/5/13 Towards an Ontological Representation of Resistance: The Case of MRSa www.ncbi.nlm.nih.gov/pmc/articles/PMC2930208/#__ffn_sectitle 1/14 Towards an Ontological Representation of Resistance: The Case of MRSa Albert Goldfain, Barry Smith, and Lindsay G. Cowell Abstract Th is pa per a ddr esses a fa m ily of issu es su r r ou n din g th e biolog ica l ph en om en on of r esista n ce a n d its r epr esen ta t ion in r ea list on tolog ies. Th e tr ea tm en ts of r esista n ce ter m s in v a r iou s ex ist in g on tolog ies a r e ex a m in ed a n d fou n d to be eith er ov er ly n a r r ow , in ter n a lly in con sisten t , or oth er w ise pr oblem a tic. We pr opose a m or e coh er en t ch a r a cter iza t ion of r esista n ce in ter m s of w h a t w e sh a ll ca ll blockin g disposit ion s, w h ich a r e collect ion s of m u tu a lly coor din a ted disposit ion s w h ich a r e of su ch a sor t th a t th ey ca n n ot u n der g o sim u lta n eou s r ea liza t ion w ith in a sin g le bea r er . A defin it ion of 'pr otect iv e r esista n ce' is pr oposed for u se in th e In fect iou s Disea se On tolog y (IDO) a n d w e sh ow h ow th is defin it ion ca n be u sed to ch a r a cter ize th e a n t ibiot ic r esista n ce in Methicillin-Resis tant Staphylococcus aureus (MRSa ). Th e on tolog ica l r ela t ion s betw een en t it ies in ou r MRSa ca se stu dy a r e u sed a lon g side a ser ies of log ica l in fer en ce r u les to illu str a te log ica l r ea son in g a bou t r esista n ce. A descr ipt ion log ic r epr esen ta t ion of blockin g disposit ion s is a lso pr ov ided. We dem on str a te th a t ou r ch a r a cter iza t ion of r esista n ce is su fficien t ly g en er a l to cov er tw o oth er ca ses of r esista n ce in th e in fect iou s disea se dom a in in v olv in g HIV a n d m a la r ia . Keywords: In fect iou s Disea se On tolog y , Ba sic For m a l On tolog y , MRSa 1. Introduction: IDO, SaIDO, and MRSa Th e ph en om en on of r esista n ce is a n im por ta n t fea tu r e of biolog ica l r ea lity , en com pa ssin g div er se ph en om en a su ch a s: th e r esista n ce of a n in div idu a l to specific disea ses, th e h er d im m u n ity of a n or g a n ism popu la t ion to cer ta in popu la t ion s of in fect iou s or g a n ism s, th e r esista n ce of disor der s (for ex a m ple, tu m or s) to specific tr ea tm en ts, a n d th e r esista n ce of cer ta in pa th og en s to cer ta in dr u g s. Tr ea tm en t decision s a n d pu blic h ea lth policies often h in g e on cor r ect ly iden tify in g ty pes of r esista n ce [1 ]. A s su ch , r esista n ce is a ph en om en on th a t n eeds to be ca ptu r ed in biom edica l on tolog ies in a con sisten t , coh er en t , a n d su fficien t ly g en er a l w a y . Ou r pr im a r y g oa l in th is com m u n ica t ion is to ch a r a cter ize r esista n ce in th e in fect iou s disea se dom a in . Th e In fect iou s Disea se On tolog y (IDO) con sor t iu m is dev elopin g a set of in ter oper a ble on tolog ies th a t tog eth er a r e in ten ded to pr ov ide pr og r essiv ely ex pa n din g cov er a g e of th e in fect iou s disea se dom a in . Cen tr a l to th is set is th e IDO Cor e on tolog y , w h ich pr ov ides a r epr esen ta t ion of en t it ies, dr a w n fr om both th e biom edica l a n d th e clin ica l dom a in s, th a t a r e r elev a n t to in fect iou s disea ses in g en er a l. Dom a in -specific ex ten sion s (e.g . , pa th og en -specific ex ten sion s) of th e IDO Cor e com plete th e set by pr ov idin g on tolog y cov er a g e for th e ty pes of en t it ies r elev a n t to specific su b-dom a in s of th e in fect iou s disea se field. IDO is itself a n ex ten sion of th e Ba sic For m a l On tolog y (BFO) a n d lin ks to oth er on tolog ies con str u cted a ccor din g to th e pr in ciples of th e Open Biom edica l On tolog ies (OBO) Fou n dr y . IDO ta kes its tr ea tm en t of disea se fr om th e On tolog y for Gen er a l Medica l Scien ce (OGMS). , w h ich dist in g u ish es betw een : 1 . a disea se, 2 . its dia g n osis, 3 . its sig n s a n d sy m ptom s, 4 . its r ea liza t ion in th e ser ies of pr ocesses w e ca ll a disea se cou r se, a n d 5 . th e u n der ly in g disor der (s) on th e side of th e pa t ien t in w h ich th e disea se is r ooted [2 ]. 1 2 3 7/5/13 Towards an Ontological Representation of Resistance: The Case of MRSa www.ncbi.nlm.nih.gov/pmc/articles/PMC2930208/#__ffn_sectitle 2/14 We m en tion th ese dist in ct ion s h er e beca u se th e con fla t ion of en t it ies of a n y of ty pes listed ca n lea d to con fu sion a n d er r or in r ea son in g a bou t com plex biom edica l ph en om en a in g en er a l a n d a bou t r esista n t en t it ies in pa r t icu la r . Th e Staphylococcus aureus In fect iou s Disea se On tolog y (Sa IDO) is a n ex ten sion of IDO con cer n in g Sta ph a u r eu s (Sa ) in fect ion . Sa ca n be pa r t it ion ed in to tw o su bty pes: Meth icillin -Su scept ible Sa (MSSa ) a n d Meth icillin -Resista n t Sa (MRSa ). Th e la t ter su bty pe is a defin ed cla ss th a t is dist in g u ish ed by its r esista n ce to m eth icillin (a n d oth er β-la cta m a n tibiot ics). Du e to its r a pid ev olu t ion in th e fa ce of a n t ibiot ic select iv e pr essu r es, MRSa h a s becom e th e pa r a dig m of r esista n ce (a so-ca lled " su per bu g " ), a n d h a s dr a w n sig n ifica n t a t ten t ion fr om NIA ID/NIH , CDC , a n d biom edica l r esea r ch er s th r ou g h ou t th e dev eloped w or ld. Su bty pes of Sa ca n a lso be specified by a ssig n in g ba cter ia l str a in s to clon a l com plex es ba sed on g en oty pic differ en ces. V a r ia n ts ca n differ in th eir deg r ee of r esista n ce a n d in th e ty pes of dr u g to w h ich th ey a r e r esista n t , for m in g a con tin u u m , in ter m s of w h ich Sa ca n be (a n d is) ca teg or ized. Th is pr ov ides on e pow er fu l r ea son to pr odu ce a n on tolog ica lly cor r ect r epr esen ta t ion of r esista n ce in th e in fect iou s disea se dom a in , a n d th er e a r e sev er a l oth er s: 1 . A cla ssifica t ion of Sa th a t w ou ld a llow in fer en ce of r esista n ce pr ofile. 