Doc 0000022067

-v- SU:·i:!.ARY is an operational system specifically desiened to make it BIO~IDD .convenient for unsophisticated computer users to study models of dy namic systems. The system features a high degree of interaction, user-oriented model-definition languages, and flc}:ib1e, in-depth model structuring. It employs a graphics console comprising a television screen, a data tablet, and a keyboard. ,. A BI0~·10D use:::- may represent a model by dra~·Ting block diagrams and handprinting or typing text; he receives immediate feedback about the system's interpretation of ~is actions. Each component of a model block diagram may be defined by another block diagram; this facilitates organizing models into meaningful substructures. A usar ultimately defines each component block by analog-computer-like elements, alge breic, differential, or chemical equations, and/or Fortran statements. A modeler may. thus define his model in whatever terminology is mean to him. Displayed curves are continually and automatically ing~ul updated during model sit.1Ulation. A user may stop the simulation and plot different variables, change scales, or alter parameter values, and then either continue or revise the description of his simL'.latin~ model. This report demonstrates BIOHOD by presenting a scenario of how a user might describe and simulate a drug-effect model, briefly de- l scribes the system implementation, and discusses experience with users. -, -5-- II, A ~10DEL FOR EVALUATWG DRVG AD!-!ISISTRATIOt~ POLICIES Medications and their prescribed dosages are designed to maintain a critical amount of drug in the blood for a specified period of time, The conventional method for determining optimnl dosages involves numer ous laboratory experiments. If the drug effects can- be modeled, how ever, a more efficient ·method is to experiment by running computer simulations. ,. One technique for maintaining the pre~cribed amount of drug is to use a ·Capsule containing a large number of differently coated pellets. The pellets dissolve .at different times, so that, as drug leaves the blood, it is replaced by drug released by newly dissolved pellets. I Garrett and Lambert [8] have proposed the follovring model to describe this situation. A capsule comprises a nu:nber of pellet populatiots ~ith different mean times of release. The rate of drug release for each population is assumed to be normally distribu~ed (\·!ith the same standard d~viation for each population) about the mean time of release for that population. The rate of adding drug to the bo~y is therefore specified by a sum of normal distributions. The transfer of drug through the The image is a graphic representation of a vault door, reminiscent of a bank vault, with intricate mechanical details and a glowing blue light emanating from its interior. To the right of the vault, white text on a black background provides information about the origin and content of the document. The text states that the document was obtained from "The Black Vault," an online database of declassified government documents, specifically from the "MKULTRA/Mind Control Collection," housing over 20,000 declassified pages from the CIA. A URL is provided for accessing the collection. There are no photographs of people, locations, equipment, handwritten annotations, signatures, official stamps, forms, diagrams, tables, redactions, or visual evidence of experimental procedures visible on this page. The page contains an excerpt from a document, likely a technical report, detailing a system called "BIOMOD." Visually, the page features standard typographical text, with a title "SUMMARY" and body paragraphs describing the BIOMOD system. There are no photographs, diagrams, tables, or forms present. A small, handwritten doodle or symbol in the upper right corner is noticeable, as is a stamp at the bottom right that appears to say "Approved for Release," indicating a declassification status. There are no redactions or visual evidence of experimental procedures. release for each population is assumed to be normally distribu~ed (\·!ith the same standard d~viation for each population) about the mean time of release for that population. The rate of adding drug to the bo~y is therefore specified by a sum of normal distributions. The transfer of drug through the body is described by where GI refers to the gastrointestinal tracts B to the·blood, and U ' to the