ene eee DMM Leen rte pr —— ee prevalent test inputs in kinetic studies, giving sums of exponential outputs. Cue ara a Each eigenvalue adds, o an exponential a cic Teed Blinn response to an cower Impulse stimulus. 1) eo : oo a | elie! OCT Matiexp sponses) depen on signals, ofthe charcericic equation, ~ yl) = Ae * Complex or repeated eigenvalues may be inherent in data, but more difficult to detect, reo sme rep ee * Called hidden yd =F Saves + sone? cmp mestgeatae TO + Hidden modes also appear due limitations on where " we stimulate and where we probe WO =X Sasier*coslont- 04) + # of compartments usually larger than # exponential aS modes whew 4 =0, +40, (125) Sm sn disineteigemaluesDUES Lear ky 0 ky ake Ka kk. 0 || ° Ok ke] | 8 ke ks wolp,st+p)'-alp,+p, 9,0) =10,- 9) = 21m. per oR ‘p> 0 real eigenvalues 1y-=0 repented eigenvalue Phe 1y-<0 complex eigenvalue DU er eos ert "he pha sce suMMaRy + Hidden modes due tothe choice of VO pert he. how we choose to Interact with thesstem) + Hidden modes ar so duet 2) “lumping” of compartments wih sini exchange rates, by dymamics that are too fatto capture inthe data ©) dueto small velumes or 1 dueto Fie relationships between the compartments that therefore eit collective dynamics ecellsina issue areal umpedtin onec) = spect input/output probes retrieve limited info about the structure of the real system, even If we have ideal noise-free data 1 HOW MANY MODES eR COMPARTMENT WL BE VISILE? yr. 218 2TED THROUGH LANDHAS BOTH 115150 xcTED THROUGH 25017 ALSO HASTHEMODEOF 2 IBLE TE MODES Wists, $0. HAS TSOWN MODE ASWELLASTHE MODES OF THE OTHER DU Presser’ summany #2 + Cyclical can exhibit osciltions in some cases (an oscilation “cost ‘te modes) + Number of ebserved modes hence less than number of compartments + Graphical analysis helps with forming predictions andhaving a crits view on experiments expected vs. predicted)Dre cue BE ee Sy reduction, or aggregation: finding a simpler representation * For LTT SISO models; 2 onder SISO structures ore of a given structure that is appropriate for some purpose reducible if pole-zero cancellations occur in TF SIMPLER: fewer state vars, fewer parameters, or * Hf pole-zero cancellations occur approximately, the both system may appear to be of smaller dim, depending on quantity & quality of 1-0 data ica: ee ates ni eset ne eg. system attributes ‘muddied’ by noise in data Sticual ues anda mode that salen beset bred in nose? «Approx pole-zero cancellations advantageous for hat othe dynaicst sine modeling abot te eemine complex tstachemcaoemtanans a he rede een building approximate, simplified models OUTER a nrc OE Re wh ‘Can use he general MC model wh Cans he general MC model ia with therates between Zand 3 Ka ‘nth the rates between 2 and avnto eo, eau, a 80, just one ng nde SSeimr [Poeun goa | SSiitm [weer lnm em : om x by hy +h) 0 ° (s-ka) {8° u) are] al 8 lye won| aoa ik, 5B} 415+) (sek) (5b )-Lseha)DTT OE Re Tae ‘Can use he general MC model Wwth the atebetween 23nd ‘ith the rate betwcen 2nd ase he general 3 model avnto eo, oa eau, ‘Abo 80st one np and one a 80, just one ng nde (sk I's ky) 1 (s-k,)[Hs- kg) MoT The [le Re kK) 1s Ke Re KK, K, MoV TR Rem Ae KT 5 KI (CAN WE CANCEL POLEAND AZO [L.A FACTOR ABOVE AND BELOW THEFRACTION)? OUTER a nrc Car 4, POV kas Ki #18) 8 Ka) oy WHAT DOES hy ACTUALLY MEAN? (CAN WE CANCEL APOLE ANDA ZERO (Le. AFACTOR ABO KFS KK. VE AND BELOW THE ACTON? 1 ALMOST, BOTH FACTORS ABOVE CANCEL BEIOW EXCEPT FOR ONEOF THE COMPONENTS ‘Can use he general MC model Wwth the atebetween 23nd THISISNOWA SECOND: fewase.arde orginal) |. 2aNO ARE ITED WA WaT THE SAME MODE BUT POSSI OF DFERENT INTENSITY 8. 