2 . IT tools for m on itor in g th e n u m ber of in fect ion s fr om r esista n t str a in s obser v ed in ea ch h ospita l, th u s a llow in g for : ea r ly detect ion of in cr ea ses, a n t icipa t ion of ou tbr ea ks, a n d tr a ckin g th e spr ea d of r esista n t str a in s. 3 . Tools to g u ide in th e w r it in g of pr escr ipt ion s. In th is pa per , w e con sider th e issu es a r isin g fr om th e r epr esen ta t ion of r esista n ce in r ea list on tolog ies a n d specifica lly , in IDO. In sect ion 2 w e list a set of desir a ble fea tu r es for su ch a r epr esen ta t ion . In sect ion 3 w e su r v ey som e pr oblem s w ith r esista n ce r epr esen ta t ion s in oth er on tolog ies a n d dev ise a defin it ion of 'pr otect iv e r esista n ce' for IDO w ith ou r desider a ta in m in d. We th en focu s ou r a tten t ion on th e a n t ibiot ic r esista n ce of MRSa to m eth icillin a s a deta iled ca se-stu dy in sect ion 4 . We ch a r a cter ize ou r r epr esen ta t ion in ter m s of blockin g disposit ion s (sect ion 5 ), a n d sh ow h ow ou r defin it ion is g en er a l en ou g h to a pply to oth er im por ta n t ca ses of r esista n ce in th e in fect iou s disea se dom a in (sect ion 6 ). 2. Desiderata for an Ontological Representation of Resistance Befor e r ev iew in g h ow 'r esista n ce' is defin ed in oth er on tolog ies a n d pr ov idin g ou r ow n defin it ion , it w ill be u sefu l to list th e desider a ta for a g ood defin it ion . We im plicit ly a ppen d to th is list th e desider a ta for a ll g ood on tolog ica l defin it ion s, su ch a s n on -cir cu la r ity , A r istotelia n for m , a n d pr ov idin g n ecessa r y a n d su fficien t con dit ion s. 2.1. Positivity Principle A n im por ta n t pr in ciple for r ea list on tolog y dev elopm en t is to a v oid a s fa r a s possible th e u se of n eg a t iv e differ en t ia (e.g . , 'n on ph y sica l', 'n ot pa r t of th e h ea r t ', 'n ot oth er w ise specified') in for m u la t in g defin it ion s. Th is " posit iv ity desig n pr in ciple" en for ces th e u se of ter m s w h ich ca ptu r e in for m a tion a bou t th e en t it ies r epr esen ted in th e on tolog y r a th er th a n in for m a tion a bou t th e sta te of ou r kn ow ledg e a t som e g iv en t im e [3 ]. A t som e lev el, h ow ev er , r esista n ce seem s to r equ ir e a n eg a t iv e a spect for its descr ipt ion . A fter a ll, a con tin u a n t is r esista n t pr ecisely w h en som eth in g does n ot h a ppen . Joh n 's r esista n ce to m a r r ia g e en ta ils a h ost of pr ocesses th a t do n ot h a ppen (for ex a m ple, Joh n does n ot bu y a n en g a g em en t r in g , does n ot g et a m a r r ia g e licen se, a n d so for th ). In th e ca se of MRSa , r esista n ce to m eth icillin en ta ils th a t a 4 5 6 7/5/13 Towards an Ontological Representation of Resistance: The Case of MRSa www.ncbi.nlm.nih.gov/pmc/articles/PMC2930208/#__ffn_sectitle 3/14 pr ocess of cell w a ll for m a tion is n ot in ter fer ed w ith . Th e key is th a t th e im plicit n eg a t iv ity of r esista n ce is on ly a sem a n tic fea tu r e of th e descr ipt ion a t som e lev el. Th e biolog ica l ph en om en on of r esista n ce is m a n ifested a t v a r iou s lev els of biolog ica l r ea lity : g en es, cells a n d th eir pa r ts, or g a n s, or g a n ism s, a n d popu la t ion s. Neg a t iv e descr ipt ion s a t a m a cr o-sca le h er e m a sk th e posit iv e a n d a ct iv e a spects of r esista n ce a t th e m icr o-sca le. A com pr eh en siv e on tolog ica l tr ea tm en t m u st , a ccor din g ly , con sider r esista n ce a t differ en t lev els of g r a n u la r ity . In BFO-ba sed on tolog ies, th e lacks r ela t ion ca n be u sed to ca ptu r e n eg a t iv e fin din g s a t on e sca le of biolog ica l descr ipt ion w h ile a v oidin g th e pr oblem s of u sin g n eg a t iv e pr edica tes or ch a r a cter ist ics [4 ]. In descr ibin g r esista n ce, w e w ill n eed to sa y th a t in depen den t con tin u a n ts of a cer ta in ty pe do n ot ex h ibit a depen den t con tin u a n t of a cer ta in ty pe. A s w e w ill see below , th is a m ou n ts to a n in depen den t con tin u a n t la ckin g a cer ta in disposit ion . 2.2. Doing Justice to Multiple Disciplinary Perspectives A lon g w ith th e v a r iou s g r a n u la r it ies a t w h ich w e w a n t to ta lk a bou t r esista n ce, w e a lso m u st a ckn ow ledg e th a t r esista n ce is r efer r ed to by sev er a l disciplin es: epidem iolog ists descr ibe th e spr ea d of r esista n ce in a popu la t ion , th e m edica l com m u n ity spea ks of pa t ien t r esista n ce to disea se a n d of pa th og en r esista n ce to dr u g s. Gen et icists m a ke r efer en ce to th e g en es th a t con fer r esista n ce w h en cer ta in a lleles a r e pr esen t . In cr em en ta lly , th e IDO su ite of on tolog ies m u st ca ptu r e a ll of th ese disciplin e-specific a spects of r esista n ce a n d th e r ela t ion s betw een th em . 2.3. Nonproliferation of New Relations and Terms Th e ter m s u sed in ou r r epr esen ta t ion w ill be der iv ed fr om IDO, th e Gen e On tolog y (GO), a n d th e Pr otein On tolog y (PRO). Th e r ela t ion s u sed a r e dr a w n fr om th e OBO Rela t ion On tolog y (RO) a n d its ex ten sion s . Na ïv ely , w e cou ld in tr odu ce a n ew r ela t ion resistant_to a n d u se it to descr ibe ev er y in sta n ce of a r esista n ce ph en om en on . How ev er , th is w ou ld h ide th e com plex ity of th e m ech a n ism s of r esista n ce w or kin g a t sm a ller sca les a n d elim in a te m a n y im por ta n t in fer en ces a bou t r esista n ce. A lso, it is im por ta n t to a v oid a pr olifer a t ion of r ela t ion s in th e OBO Fou n dr y , sin ce r estr ict ion to a sm a ll set of r ela t ion s pr om otes r eu se a n d in ter oper a bility of th e con st itu en t on tolog ies. 2.4. Explanatory Value A n a sser t ion of r esista n ce of X to Y sh ou ld n ot be ta u tolog ica l or oth er w ise tr iv ia l. A ppea ls to r esista n ce sh ou ld be explanatory, w h ich m ea n s th a t r esista n ce itself sh ou ld be r epr esen ted in su ch a w a y a s to pr ov ide som e ex pla n a t ion of w h y cer ta in pr ocesses u n fold th e w a y th ey do. Th e a sser t ion of r esista n ce of X to Y sh ou ld be a u sefu l r espon se to a qu er y ; it sh ou ld be a pr oposit ion on w h ich to ba se fu r th er r ea son in g [5 ]. 2.5. Formalizability Fin a lly , th e defin it ion sh ou ld be ex pr essible u sin g th e on tolog ica l tools of th e tr a de. IDO su ppor ts m a ch in e-r ea da ble r epr esen ta t ion s u sin g both OWL a n d OBO for m a ts. For u se in OWL, r esista n ce sh ou ld be ex pr essible u sin g descr ipt ion log ic r estr ict ion s. In su m m a r y , w e h a v e fiv e desider a ta for a r epr esen ta t ion of r esista n ce: 1 . Positivity Principle: Wh a t is th e a ct iv e m ech a n ism pr odu cin g r esista n ce a n d w h a t is th e a ssocia ted ph y sica l ba sis? 2 . Multiscale and Multiperspective: Wh a t a r e th e r ela t ion s betw een w h a t h a s r esista n ce a n d w h a t con fer s r esista n ce? 7 7/5/13 Towards an Ontological Representation of Resistance: The Case of MRSa www.ncbi.nlm.nih.gov/pmc/articles/PMC2930208/#__ffn_sectitle 4/14 3 . Nonproliferation of New Relations and Terms: Wh a t OBO Fou n dr y r ela t ion s a n d ter m s ca n be u t ilized? 