommis 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  \nout side o f thi s pr ojec t .  \nJB: N o com peting int er es t s \nFC: 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  \nAWH : 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,  \nAstra  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  \nco 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  \nwork . 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 .  \n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 10, 2023. ; https://doi.org/10.1101/2022.05.16.22274828doi: medRxiv preprint \n\nLH: no  compe t i ng int ere s ts in r e la tion t o this wo rk \nJM: no c ompe ting int er e st s \nEMP-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 \nadv 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  \nscien 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 \nand 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 \nInitia 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 \nrece 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 \nEF PIA . All mone y w ent to th e ins titu t io n E.M.P . -Z. is  w orking for .\n \nAH: Employ ee o f Ba yer AG, Germa ny.  \nCS: decl a r e s  no  compe t in g int ere s t s  \nIT: 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  \nva 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  \nCounc 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  \nFE 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 -\nac ademia  con sor tium.  \nRDT: 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  \nSAM: 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  \nthe 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  \nFou 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 .  \nKTZ : 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  \nDiagn 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.   \nJN: Employ e e and  s ha reh olde r of B ay er AG , German y  \nKV: 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  \nas 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.  \n \n \nAuthor ’s c ont ributions \nLD, 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  \nprojec t  and r evi ewed and e di t e d  the ma nuscrip t.  \n \n \nReference s  \n \n1.  E s ke nazi B , War ner ML. Epid emio logy of endome trio si s . O b ste t G y neco l Clin N ort h Am. \n19 97;24(2) :235 –58.  \n2.  Z ondervan KT, Yud kin PL , Ve s s e y M P, J en k ins o n CP, Daw e s  M G, Ba r l ow  DH ,  e t al. T he \nc ommunity pr e vale nce o f chronic  p elvi c pa in in w omen a nd a s s oc iat ed il lne s s  be haviou r . Br  J \nGen P r a ct . 2001 ;51(468 ):541 –7 .  \n3.  Z ondervan KT, Bec ker C M, Ko ga K, M i s s mer SA, T aylor RN , Vig an ò P. E ndom etri o s i s. N at R ev  \nDi s Prim. 2 018;4 (1) .  \n4.  Aha ngari A . Pr ev alenc e of c hro nic pe lvic  pain  among women: an upda ted  r e view . Pain \nPh ysicia n . 2014;1 7(2 ):E141–7 .  \n5.  Dani el s JP, Khan KS. Chr onic  pelv ic p ain in women. Bmj. 2010 ;341.  \n6.  S ingh S S, Gude K, P erd eaux  E, Gat tr ell W T, Becke r  CM.  Surgic al ou tc ome s in pati e nt s w ith  \ne ndome trio s i s: a  s y stem atic  revie w. J Ob s t et Gyna ecol C anad a . 2020;4 2(7 ):881 –8.   \n7.  Horne A W, D anie l s  J , H umme lsho j L, Cox E,  Coope r KG. 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Neur o- QOL: brie f  \nme as u r e s o f he al th -r e l at ed qua lity o f li fe  for  clini cal r e sea r c h in n e ur ol ogy. Neur ol og y. \n20 12;78(23) :18 60–7.  \n40.  Pe nn ebak er JW , Su sman JR. Di sclo sure o f tra uma s and p s y chos omatic pr o c e sse s. S oc S ci \nMed . 1988;2 6 (3) :327–32.   \n41.  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. \nPrec 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 \nIn 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 \nre sea rch  in pel vic pain. P ain. 20 21;  \n \n \n  \n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 10, 2023. ; https://doi.org/10.1101/2022.05.16.22274828doi: medRxiv preprint \n\n \nFig ur e s  a nd Tables \nSe 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  \nmanu 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.  \nAddition 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  \ndepo sito ry (e .g . Fig s h a r e ).  \n \n \n \n  \nFigu 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 \nOxford  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  \nPo 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. \nPh 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.  \n \n \nAdditional Questionnaires\nP h y s io lo g i c a l  T e s t in g\nfM RI ( onl y  cond uct ed  at  O xf ord )\nA d ditio nal  Ques t i on naires\nE A P,  E A B P,  B P S ,  P P,  C o n\n( s e le c t e d  f r om  E nd O X a n d BC E )\nBPS\n(recru it ed  at  I BMC)\nBas el in e  Q u es t i on naires ,  Bl oo d, \nSali v a, U r in e (p r eviou s l y  \nco l l e c te d )\nPhase II\nPh\nase I\nII\nPhase IV\nPh\nase I\nPhase I and II\nBaseli ne Ques tio nnai r es + Blo od,  \nSali v a,  Uri ne\n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 10, 2023. ; https://doi.org/10.1101/2022.05.16.22274828doi: medRxiv preprint \n\n \nTable 1. TRiPP Study Measures and Outcomes. \n \n \n \n \n \nDomain Tool Study Component Study \nPhase \nPain:     \n• Cli n ic a l  \nhis tor y of  \npelv ic p a i n  \nEP He c t cli n ic al co v ari at e s  q ue sti o nnai r e \n(2 3)  \nBas e li ne q ue s tion n a ire  \nFo l lo w- up  qu est ion na i re  \nI \nII \n• Int ens it y N R S  Bas e li ne q ue s tion n a ire  \nFo l lo w- up  qu est ion na i re  \nHow  are you t od ay ?  \nI \nII \nIII  \n• Nat ure  i) pa i n DET ECT (2 4 )  \nii) S h ort-f orm  M c Gil l  Pai n Quest io n naire 2 \n( S F M PQ 2)  (2 5 ) \nP a in  C ha r a c t e r i st i c s  II \n• Lo ca ti o n i) Fibr om yalgia s urv ey sc ale (2 6)  \nii) Bod y  m ap  \nO t he r  sym pto m s a nd  \nexperi ences  \nHow  are you t od ay ?  \nII \n \nIII  \n• Co mo r bi d \npain  \nc o n dit ion s  \ni) D iag n o s es  gi v e n  \nii) Co m pl ex  m edic a l sym pt o m s  in v e n t ory \n(2 7)  \niii) T M D -p a i n screen i n g  t oo l ( 28)  \nBas e li ne q ue s tion n a ire  \nFo l lo w- up  qu est ion na i re  \nO t he r  sym pto m s a nd  \nexperi ences  \nI \nII \n \nII \nGastr oin tes ti nal \nsy mp t o ms \ni) EP H ect  c l i nical  c ovariate s q u es t io nn a ire \n(2 3)  \nii) The  G a s t roint es ti na l  Sy mpt om  Rati n g \nScale  (2 9) \nBas e li ne q ue s tion n a ire  \nFo l lo w- up  qu est ion na i re  \nO t he r  sym pto m s a nd  \nexperi ences  \nI \nII \nMo o d Hos p i tal  Anxie ty a n d  Depres si on Scal e  \n(HADS) ( 30)  \nO t he r  sym pto m s a nd  \nexperi ences  \nII \n 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  \n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 10, 2023. ; https://doi.org/10.1101/2022.05.16.22274828doi: medRxiv preprint \n\nPa 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 \nF ol l o w -up  quest io n n a ire  \nHo w  a re  y o u t o d a y \nI \nII \n \nIII \nPe 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 \nex pe r i e nc es  \nII \nSoma tos ens ory   \nproces si n g \ni) Q ST ( 34)  o n t he  l ower abd o m e n (tes t \nsite)  an d d ors um  o f  t he  f oo t (c on trol  s ite)  \nii) f M RI wi t h p u nctat e  s timu li  o n t he t hig h  \nP hy si o log i ca l te s ti n g \nfM RI  \nIII \nIV \nVisceral  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 \nA u t o no m i c  ne r v ou s  \ns y st em  fun c t ion \ni) heart  ra t e mon it oring  bef ore a n d aft er \np a in s ti m u li \n \nP h ys io l o g ic a l  t est ing  III \nHP 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)  \nii) c ort is ol  bef o re  an d a fter p a i n s ti m u li \n(saliv a) \nP h ys io l o g ic a l  t est ing  III \nEn d og enou s pa in  \nm o du la t ion \nCo ndit ion ed  pain m odu la t io n  paradi gm \n(3 6 )  \nP h ys io l o g ic a l  t est ing  III \nFl ares  i n  sy mpt o ms \nand tri g g ers  \nCh a racterist ic s o f fl are s  i n s ym pt oms  an d  \nass ociat ed tri g g ers  ( 37)  \nF la r e s  qu es tion na i\nr e  II \nSl 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 \n(3 8 )  \nii) N eur o-Q OL  v1  F a t ig ue ( 3 9 )  \nOth e r s y mpt o ms  a nd \nex pe r i e nc es  \nII \nM 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  \nii) All e r gies  \nB as eline  ques ti onn aire \nF ol l o w -up  quest io n n a ire  \nOth e r s y mpt o ms  a nd \nex pe r i e nc es  \nI \nII \n \nII \nT 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 ) \nRece n t  tra u m at ic e v e nt s sc ale (4 0)  \nOth e r s y mpt o ms  a nd \nex pe r i e nc es  \nII \nTre a tm ents  Tre a tm ents  t ri e d  qu esti o n s  wi th  s cori ng of  \nou t c om e \nT rea tme nts  trie d \nques ti onn aire \nII \nOve 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 \nF ol l o w -up  quest io n n a ire  \nI \nII \nTabl 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. \n \n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted April 10, 2023. ; https://doi.org/10.1101/2022.05.16.22274828doi: medRxiv preprint","source_license":"CC0","license_restricted":false}