urine and other excretory parts of the body; this means that drug flows from GI to B at rate kGI,B and from B to U at rate k~,u· Thus, for exarr.ple, •;.:here DB is the arr.ouut of drug in B, and DGI the amount of drug in GI. Given this description together with the requisite parameter . values, RTO~On c&n be used to simulate the model. ~ote that the follow- sar.1~ goal, and that BIO~-!OD does not force the user to t<lke actiO<ilf L• ·. :. -6- \·.'hen u:;itig iHO:iC.::>, ,.;c cc:~:.,•.:,licat:e via a data tablet pen and tl keyboard. rhe pe111s locntion on the tablet is ahJ.:tys indicated by.a dot displayed in the corresponding location on the television screen. BIO}fOD' s interpretation of user pen nctions depends on where the pen is placed and on •.vhnt is currently displayed on the screen. t·le may ha'ndprint character·s in most areas. As we ·.-~rite, a displayed "ink." track appears to flow from the pen; each time we complete a character, its track is replaced by a stylized character. He can change a char- :1 acter by writing another over it. Some symbols are used for editing; for example, we may use a caret to insert text, or we may scrub with the pen to delete text. Some areas displayed on the screen act as pushbuttons; if we "push" one of these (by touching the pen down), the system performs the indicated action. If we push a displayed arrow, a continuous actfon takes place, such as the rescaling of a set of curves. Some figures can be "dragged"; if we 11touch11 one of these and ~ove the ?en, the displayed figure follows .the pen's motion, We may type (with the keyboard) in any area where writ::ing is possible. The keyboard cursor may be positioned either with che pen or with keyboard control keys. \ To create our model, tve enter our identification, name our r.1odcl DRUGS, then begin constructing the model. Because it The document page primarily consists of typed text, with a section of a diagram that visually represents the flow of a drug through a biological system. The diagram uses boxes labeled "GI", "B", and "U" connected by arrows, indicating transitions with associated rate constants (e.g., "kGI,B"). There are no photographs, handwritten annotations, signatures, official stamps, forms, tables, or redacted content visible on this page. The visual presentation is purely textual and symbolic, with the diagram serving to illustrate a concept described in the accompanying text. pen's motion, We may type (with the keyboard) in any area where writ::ing is possible. The keyboard cursor may be positioned either with che pen or with keyboard control keys. \ To create our model, tve enter our identification, name our r.1odcl DRUGS, then begin constructing the model. Because it has two major I components, we first draw t~vo rectangles; these are replaced by styl.- 1 ized· function boxes. He Hrite CAPSULE in one box and names of parts of the body in the other box, and then a flowline to connect them. dra~v Tnis diagram (Fig. 2) provides not only a picture of our model, but also a means of defining the two components of the model separately. To define the capsule component, we first push the DEFN button on its box. The system replaces the block diagram with a list of lan guages that we may choose from to the component. The languages d~fine are block diagrams, mathematical equations, chemical equations, and Fortran statements. choose block di£1gr.:lms so that we can define ~~:a the as a set of boxes, each a pellet population. caps~le repr~senti~g This ability to define a bo:< by block Hngro.m us to anoth~r ~nnbles o-c;;anize a r.1odel as a hierarchical collection Jf a number of CO::'.?onents at di.ff~~·c~t levels. ~;i· dra~1 feu~: ~1o:-:cs .:;:-;,d ''rite PILL on t~c to::> li::r~ -7- -----~ etono ---- Fig. 2--The DRUGS model block diagrom -8- in this way 1•hcnevcr I.JC anticipate using the sumc function repeatedly. Because each population is defined by a normal distribution, we indicate that we want to define the PILL function with rnathcmaticol equations. BIO~OD responds by displaying a form for writing algebraic and differential equations. ~·le assume tha~ the probability of a pellet. dissolving in an interval about time t is given by the p~obability density function . 2 2 1 - (t-m) ·'/2o p = --- e oi21T Using this to approximate the drug release rate by a deter f~nction ministic variable, we write P "" 1/ (S IG:.-4<\.