4 . Explanatory Value: Is r esista n ce ch a r a cter ized so a s to be a su ita ble r esu lt of a n in fer en ce or a r espon se to a qu er y ? 5 . Formalizability: Ca n r esista n ce be in fer r ed fr om a for m a l r epr esen ta t ion of th e r elev a n t dom a in u sin g fir st or der log ic? Ca n it be ex pr essed u sin g descr ipt ion log ic? 3. Resistance in Existing Ontologies We su r v ey ed th e tr ea tm en t of r esista n ce in ex ist in g on tolog ies. 3.1. Gene Ontology (GO) Th e tr ea tm en t of r esista n ce is, str ict ly spea kin g , ou tside th e scope of th e GO, a s r esista n ce is n ot a biolog ica l pr ocess, m olecu la r fu n ct ion , or cellu la r com pon en t . With in th e su b-on tolog y of biolog ica l pr ocesses, h ow ev er , GO con ta in s th e ter m 'r espon se to dr u g ', w ith pu ta t iv e sy n on y m s dr u g r esista n ce' a n d 'dr u g su scept ibility /r esista n ce' (a lth ou g h 'dr u g r esista n ce' h a s been obsoleted fr om GO, it st ill r em a in s a sy n on y m for th e ter m 'r espon se to dr u g ') [GO:004 2 4 9 3 ] Respon se to Dr u g : A ch a n g e in sta te or a ct iv ity of a cell or a n or g a n ism (in ter m s of m ov em en t, secr et ion , en zy m e pr odu ct ion , g en e ex pr ession , etc.) a s a r esu lt of a dr u g st im u lu s. It is of cou r se in cor r ect to v iew th e n a r r ow er ter m 'dr u g r esista n ce' a s a sy n on y m of th e br oa der ter m 'r espon se to dr u g '. Dr u g r esista n ce a r ises spon ta n eou sly a s th e r esu lt of g en et ic div er sifica t ion . Th e pr esen ce of th e dr u g pr ov ides a n en v ir on m en t in w h ich th ose in div idu a ls (cells or v ir a l pa r t icles) th a t h a v e th e r esista n ce con fer r in g g en e or m u ta t ion h a v e a fitn ess a dv a n ta g e, th u s th ey ou tcom pete th e su scept ible in div idu a ls. Th e r esista n ce is n ot a dir ect r espon se to th e dr u g st im u lu s, a lth ou g h th e m a n ifesta t ion of r esista n ce m a y be a con sequ en ce of pr ior ex posu r e to th e dr u g . A r espon se to a dr u g is a pr ocess, w h er ea s r esista n ce is a con tin u a n t , a n d th u s 'r espon se to dr u g ' sh ou ld n ot be a sy n on y m of 'dr u g r esista n ce'. Th e GO defin it ion defin es r esista n ce a t th e sca le of cell or or g a n ism , bu t w ou ld n ot a pply to m olecu les or popu la t ion s. Fin a lly , th e defin it ion seem s to h in g e on a 'ch a n g e in sta te', bu t cells w h ich do n ot ch a n g e sta te a r e m a n ifest in g a 'r espon se to a dr u g ' ju st a s m u ch a s a r e th ose w h ich do, a n d in fa ct , r esista n t cells m a y n ot ch a n g e sta te a t a ll. 3.2. NCI Thesaurus Th e NCI Th esa u r u s h a s th e follow in g en tr y for 'r esista n ce': [C1 9 3 9 1 ] Resista n ce: Na tu r a l or a cqu ir ed m ech a n ism s, fu n ct ion s, a ct iv it ies, or pr ocesses ex h ibited by a n or g a n ism to m a in ta in im m u n ity to, or to r esist th e effects of, a n a n ta g on ist ic a g en t , e.g . , pa th og en ic m icr oor g a n ism , tox in , dr u g . Th e pr im a r y pr oblem s w ith th is tr ea tm en t of r esista n ce a r e th a t : i. th e defin it ion is cir cu la r , sin ce it u ses 'r esist ' in defin in g 'r esista n ce', a n d ii. th e defin it ion a pplies a t th e sca le of th e or g a n ism , ig n or in g th e sca le of th e cell, m olecu le, or popu la t ion iii. th e ter m 'r esista n ce' is a ch ild of " r esista n ce pr ocess" , m a kin g r esista n ce a pr ocess a n d ex clu din g m a n y ty pes of r esista n ce, beca u se th e defin it ion of 'r esista n ce pr ocess' is bia sed tow a r ds m u lt icellu la r or g a n ism r esista n ce m edia ted by h ost defen se m ech a n ism s. 3.3. SNOMED-CT 7/5/13 Towards an Ontological Representation of Resistance: The Case of MRSa www.ncbi.nlm.nih.gov/pmc/articles/PMC2930208/#__ffn_sectitle 5/14 SNOMED-CT con ta in s th e en tr y 'dr u g r esista n ce (disor der )' w ith tw o defin in g r ela t ion sh ips: Dr u g Resista n ce Is a Dr u g -Rela ted Disor der Dr u g Resista n ce h a s Ca u sa t iv e A g en t (A ttr ibu te) Dr u g or Medica m en t. Th e for m er , w h ich a ssig n s to 'dr u g r esista n ce' th e pa r en t ter m 'dr u g -r ela ted disor der ', is for m u la ted fr om th e per spect iv e of th e pa t ien t . Fr om th e per spect iv e of th e pa th og en or tu m or , in con tr a st , dr u g r esista n ce is n ot a disor der , bu t r a th er a ben efit . Th a t SNOMED a dopts th is pa t ien t-ba sed per spect iv e is n ot su r pr isin g . SNOMED, specifies th a t dr u g r esista n ce is ca u sed by a dr u g , bu t dr u g r esista n ce is ca u sed by th e pr esen ce of a g en e or m u ta t ion . It is on ly th e m a n ifesta t ion of su ch r esista n ce th a t r esu lts fr om th e pr esen ce of th e dr u g . Fin a lly , a s w ith oth er ter m s in SNOMED, on ly n ecessa r y bu t n ot su fficien t con dit ion s for dr u g r esista n ce a r e pr ov ided. Good defin it ion s sh ou ld spell ou t both . 3.4. Infectious Disease Ontology (IDO) In IDO, r esista n ce is r epr esen ted a s a BFO disposit ion Disposition = A disposit ion is a r ea liza ble en t ity w h ich is su ch th a t , if it cea ses to ex ist , th en its bea r er is ph y sica lly ch a n g ed, a n d w h ose r ea liza t ion occu r s in v ir tu e of th e bea r er 's ph y sica l m a ke-u p w h en th is bea r er is in som e specia l cir cu m sta n ces. In En g lish , th e w or d 'r esista n ce' is poly sem ou s a n d ca n be u sed to r efer to eith er a disposit ion or a qu a lity (i.e. , a ca teg or ica l pr oper ty ). Wh en r efer r in g to a qu a lity , 'r esista n ce' is r ou g h ly sy n on y m ou s w ith 'low su scept ibility '. If w e th in k of deg r ee of su scept ibility a s a con tin u u m , th en th e qu a lity of r esista n ce is th e r eg ion of th is con tin u u m ben ea th a cer ta in th r esh old. A s a disposit ion , r esista n ce is possessed in v ir tu e of th e in ter n a l ph y sica l a r r a n g em en t of its bea r er , is n ot a lw a y s m a n ifested w h en bor n e, a n d is r ea lized in a ct iv e pr ocesses a t som e ph y sica l sca le. It is th is r ea liza ble sen se of 'r esista n ce' th a t w e w a n t to r epr esen t: r esista n ce is th e ca pa bility (a n d in som e ca ses th e fu n ct ion ) to res