2AN0' HAVE EIA Lowes ears an TALS EcuaL ora / 22ND SL HAVE THE SAME OMANI RESPONSE (COLLECTIVE DMNA) ky es SE ary AoH(ha thy) aah g f= thy) 4h G Gna thy a ahs ath, (How DIFFERENT ABE AND When k, =A, thetwo ODEs arethe same, SA ‘hel solutions will be same as well fect Bing vs Baby Bag aateniok? “= 2 and C3 will have cratly the same dynamics tC]UE Rr nec roRciARTY a oor ar ieeqUarON (5-4) (5+Ka) <2 and at) ace exactly the same excent net P| kk OUTER a nrc OE Re ae ‘A COMBNE CASES 16 28107 ara [ANDARGUE WH THESE WL ky a [aprEAR TOBE 2" ORDER 7 1 METER] 4 (sk) 4k) (sk 4s) " as TKK, te Je ks kK) 18k 1e 1K, k, Th, k te ke sk] 1e 15k) kk, Omer a-e @ kerk, Omer a-e @ york My wes a meee By wes i, AE EETELE iCompartmental model for digoxin intake 1. Case I: fntravenons adiniisration (ev. Her tole of ts plea afd the epones >{) al ‘Trsusormatioas we ders ring th en he erect ate ce (eb opp Laplce 2. aap Is oral adeinintention (x): detente th core state space mela FFiguur 1: The structural formula of Digoxin ie a ha the npn a}. HF 10 a 0) apg place ‘Tusocumtios ts doce tig tees. Case I: itrvenous admalstration (Lv. dea cts Ate 946 2. Cap TE: oral ainraton este he ne oes trode ef ths onal ft the ese) a 1) by ang apace thir fobien and fd the responses (2) and 2) by apna Laplace TWarnrnaions a dicted ring th et ts ofcblem end td the respons =) 1, fei =he) sty = Hit fas A Hs — fas (aah ye hay kana) Thay ales 33) foxkis ie fyb tn= fa) A tye Gy Gr Suxkokt ayy hakaksr T= mn0a =" * Tay da) a ashok, GB)eee 2s opr nttaacatsongetnerited pata RU sy Pee oats ‘The Distinguishability Problem Re eda) Problem: how to distinguish among a finite but a small # of alternative and feasible comp structures that fit the data? SUPPOSE WE KNOW THAT THERE AREN COMPARTMENTS B HOw D0 w CHOOSE THE STRUCTURE ANO THE CONNECTIONS BETWEEN + Muti fis of data obtained from several stimulusresponse ‘THEN COMPSBY INTERPRETING THE OATA? :NISTINGUSHABLE periments Ter ARE INPUT/OUTPUT EQUIVALENT + Independent experiments wit isolated subsystems NAMELY, DIFFERENT STRUCTURES CAN PERFECTLY FIT THE SAME DATA + terature research can already ildinfo about rates k and values V but we must choos jst one that corecty reeks + Physcal/chemica/o prior knowledge bys chemcal0 phenomenaLote ‘The Distinguishability Problem EUnet Problem: how to distinguish among a finite but a small # of alternative and feasible comp structures that fit the data? ‘We must first learn how to detect the ambiguity “TASK: SHOW TRATTHE TWO MODELS BELOW ARE INPUT/OUTPUTEQUVALENT 2 ae Sweater ty Fertons anor He Sinerone rs mY fotiecaatc wort rom ch le + notion ao freeman ‘Seat physlogea Fede sri n ‘at Sia fect in o" fig setcator feted 0) ‘ape eseased sin fncarcetaneny ‘lowasan ane Iromaced Nav a Re eda) Problem: how to distinguish among a finite but a small # of alternative and feasible comp structures that fit the data? Example: discriminating among different 2 compartment models of a real biosystem Hormones and salmon migration in the river ‘Thyroune ad he sion anean oe ar eo Rowen Fi rec lm, Onna ih sur ware A STIMULUS-RESPONSE EXPERIMENT WAS CARRIED OU’ Modeling goaliis to perform hypothesis testing “L_ Because they swim from sweet to salt water (saline eect) + Small quantity of Radioactive Thyroxine (Z,) injected asa tracer 2. Because they ae maturing (develooment fet) + Conant inplasma dained following he ple des of tac eens : Z + exponen shed te bs Ses sree '\ S180 Two-Compartment Model cn be used i ALAA poset and ya : can senn se 3 Ambigultes. where are the lesks? Comp 1 or 2or bo?SOMATSTHE RESON LETS TAKE THAT FORTHE TaPEAKN ‘i-uasma (8.000) agcovapRi? (Q2-ALL AGGREGATED (UMPED) TISSUE warex on SOMETHING tse ‘elma ces ocring st ‘Sesometene smi OF eens 2) leaks in both compartments prsunne Fy noting =] Nove gee = Sino sin ioginegoie Wm FAST SAMPLING THERE 1SNO TIME FOR UPTAKE OF TN G2, tn There a8 ft sks inplasma => ol ban opon VW {OW SAMPLING, We WAY BE ABLE TOSEE A LEAK OFT, N EXTRAVASCLLAR SPACES a} must becomsideed ‘erlotinib Dee Ur aL ec ey UU A Pu ELL Cr ra a ton 4 'USETHE GINERALMODEL AND FIND THE OUTPUT PRS WHE & BOLUS IS APPLIED @ INPUT ONE ONLY (aJAND @ INPUT 2ONtY 8) There are 4 wnowa poamdes:k,, yA and (at, can be foun fom thm) -alt}andu,(t]=0 | when (1) =o andu,{t)=0 lt) Model Moat 2 Models IARAIMO MODELWE CAN 00 THA. Bx Both comps accessible: u(9, &u,(9 & outputs y,(9 &y.(0- We know exchange exists, but don’t know where the “leaks” are,Dee CU aL ec CCL ey Dee Ur aL ec ey ae 'USETHE GENERAL MODEL AND IND THE OUTPUT “A oy Egy TABERNDTHE AS FOR BOTHOUTS NOTH CASES YRS WHEN A BOLUSIS APPLED @ INPUT ONEONKY : (aJAND @ INPUT 20NW (8) ave} Va eT puesta) <2 te BUT WE CAN TELL WHE MODEL WE RAVE BY USING A swomteut e © eereenncnenane when y(t) =D alt) andu(t)=0 | when) ‘ee OBTANED OA We