*SQRT (2*P I)) *EXP (-(TIHE-l1EAm ~:*2/ (2:~s IGHA**2) The system analyzes this statement and immediately responds I.Jith the message UNBALAXCED PARE~THESES He then add a closing parenthesis to correct the statement. He also realize that we should parameterize the amount of released by d~ug each pellet population, so we insert DOSAGE after the equals sign and scrub the 1. The display now e?pears as The page is made up of text only and appears to be a typewritten document. There are no photographs, handwritten annotations, signatures, stamps, forms, diagrams, or tables visible. The text discusses the use of a data tablet and pen for communication with a system called BIOMOD, and outlines steps for creating a model related to "DRUGS." There are no visual elements that suggest experimental procedures, equipment, or facilities. immediately responds I.Jith the message UNBALAXCED PARE~THESES He then add a closing parenthesis to correct the statement. He also realize that we should parameterize the amount of released by d~ug each pellet population, so we insert DOSAGE after the equals sign and scrub the 1. The display now e?pears as in Fig. 3. has generated separate lists of the defined and undefined BIO~fOD variables; does not appear because it is al\.:ays the simulation TI~·fE independent variable. These lists enable us to indicate t.;hich vari ables have different meanings or values each ti~e we use the functi~n. We indicate that the names (and therefore the values) of PI, SIGK<\. 1. and DOSAGE are the same each tirr:e t.Je use the PILL function. This is because PI is .::1 constant, and because we assume that tha standard de viation and dosa312 amc·unt are the same for each popul<1.tion, On the other hand, t·:e h:.dicn.te that :·{L\~{ o.~ay hav2 a diff·?.rent 'Jalu~ for e.,.ch p2llet ?Opulntion, ·. -9- -r· •rn•r , ~FCAU ~no n• . I o:no~l .rriT<H 1 t:~r.11rnrv I( ~OLL ~ '"'"' t'ooooo r::S:fA-s:t--·-r;o;n-rt'~i'·.;·Y,oc:· ~··-, ~ .1 ; 7 c .'( y "7 o :: o -: ; !'l ; .· rt .- - ,c r ~"··-j- ~ i -, : -;; ' -. . ·t~-~ rae;£"" "" • 0'-lf.~ t~frj'J t ~CROLl ' IUTH!'4ATIC&L F.'ll &Till~~ (OOING FOP.>! DFFI'F~ Df.FI~ITIIl~ I ~· ~I ~: r~---' r--;, r t, - .. - - - -- ,.II , ' OOH!;FII ~ICIUotQ~1'1 pFIIIIFXPl·ITI"f·"~l'ltOl'" 2•t101fl. .. lJ I ~II ~~. ~l.t l ~IJ.. ~ YUIASLH or.n~to HE~£ YHI4DL!t tlEPIN!O H~CCiftQe .. , CHH~ (HCCK I' . t ~c ~IlL L ' Ill HIT ·,a~JABLP R!Hl10[A6l! 1• Pl T ,!LO.C. ,H .. ,. , & ~I & 8L P. t•ON·R!HA"UH! IHHT ~ Cll'-'"!"T b "'"' co~~t~T itic-· ;LLI! ;; --~ :·~ •~ I- -- ; I <I G4" cl I I ' COHCl·, ~* ' a ' ~ ' I u ' II - n ~r·· .·:·. -:. ::· --- ' r~ . ' . . ~-~ ~ . =- .. - . -· - :: .. - . ~ . ~ - .. -=~ . - -= - - -· - - - -· - - --- . r-- .. Fig. 3 -The definition of a pellet population ·. -10- it to define the imlividual populations. w.~ push 3 button to get back to The image displays a page from a document with a title "Fig. 2-The DRUGS model block diagram" at the bottom. At the top, there is a header with fields like "STORE," "RECALL," "FRAME COSING," "LOG ON," "MODEL EDITOR," "HARDCOPY," and "ROLL." Below this header, a box contains the word "DRUGS." The central and most prominent feature is a block diagram illustrating a system labeled "DRUGS." This diagram shows two main blocks, "DEFN" and "DEFNY," connected by arrows. Within these blocks are sub-elements such as "CAPSULE" in one, and "GI TRACT," "BLOOD," and "URINE, ETC." in the other, indicating a flow or process. There are no photographs, handwritten annotations, stamps, or redacted content visible on this page. :: .. - . ~ . ~ - .. -=~ . - -= - - -· - - - -· - - --- . r-- .. Fig. 3 -The definition of a pellet population ·. -10- it to define the imlividual populations. w.~ push 3 button to get back to our diagram of the four PILL boxes, then push the DEF~ button on one of these. Because PILL is nor,r defined, BIOHOD displays p ~ MEAN -+- PI + PI SIQ!A ''+ SIGMA DOSAGE + DOSAGE for us to provide the names of the output and mean of this particular population. ~{e ,.,.rite Pl next to P -+, to name this output Pl, and •..'rite !-11 next to HEAN +, to name this mean time of release Hl. He similarly establish the correspondence bettveen the names of variables in the other three·pellet populations and the name~ (P and MEAN) used when definfng the function PILL. He can describe the flow of the drug through the body by chemical equations because these are mathematically equivalent to mass transport equations. Hhen we push the DEFN button or. the box that describes the I body, and select chemical equations, BIO~OD presents an appropriate I fqrm. According to our original model description, He t-Tould like to write k kB,U GI,Bi> D 0 > ou GI B or kGI,B 0 t> on GI < o. k . DB ~~.