is t under certain conditions . IDO in clu des th e ter m 'pr otect iv e r esista n ce', th e defin it ion of w h ich a ttem pts to a ddr ess som e of th e pr oblem s descr ibed a bov e: Pr otect iv e r esista n ce is a disposit ion th a t in h er es in a m a ter ia l en t ity (x) by v ir tu e of th e fa ct th a t th e en t ity h a s a pa r t (e.g . a g en e pr odu ct), w h ich itself h a s a disposit ion 1 ) to en su r e a ph y siolog ic r espon se of a cer ta in deg r ee to a n en t ity of ty pe Y w ith th e ca pa bility to da m a g e x, or 2 ) to pr ev en t th e com plet ion of som e pr ocess ca u sed by a n en t ity of ty pe Y w ith th e ca pa bility to da m a g e x. Th e r ea liza t ion of th e disposit ion pr otects x fr om or m it ig a tes th e da m a g in g effects of Y . Th e pr otect iv e r esista n ce disposit ion is r ea lized in a biolog ica l pr ocess. Her e w e w r ite low er ca se x to in dica te a n in sta n ce, a n d ca pita l Y to in dica te a ty pe. 4. Towards a More Robust Ontological Treatment of Protective Resistance To better u n der sta n d th e r epr esen ta t ion a l dem a n ds posed by r esista n ce (a n d to ex pose th e pr oblem s r a ised by th is a n d sim ila r ph en om en a fr om a n on tolog ica l poin t of v iew ), it w ill be u sefu l to g o th r ou g h a deta iled ex a m ple. We ch oose dr u g r esista n ce for a sin g le com bin a t ion of pa th og en , a n t ibiot ic, a n d r esista n ce-m ech a n ism ty pes. In th is sect ion w e sketch th e ou t lin es of a for m a l r epr esen ta t ion of th e r esista n ce of MRSa to m eth icillin a s con fer r ed by PBP2 a , a pen icillin bin din g pr otein (PBP) a n d a pr odu ct of th e g en e mecA. Both m eth icillin a n d pen icillin a r e β-la cta m a n tibiot ics a n d, for th e pu r poses def 8 7/5/13 Towards an Ontological Representation of Resistance: The Case of MRSa www.ncbi.nlm.nih.gov/pmc/articles/PMC2930208/#__ffn_sectitle 6/14 of ou r for m a liza t ion , a PBP ca n be con sider ed to be a m eth icillin bin din g pr otein . Ch a m ber s g iv es a con cise descr ipt ion of th e for m of r esista n ce in v olv ed: [M]eth icillin r esista n ce in sta ph y lococci is du e to ex pr ession of PBP2 a , a n ov el, low a ffin ity PBP for w h ich th er e is n o h om olog u e in m eth icillin -su scept ible str a in s[7 ]. We for m a lize th is in for m a tion a s a set of tr iples ex pr essin g th e r elev a n t on tolog ica l r ela t ion sh ips. We a lso in clu de a ser ies of in fer en ce r u les th a t w ou ld lea d a log ic-dr iv en r ea son er to dedu ce fr om th e tr iples th a t MRSa is r esista n t to m eth icillin . Su ch in fer en ce r u les w ill on e da y be u sed by a u tom a ted r ea son er s to com pu te a n t ibiot ic r esista n ce fr om log ica l for m a liza t ion s of su ch dom a in s. Usin g on tolog ies a s pr edict iv e tools w ill h elp to g u ide tr ea tm en t decision s a n d su ppor t a u tom a ted dr u g discov er y . A fa ith fu l r epr esen ta t ion of th e MRSa dom a in r equ ir es a t lea st th e follow in g com pon en ts (w h er e is_a a n d has_part a r e u sed for r ela t ion s betw een both con tin u a n t a n d occu r r en t u n iv er sa ls): 1 . ba cter iu m is_a or g a n ism 2 . MRSa is_a ba cter iu m 3 . sy n th esis_of_peptidog ly ca n is_a pr ocess a n d has_participant Pen icillin _Bin din g _Pr otein (PBP) 4 . PBP has_function_realized_as_process sy n th esis_of_peptidog ly ca n 5 . Ba cter ia l_cell_w a ll is_location_of PBP 6 . Ca n on ica lly , sy n th esis_of_peptidog ly ca n results_in_development_of ba cter ia l_cell_w a ll 7 . for m a tion _of_ba cter ia l_cell_w a ll is_a pr ocess 8 . PBP2 a is_a PBP 9 . m eth icillin _PBP_bin din g _pr ocess is_a bin din g pr ocess th a t has_participants m eth icillin a n d PBP 1 0. a ffin ity _to_m eth icillin disposition_of som e PBP to u n der g o a m eth icillin _PBP_bin din g _pr ocess th a t is r ea lized in th e pr esen ce of a m eth icillin . 1 1 . m eth icillin _PBP_bin din g _pr ocess negatively_regulates sy n th esis_of_peptidog ly ca n . 1 2 . PBP2 a lacks a ffin ity _to_m eth icillin 1 3 . mecA is_a g en e 1 4 . MRSa has_part m ecA 1 5 . mecA participates_in PBP2 a _pr odu ct ion 1 6 . PBP2 a _pr odu ct ion results_in_formation_of PBP2 a A su bset of th ese tr iples is depicted g r a ph ica lly in Fig u r e 1 . Resista n ce to m eth icillin sh ou ld be in fer r ed fr om su ch r epr esen ta t ion s in a log ica l m a n n er . Su ch in fer en cin g sh ou ld be ex pla n a tor y : it sh ou ld tell u s w h y MRSa bea r s su ch r esista n ce. Fi gur e Th ese tr iples w ill be u sed a lon g w ith sev er a l r u les of in fer en ce a n d der iv ed fa cts (la beled IRn a n d Dn r espect iv ely in w h a t follow s). For r ea da bility , a ll v a r ia bles a r e ita licized a n d in it ia l u n iv er sa l qu a n tifier sy m bols a r e su ppr essed. Fir st , w e specify th a t is_a a n d has_part (for both con tin u a n ts a n d occu r r en ts) a r e tr a n sit iv e, a llow in g u s to der iv e som e ba sic ta x on om ic fa cts a bou t th e dom a in : (IR1) x is_a y ∧ y is_a z → x is_a z (IR2) x has_part y ∧ y has_part z → x has_part z 9 7/5/13 Towards an Ontological Representation of Resistance: The Case of MRSa www.ncbi.nlm.nih.gov/pmc/articles/PMC2930208/#__ffn_sectitle 7/14 (D1) MRSa is_a organism Th e pa r ts of a n or g a n ism a r e th e pr odu cts of th e or g a n ism 's ex pr essed g en es, a n d th ese pr odu cts a r e loca ted in th e a ppr opr ia te pla ces: (IR3)o is_a organism ∧ g is_a gene ∧ o has_part g∧ g participates_in proc ∧ proc results_in_formation_of prod ∧ o has_part locp ∧ locp is_location_of prod → o has_part prod located_in locp (D2)MRSa has_part PBP2a located_in bacterial_cell_wall Th e in fer en ce r u le (IR3 ) m a kes a few sim plify in g a ssu m ption s. Sin ce n ot a ll g en es a r e ex pr essed, w e a r e on ly m odelin g th e situ a t ion in w h ich g is a n ex pr essed g en e. We a lso a ssu m e th a t th e pr ocess proc lea din g to pr od is a ct iv e, a n d th a t th e sin g le g en e g pa r t icipa tes in proc (r a th er th a n a set of g en es). If a con tin u a n t la cks a disposit ion to u n der g o a pr ocess in som e situ a t ion , a n d th a t pr ocess n eg a t iv ely r eg u la tes a secon d pr ocess w h ich h a s th e con tin u a n t a s a pa r t icipa n t , th en th e con tin u a n t pa r t icipa tes in th e secon d pr ocess in th a t situ a t ion : (IR4)p lacks disposition to undergo proc realized in situation s∧ proc negatively_regulates proc ∧ proc has_participant p → In situation s, p participates_in proc (D3)In the presence of methicillin, PBP2a participates_in synthesis_of_peptidoglycan Th is la ck of a disposit ion (i.e. , th e a ffin ity to m eth icillin ) h a s a ca teg or ica l ba sis in th e fa ct th a t m eth icillin bin ds to PBPs a n d pr ev en ts th em fr om ca r r y in g ou t th eir fu n ct ion . How ev er , PBP2 a la cks th is a ffin ity , so th e pr esen ce of m eth icillin does n ot pr ev en t th e essen t ia l su b-pr ocesses of cell-w a ll con str u ct ion in MRSa . If a n or g a n ism h a s a con tin u a n t a s a pa r t a n d th a t pa r t pa r t icipa tes in a pr ocess in som e situ a t ion , th en th e pr ocess u n folds in th e or g a n ism in th a t situ a t ion . (IR5)In situation s, p1 participates_in proc∧ p1 located_in p2 ∧ o has_part p2 → proc unfolds_in o in situation s (D4)synthesis_of_peptidoglycan unfolds_in MRSa in the presence of methicillin 1 1 2 2 2 7/5/13 Towards an Ontological Representation of Resistance: The Case of MRSa www.ncbi.nlm.nih.gov/pmc/articles/PMC2930208/#__ffn_sectitle 8/14 Fin a lly , if a pr ocess u n folds in a n or g a n ism in som e situ a t ion a n d th e pr ocess r esu lts in th e dev elopm en t of a con tin u a n t w h ich (ca n on ica lly ) is a pa r t of th e or g a n ism , th en th e or g a n ism h a s th e con tin u a n t a s a pa r t in th a t situ a t ion . (IR6)In situation s, proc unfolds_in o∧ Canonically, proc results_in_development_of p → p part_of o in situation s (D5)Bacterial_cell_wall part_of MRSa in the presence of methicillin Th e ca n on ica l cell w a ll is a r ig id con fig u r a t ion of pept idog ly ca n . Th e ca n on ica l cell w a ll is a h ea lth y on e for MRSa . Th e a sser t ion (D5 ) ca ptu r es th e a ct iv e, a n d th u s posit iv e, m icr oph y sica l side of th e r esista n ce coin . How ev er th e ch a in of r ea son in g h er e pr esen ts a pu zzle. Wh a t does th e la ck of a disposit ion in (IR4 ) a m ou n t to? Con sider th e follow in g pa ir : A . Con tin u a n t C la cks disposit ion D to u n der g o pr ocess P in situ a t ion S B. Con tin u a n t C u n der g oes P in a situ a t ion S. Both (A ) a n d (B) ca n be tr u e a t th e sa m e t im e. In fa ct th e con ju n ct ion of (A ) a n d (B) im plies th a t (B) h a ppen s for a n on -disposit ion a l r ea son (i.e. , (B) is n ot , in th e cor r espon din g ca se, a m a n ifesta t ion of th e disposit ion D). Ev en if Joh n la cks th e disposit ion to feel h u n g r y w h en in th e pr esen ce of su sh i, h e m a y st ill feel h u n g r y in su ch a situ a t ion beca u se h e h a s been fa st in g for th r ee da y s. We n eed a w a y to ex pr ess th e fa ct th a t PBP2 a n ecessa r ily la cks a ffin ity to m eth icillin , a n d th a t th is is w h a t a llow s for th e r elev a n t cell-w a ll for m a tion to ta ke pla ce. In or der to fr a m e th e n ecessa r y la ck a s a posit iv e a n d ex pla n a tor y a ccou n t , w e w ill n eed th e fr a m ew or k of blockin g disposit ion s descr ibed below . A n im por ta n t a spect of th e ch a in of r ea son in g is th e u se of ca n on icity in dom a in tr iple 6 : Canonically, synthesis_of_peptidoglycan results_in development_of bacterial_cell_wall. Her e 'ca n on ica lly ... ' w or ks to specify a ba selin e of w h a t is h eld to be tr u e a ccor din g to som e ca n on ica l on tolog ica l r efer en ce (e.g . , th e a n a tom y of a m odel or g a n ism ). A lth ou g h th is con str u ct ion r esem bles th e sy n ta x of th e m oda l oper a tor 'Necessa r ily ,... ', it does n ot y ield a su bsta n t ia l on tolog ica l cla im , bu t r a th er ju st sa y s w h a t is tr u e r ela t iv e to th e pa r t icu la r r efer en ce. Th is for m of r ea son in g w ith ca n on icity is con sisten t w ith its u se in a n a tom ica l r ea son in g [8 , 9 ]. In ou r ca se, w e a ssu m e th a t a r efer en ce on tolog y of th e cell specifies th a t sy n th esis of pept idog ly ca n r esu lts in th e dev elopm en t of a cell w a ll. Su ch a ssu m ption s a r e a x iom a tic for IDO beca u se th ey a r e bey on d th e scope of th e cor e on tolog y a n d th ey pr ov ide a u sefu l con str a in t for a r ea son er . Th e ch a in of r ea son in g r elies on su ch a x iom s a n d w e ex pect th a t th ey w ill g r ow in n u m ber to a ccom m oda te th e r ea son in g n eeds of IDO ex ten sion s. 5. Resistance as Blocking Disposition A n ex pla n a tor y posit iv e a ccou n t for PBP2 a la ckin g a n a ffin ity to m eth icillin ca n be g iv en if w e con sider 10 7/5/13 Towards an Ontological Representation of Resistance: The Case of MRSa www.ncbi.nlm.nih.gov/pmc/articles/PMC2930208/#__ffn_sectitle 9/14 w h a t pr ev en ts th e m a n ifesta t ion of th is disposit ion . Often w h a t pr ev en ts th e r ea liza t ion of a disposit ion is th e m a n ifesta t ion of a n oth er disposit ion . We ca ll th e la t ter a blocking disposition a n d th e for m er a blocked disposition. Disposit ion s a r e often sa id to m a n ifest g iv en cer ta in ba ckg r ou n d con dit ion s, con tex ts, or cir cu m sta n ces [1 1 , 1 2 ]. Blockin g disposit ion s em ph a size th e on tolog ica l in ter a ct ion s in th e ba ckg r ou n d. In g en er a l, if D is a disposit ion a n d D is a blockin g disposit ion for D , th en it m u st be th e ca se th a t th e r ea liza t ion of D pr ev en ts th e r ea liza t ion of D . A blockin g disposit ion m ig h t be u n der stood in differ en t w a y s: 1 . Incompatible occurrents: Th e r ea liza t ion of D a n d th e r ea liza t ion of D a r e som eh ow in com pa tible occu r r en ts, m ea n in g eith er th a t th ey ca n n ot co-occu r or th a t on e n eg a t iv ely r eg u la tes th e oth er . 2 . Incompatible qualities: Th e r ea liza t ion of D r esu lts in a qu a lity of a con tin u a n t th a t is in com pa tible w ith th e qu a lity of th e sa m e con tin u a n t th a t w ou ld h a v e r esu lted fr om th e r ea liza t ion of D . Th a t is, w e h a v e tw o qu a lit ies th a t ca n n ot be sim u lta n eou sly ex h ibited (e.g . , a squ a r e cir cu la r object). By g iv in g r esista n ce a posit iv e ch a r a cter iza t ion , in w h ich w e descr ibe w h a t disposit ion s a r e a ct iv ely r ea lized, r esista n ce ca n pla y a m or e ex pla n a tor y r ole. We ca n descr ibe th is r esista n ce w ith ou t r efer en ce to blockin g disposit ion s by n ot in g th e la ck of a ffin ity to m eth icillin (a disposit ion ) in th e r elev a n t por t ion of th e pen icillin -bin din g pr otein of MRSa (PBP2 a ). A s a n ex pla n a t ion of w h y MRSa is r esista n t , h ow ev er , in v okin g th e la ck of a ffin ity to m eth icillin seem s to be beg g in g th e qu est ion ; MRSa is r esista n t to m eth icillin beca u se on e of its pa r ts la cks a n a ffin ity for it . Th e sa m e situ a t ion ca n be descr ibed in a posit iv e (a ct iv e) w a y by con sider in g th e disposit ion of PBP2 a to sy n th esize pept idog ly ca n (a n essen t ia l com pon en t of th e ba cter ia l cell w a ll) a s a blockin g disposit ion for th e disposit ion of m eth icillin to bin d to pen icillin -bin din g pr otein s. In th is w a y , pr otect iv e r esista n ce ca n be r edescr ibed a s a n a ct iv e r espon se to m eth icillin . In th is situ a t ion , w e ca n a r g u e for in com pa tible occu r r en ts: th e pr ocess of cell w a ll con str u ct ion (a s a r ea liza t ion of th e ty pica l disposit ion of PBP) is in com pa tible w ith th e pr ocess of m eth icillin bin din g (w h ich is th e r ea liza t ion of a ffin ity to m eth icillin th a t PBP2 a la cks). We cou ld a lso a r g u e for in com pa tible qu a lit ies: for a pa r t icu la r pept idog ly ca n m olecu le bein g bou n d by m eth icillin is in com pa tible w ith bein g bou n d to pept idog ly ca n pept ide su bu n its. A s a r esu lt , th e m olecu la r str u ctu r e of a w ell-for m ed ba cter ia l cell w a ll (i.e. , a pept idog ly ca n la t t ice) is in com pa tible w ith th e m olecu la r str u ctu r e of a com pou n d su fficien t ly bou n d to m eth icillin . Cell w a ll con str u ct ion is som eth in g a ba cter iu m w ill pa r t icipa te in w h en n o m eth icillin is pr esen t . In or der to see th is ca n on ica l pr ocess a s a n a ct iv e r espon se, w e n eed th e m a ch in er y of blockin g disposit ion s. Pr otect iv e r esista n ce to m eth icillin is ex h ibited by MRSa in th e pr ocess of cell w a ll con str u ct ion by blockin g th e disposit ion of m eth icillin to bin d to PBP. In or der for a th eor y of blockin g disposit ion s to be u sefu l in com pu ta t ion a l in fer en ce, it sh ou ld be ex pr essible in a for m a l la n g u a g e. For th is ta sk, w e pr efer descr ipt ion log ic beca u se: (1 ) it is th e log ic u n der ly in g OWL-DL, a n d (2 ) descr ipt ion log ic is r ela t iv ely in ex pr essiv e, so if w e ca n ca ptu r e blockin g disposit ion s in descr ipt ion log ic, w e sh ou ld be a ble to r epr esen t blockin g disposit ion s in a m or e ex pr essiv e for m a lism . It is ea siest to for m u la te a blockin g disposit ion a s a descr ipt ion log ic r estr ict ion by u sin g th e RO_Pr oposed r ela t ion negatively_regulates D_blocking_disposition_of_D ≡ realized_by ( negatively_regulates realizes D ∏ realizes D) Bu t w e m a y a lso descr ibe th e in a bility for D a n d D to co-occu r u sin g a ca r din a lity r estr ict ion : 1 2 1 2 1 1 2 2 1 11 2 1 1 2 1 2 12 7/5/13 Towards an Ontological Representation of Resistance: The Case of MRSa www.ncbi.nlm.nih.gov/pmc/articles/PMC2930208/#__ffn_sectitle 10/14 realizes D ∏ realizes D ∏ occurs_at T = ∅ Descr ipt ion log ic does n ot pr ov ide sch em a v a r ia bles in th e w a y w e h a v e u sed th em in D blocking_disposition_of D , so ea ch su ch disposit ion m u st be flesh ed ou t in con cr ete ter m s by th e IDO ex ten sion on tolog ies. Su ch a n a n a ly sis is n ot w ith ou t its pr oblem s. On e m in or con cer n is th a t ca llin g som eth in g a blockin g disposit ion m a y be con sider ed too per spect iv a l, bia sin g th e on tolog ica l ter m tow a r ds D bein g blocked by r a th er th a n blockin g D . A m or e ser iou s pr oblem is h ow ca n w e em pir ica lly dist in g u ish betw een som eth in g n ot h a ppen in g to a specific con t in u a n t a s th e r esu lt of (1 ) a n ex ter n a l blockin g disposit ion or (2 ) a s th e r esu lt of its ow n in ter n a l m a keu p. A fu r th er w or r y in v olv es th e iden tity cr iter ia for blockin g disposit ion s. Storm -r esista n t w a lls on a pa r t icu la r h ou se a r e m ost likely a lso lemonade-r esista n t a s w ell, bu t in v ir tu e of th e sa m e u n der ly in g str u ctu r e (i.e. , ca teg or ica l pr oper t ies). So is th e pa r t icu la r lem on a de r esista n ce in h er in g in th ose w a lls iden tica l to th e pa r t icu la r w a ter r esista n ce in h er in g in th ose w a lls? It seem s cou n ter in tu it iv e to sa y so, bu t if w e sa y th ese a r e n ot iden tica l a r e w e n ot open in g th e door to a com bin a tor ia l ex plosion of r esista n ce disposit ion s? Sim ila r ly , pen icillin bin din g pr otein h a s a n a ffin ity to pen icillin (a s its n a m e su g g ests) w h ich is con fer r ed by th e sa m e qu a lit ies th a t y ield m eth icillin r esista n ce, bu t w e do n ot w a n t to sa y th a t th ese for m s of r esista n ce a r e iden tica l beca u se som e sta ph a u r eu s m a y be su scept ible to m eth icillin bu t r esista n t to pen icillin . Th e sta n da r d a n sw er to su ch w or r ies fr om th e r ea list on tolog y ca m p is th a t ter m s a r e in clu ded in a n on tolog y in r eflect ion n ot of w h a t is com bin a tor ia lly possible bu t r a th er of th e a ctu a l n eeds of biolog ists w h o a r e descr ibin g r ea l biolog ica l ph en om en a . Wh eth er disposit ion s r efer r ed to by su ch ter m s a r e or a r e n ot iden tica l w ill n eed to be decided on a ca se-by -ca se ba sis, bu t su ch a decision is th en n ot in pr in ciple m or e pr oblem a tic for disposit ion s th a n for en t it ies of oth er sor ts. 6. Other Examples Th e blockin g disposit ion ch a r a cter iza t ion pr esen ted a bov e ca n be a pplied to differ en t ty pes of r esista n ce. In th is sect ion , w e pr esen t tw o ex a m ples in v olv in g in fect iou s disea se: (1 ) CCR5 m u ta t ion con fer s pr otect iv e r esista n ce a g a in st cer ta in str a in s of HIV , a n d (2 ) th e sickle cell t r a it con fer s pr otect iv e r esista n ce a g a in st m a la r ia . Like th e ca se of MRSa , w e w ill see th a t th e sim ple m a cr osca le ch a r a cter iza t ion of r esista n ce g iv es w a y to a n etw or k of r ela ted en t it ies a t th e m icr osca le. 6.1. CCR5Δ32 and HIV Cer ta in str a in s of HIV h a v e a disposit ion to bin d to CCR5 (com plem en ted, like a lock a n d key , w ith th e disposit ion of CCR5 to bin d to HIV ) a n d th u s en ter cells. CCR5 -Δ 3 2 is a delet ion m u ta t ion of th e CCR5 g en e r esu lt in g in cells w h ich la ck a fu n ct ion in g CCR5 r eceptor on th eir su r fa ces[1 3 ]. Note th a t HIV does n ot lose th e disposit ion to bin d to CCR5 , th e disposit ion sim ply g oes u n m a n ifested. Sim ila r to th e ca se of a n t ibiot ic r esista n ce in MRSa , w e a r e dea lin g h er e w ith a pa r t of a n or g a n ism la ckin g a con tin u a n t; in th is ca se, h ow ev er , w h a t is m issin g is a n independent continuant (i.e. , a por t ion of ca n on ica l CCR5 ). To ch a r a cter ize som eth in g a s la ckin g a disposit ion is to pr ov ide a n eg a t iv e ch a r a cter iza t ion th a t sta n ds in n eed of fu r th er ex pla n a t ion - a s con tr a sted w ith ch a r a cter izin g som eth in g a s la ckin g a pa r t , w h ich is a posit iv e ch a r a cter iza t ion . Th e fa ct th a t a cell la cks CCR5 r eceptor s on its su r fa ce is a qu a lity of th e cell. Th is ca se of r esista n ce to HIV is cov er ed by th e cla u se of th e IDO defin it ion for pr otect iv e r esista n ce in w h ich th e pr ocess ca u sed by a poten t ia lly da m a g in g en t ity is pr ev en ted fr om com plet in g . In ter m s of 1 2 2 1 1 2 7/5/13 Towards an Ontological Representation of Resistance: The Case of MRSa www.ncbi.nlm.nih.gov/pmc/articles/PMC2930208/#__ffn_sectitle 11/14 blockin g disposit ion s, th is situ a t ion ca n be descr ibed in ter m s of in com pa tible qu a lit ies. If d1 is th e disposit ion of HIV to bin d to a CCR5 m olecu le, a n d d2 is th e disposit ion of in div idu a ls w ith th e CCR5 Δ 3 2 m u ta t ion to dev elop cells w ith ou t CCR5 on th eir su r fa ce, th en w e h a v e d2 blockin g d1 beca u se th e r ea liza t ion of both w ou ld r equ ir e th e sa m e con tin u a n t (i.e. , a T cell or m a cr oph a g e) to ex h ibit in com pa tible qu a lit ies by sim u lta n eou sly h a v in g a n d la ckin g CCR5 on its su r fa ce. 6.2. The Sickle-Cell Trait and Malaria Th er e a r e m a n y h y poth esized m ech a n ism s by w h ich th e sickle cell h em og lobin g en e (HbS) con fer s r esista n ce to Plasm odium falciparum , on e of th e in fect iou s or g a n ism s th a t ca u ses m a la r ia . On e su ch m ech a n ism is th r ou g h th e im pa ct of HbS on r ed blood cell h y dr a t ion a n d den sity [1 4 ]. In in div idu a ls w ith HbS, r ed blood cells a r e disposed to deh y dr a t ion a n d a con sequ en t in cr ea se in den sity . Pla sm odiu m fa lcipa r u m m er ozoites h a v e a disposit ion to spr ea d th r ou g h h ost r ed blood cells. Th is spr ea din g pr ocess con sists of fou r su bpr ocesses: pla sm odiu m r eplica t ion in side a sin g le r ed blood cell, r ed blood cell ly sis, r elea se of pla sm odiu m m er ozoites fr om th e ly sed cell, a n d en tr y of r elea sed m er ozoites in to a n ew r ed blood cell. Mer ozoite in v a sion of den se, deh y dr a ted r ed blood cells is r edu ced. Th u s, a n essen tia l su bpr ocess of th e spr ea d of pla sm odiu m in th e h ost is r edu ced (th e pr ocess is n eg a t iv ely r eg u la ted), th u s con fer r in g pr otect iv e r esista n ce a g a in st m a la r ia . Usin g blockin g disposit ion s, w e ca n a g a in ch a r a cter ize th is situ a t ion in ter m s of in com pa tible qu a lit ies. If d1 is th e disposit ion of cer ta in r ed blood cells to becom e deh y dr a ted, a n d d2 is th e disposit ion of pla sm odiu m to spr ea d th r ou g h r ed blood cells, th en th e r ea liza t ion of d1 r esu lts in a h y dr a t ion qu a lity in h er in g in th e r ed blood cells, th er eby n eg a t iv ely r eg u la t in g th e r ea liza t ion of d2 , w h ich r equ ir es h y dr a ted r ed blood cells. Th e qu a lit ies a r e in com pa tible beca u se a r ed blood cell ca n n ot sim u lta n eou sly be h y dr a ted a n d deh y dr a ted. 7. Mereological Issues If w e ta ke r esista n ce to be a specifica lly depen da n t con tin u a n t th a t in h er es in a n in depen den t con tin u a n t , th en w e m u st st ill a n sw er som e m er eolog ica l qu est ion s: Is th e r esista n ce of th e r elev a n t por t ion of PBP2 a (i.e. , of a pa r t) iden t ica l to th e r esista n ce of th e cell (i.e. , of th e in clu din g w h ole)? Fu r th er m or e, is cell r esista n ce iden tica l to th e r esista n ce of a por t ion of t issu e in w h ich th e cell r esides or th e con ta in in g h ost or g a n ism or , for th a t m a tter , of th e con ta in in g popu la t ion ? Th e on tolog y of r esista n ce m u st a ddr ess w h ich sca les of biolog ica l r ea lity r esista n t con tin u a n ts occu py , a n d th e iden tity of r esista n ce a cr oss sca les. We ca n beg in to a ddr ess th is qu est ion for ou r ca se stu dy by con sider in g a bioch em ica l ex pla n a t ion of w h y m eth icillin does n ot bin d to PBP2 a . In deed, a str u ctu r a l ex pla n a t ion in v olv in g th e bioch em istr y of PBP2 a a n d β-la cta m a n tibiot ics is kn ow n [1 5 ]. Th is ex pla n a t ion in v olv es fa cts a bou t ch em ica l str u ctu r e of th e pept ide lin ks betw een g ly ca n ch a in s in pept idog ly ca n a n d th e ch em ica l str u ctu r e of m eth icillin . Th e con fig u r a t ion of su ch str u ctu r es, in tu r n , h in g es on fa cts a bou t h ow pr otein s fold a n d th e ba sic ch em ica l r u les g ov er n in g h ow bon ds betw een ca r bon , ox y g en , h y dr og en , a n d n itr og en for m . Th er e a r e sev er a l on tolog ica l r esou r ces to r epr esen t su ch ch em ica l str u ctu r es (e.g . , Ch EBI ), bu t a t th is m olecu la r sca le w e a r e on ly r ea son in g a bou t str u ctu r es (qu a lit ies in BFO) th a t a r e th e ph y sica l ba sis for th e r esista n ce disposit ion , n ot a bou t th e disposit ion itself. Sim ply pu t , th e r esista n ce of MRSa to m eth icillin is n ot iden tica l to a n a g g r eg a te of ch em ica l str u ctu r es, bu t it is bor n e in v ir tu e of su ch str u ctu r es. Im por ta n t ly , w e a lso w a n t to be a ble to ta lk a bou t r esista n ce a t th e ph y siolog ica l a n d popu la t ion lev els w h en w e ca n ta lk a bou t th e con sequ en ces a t th ose lev els of th e ch em ica l str u ctu r es th a t con fer r esista n ce, a n d a lso w h en w h en w e h a v e in com plete m icr osca le in for m a tion a bou t su ch 13 7/5/13 Towards an Ontological Representation of Resistance: The Case of MRSa www.ncbi.nlm.nih.gov/pmc/articles/PMC2930208/#__ffn_sectitle 12/14 str u ctu r es. Th is is a n oth er r ea son a n on tolog y like IDO sh ou ld pr ov ide ter m s for th e en t it ies ex ist in g a t both sca les. A r ela ted issu e th a t sh ou ld be a ddr essed a t differ en t sca les of biolog ica l r ea lity is th e w a y in w h ich fa cts a t ea ch sca le a r e u sed to ex pla in th e ph en om en on of r esista n ce. A t th e g en et ic sca le, MRSa h a v in g m ecA a n d MSSa la ckin g m ecA a r e ex pla n a tor y . A t th e cellu la r lev el, in fer en ce (D5 ) is ex pla n a tor y . To h elp lin k sca les of biolog ica l r ea lity , th e pr oposed IDO defin it ion for pr otect iv e r esista n ce g iv en a bov e specifies th a t a m a ter ia l en t ity is r esista n t in v ir tu e of on e of its pa r ts (or on e of its m em ber s in th e ca se of a popu la t ion ), bu t fu r th er w or k of specifica t ion of pa r ts m u st be don e in th e r espect iv e IDO ex ten sion on tolog ies in or der for u s to be a ble to ex ploit m u lt isca le r ea son in g . A s sta ted a bov e, str u ctu r a l fa cts (BFO qu a lit ies) a lon e m a y n ot be ex pla n a tor y beca u se th ey do n ot in clu de in for m a tion of h ow en t it ies w ith differ en t str u ctu r es in ter a ct . In ter a ct ion s (BFO pr ocesses) a lon e a r e n ot ex pla n a tor y beca u se th ey do n ot in clu de in for m a tion a bou t w h a t it is in th e in ter a ct in g pa r t icipa n ts th a t en a bles th ese in ter a ct ion s to h a ppen . Disposit ion s a r e th e ex pla n a tor y g lu e betw een str u ctu r es a n d in ter a ct ion s. 8. Conclusion We h a v e a ttem pted to pr ov ide a defin it ion of pr otect iv e r esista n ce th a t is g en er a l en ou g h to cov er th e v a r ied ty pes of r esista n ce in th e in fect iou s disea se dom a in , specifies th e com pon en ts of r esista n ce a t m u lt iple sca les a n d a cr oss on tolog ica l ty pes (a lon g w ith h ow th ose com pon en ts r ela te to ea ch oth er ), a n d is ca pa ble of bein g ex ten ded to cov er specific for m s of r esista n ce in th is dom a in . We h a v e seen th a t r esista n ce is a n im por ta n t m u lt i-sca le ph en om en on , often w ith a on e-to-m a n y r ela t ion sh ip betw een a r esista n t or g a n ism a n d th e u n der ly in g m ech a n ism s of r esista n ce. Sev er a l desider a ta for a n on tolog ica l r epr esen ta t ion w er e fou n d la ckin g in ex ist in g on tolog ies. Ou r pr elim in a r y for m a l r epr esen ta t ion of r esista n ce h on or s a posit iv ity desig n pr in ciple, by pr ov idin g a n a n a ly sis for its n eg a t iv e ch a r a cter iza t ion s (e.g . , th e la ck of a disposit ion ). It a lso con for m s to a pr in ciple of n on -pr olifer a t ion of r ela t ion s by r eu sin g ex ist in g RO r ela t ion s. Usin g th e for m a lism of blockin g disposit ion s, w e a r e a ble to a n a ly ze th e m u lt isca le in ter a ct ion s th a t g iv e r ise to r esista n ce. Su ch a n a n a ly sis a dds ex pla n a tor y v a lu e to a n in fer r ed fa ct a bou t th e r esista n ce of MRSa to m eth icillin . Cer ta in a ssu m ption s of ca n on icity a r e n eeded, n a m ely th e a ssu m ption s th a t a ll en t it ies (e.g . , a n a tom ica l a n d cellu la r com pon en t en t it ies) a r e ca n on ica l a n d th a t n o ex og en ou s fa ctor s a r e pr esen t u n less ex plicit ly sta ted (e.g . , m eth icillin ). Th is ca n on ica l r epr esen ta t ion of r esista n ce is, h ow ev er , a ble to cov er sev er a l differ en t ty pes of r esista n ce. Ou r defin it ion of pr otect iv e r esista n ce w a s sh ow n to be su fficien t ly g en er a l to cov er r esista n ce ph en om en a in v olv in g m a la r ia a n d HIV . In th ese ca ses, a s in th e ca se of MRSa , w e dem on str a ted h ow r esista n ce in v olv es th e pr ev en tion of th e com plet ion of a n essen t ia l su bpr ocess by th e poten t ia lly h a r m fu l en t ity . Som e issu es r em a in (e.g . , in pr ov idin g a sy stem a tic a ccou n t for th e la ck of a disposit ion th a t ov er com es som e of th e issu es w e h a v e iden tified), bu t w e a r e con fiden t th a t fu r th er stu dy of r esista n ce w ill h a v e g r ea t ben efits for biom edica l on tolog ies. For ex a m ple, th is w or k m ig h t be ex ten ded by con sider in g th e log ica l r u les n ecessa r y to in fer n ov el for m s of r esista n ce fr om a kn ow n r esista n ce ty pe, poten t ia lly a cr oss r ela ted dr u g s a n d species. Acknowledgements Th is w or k w a s fu n ded by th e Na tion a l In st itu tes of Hea lth th r ou g h Gr a n t R01 A I 7 7 7 06 -01 . Sm ith 's con tr ibu t ion s w er e a lso fu n ded th r ou g h th e NIH Roa dm a p for Medica l Resea r ch , Gr a n t 1 U 5 4 HG004 02 8 (Na tion a l Cen ter for Biom edica l On tolog y ). Cow ell's con tr ibu t ion s w er e a lso fu n ded by a Bu r r ou g h s Wellcom e Fu n d Ca r eer A w a r d a t th e Scien t ific In ter fa ce. We w ou ld like to th a n k Wa cek Ku sn ier czy k a n d tw o a n on y m ou s r ev iew er s for th eir feedba ck on ea r lier dr a fts of th is w or k. 7/5/13 Towards an Ontological Representation of Resistance: The Case of MRSa www.ncbi.nlm.nih.gov/pmc/articles/PMC2930208/#__ffn_sectitle 13/14 Footnotes This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. http://www.ifomis.org/bfo http://www.obofoundry.org/ http://code.google.com/p/ogms/ Further refinement of SaIDO may involve the creation of MRSaIDO and MSSaIDO sub-ontologies which overlap in SaIDO. http://www3.niaid.nih.gov/topics/antimicrobialResistance/Research/niaidsRole.htm http://www.cdc.gov/ncidod/dhqp/ar_mrsa_CDCactions.html http://www.obofoundry.org/ro/ For more on BFO realizable entities, see [6]. Here we chain together two triples for brevity. This section is adapted from a conference submission by the authors to Formal Ontology in Information Systems [10]. Note that since we are dealing with the impossibility of co-occurrence, we could also take the disposition to bind to PBP as a blocking disposition for the disposition to synthesize peptidoglycan. By our notational convention, ∅ denotes a cardinality of 0 http://www.ebi.ac.uk/chebi/ Article information J Biomed Inform. Author manuscript; available in PMC 2012 February 1. Published in final edited form as: J Biomed Inform. 2011 February; 44(1): 35–41. Published online 2010 March 2. doi: 10.1016/j.jbi.2010.02.008 PMCID: PMC2930208 NIHMSID: NIHMS186031 Albert Goldfain, Barry Smith, and Lindsay G. Cowell Blue Highway, 2-212 Center for Science & Technology Syracuse, New York 13244-4100 University at Buffalo, Buffalo, NY Duke University Medical Center, Durham, NC Corresponding author: Email: agoldfain/at/blue-highway.com (Albert Goldfain), Email: phismith/at/buffalo.edu (Barry Smith), Email: lgcowell/at/duke.edu (Lindsay G. Cowell) Copyright notice and Disclaimer The publisher's final edited version of this article is available at J Biomed Inform See other articles in PMC that cite the published article. References 1. Knobler SL, Lemon SM, N ajafi M, B T, editors. 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