> Du <1 0. ':.;rhcr:e 0. indicates that there is ,,o bac!,•,;,;.rd flo•. . ,r. BIO~·~CD t·cquir:cs that .. \.Je linearize each cattdtion. and ,:·.-i.t~ t:~.::. :.·at~ co~:Eficie::1cs and ~~uatic. s ·. -11- s KCIB o. DGI '"' DB s KBlf o. DB ... DU Here S (for slou re~ction) means that BIOXOD should derive integral equations from our equation. Since the pellets release drug into the gastrointestinal tract, we also write G DGI _. Pl+P2+P3+P4 This statement ("'ith G for gain) indicates that the gain of DGI, i.e., .the increased rate of change of DGI due to drug entering the body from outside, is equal to the sum of the rates o£ drug relaese from the four pellet populations. The model is defined except for parac.eter \-then \te no~-1 va.lu.~s. indicate that we are ready to provide these vilues, BIO~OD d{splays the names of model variables and parameters in t..,;o separate lists (Fig. 4). Na~~s such as DGio indicate initial values; they are derived fro:1 the The document is a text-heavy page, likely from a technical report or manual, as indicated by the equation and programmatic-looking variable names. There is a page number "-8-" in the upper right corner. The text discusses a "PILL function" and probability density functions, using terms like "normal distribution," "algebraic and differential equations," and "drug release rate." The only visual elements beyond the text itself are a few stray dots or specks, likely artifacts from the scanning or printing process, and no other visual content such as photographs, stamps, forms, diagrams, or handwritten annotations are present. four pellet populations. The model is defined except for parac.eter \-then \te no~-1 va.lu.~s. indicate that we are ready to provide these vilues, BIO~OD d{splays the names of model variables and parameters in t..,;o separate lists (Fig. 4). Na~~s such as DGio indicate initial values; they are derived fro:1 the chemical equations by BIOHOD. We en~er the values given or i~plied by Garrett and Lambert. We assume that some drug is immediately released 'into the gastrointestinal tract and therefore set DGio to 5; the other drug amounts are initially zero. In order to minimize storase requirements, limits the number of variables \.'hose values i'!re Bim~OD saved during simulation and the number of parameters whose values can be modified during simulation. Since this ,model is small, we indicate that we want to save values of (and possibly plot) all the variables, and that we Lrlght want to modify values of all except PI. param~ters It has taken us less then half an hour to· complatcly describe our model, We now indicate that we would like to simulate it. BIOMOD first produces a CS~W/360 [2] program that describes our model and pro vides for graptic display of the results. in turn, generates a CS~~, r'ortran prograr:1, ..: hich is conpiled and linked '-'!i th other programs re quired to run the simulation. If an error is detected at one of these ·.· -12- ___ - ~ H ! I \ ) M ~ i ! e ; o 1 a i 9 lf 1 C s A , L I. rr -. -· . ; .r ' . , .i ; .. ; • ,: r ; ; r l : •J r O rl i O r N ~ :r....-...- ..: J , - , ;: ; n : : ; -> ·~ n- : '7 ·7 t .D ' - - IT rr O. ~ ! ' t r . - ! , . --. - H-t.nO;C.OrH; ·•- ' AOLL t o::ua , . I. I,. '1/, ·r.\ •...• ,. ~"' -:. PAQI ,. • O'IIIJIIW \'ArtlULU rAIUIIlTU .• " CII!CII "' Clf~CK "' t ~C ~Ol Ll ' ~lOTTACU! >•OD" lA aL! l~OT PLOTT40L! rOT 140D. IPIHLI ,J IIA~t CO:lii!IIT ~ IIAIU \'ALl.'! CC<!•~eNT II"'' '·' ........ EEf,~~ ~~'.Uo J~•O.G)'O~•O II\ : ~1.: (!). UQ.1Z..!JI..!. Li..U.u .,!),3, K J ~ • h.!..L..li~~_; • 0 ( [-'.J 1 "ti7ITii'-J,;: 1~i.,c The page appears to be a computer printout, likely from the 1970s, detailing a form titled "MATHEMATICAL RELATIONS CODING FORM". It contains several sections, including "STORE", "RECALL", "LOG ON", "MODEL EDITOR", and "HARDCOPY". There are also tables for "VARIABLES DEFINED HERE" and "VARIABLES DEFINED ELSEWHERE," listing "NAME" and "COMMENT" fields. One field shows a long mathematical formula. A caption at the bottom reads "Fig. 3-The definition of a pellet population." There are no photographs, handwritten annotations, or official stamps visible. CII!CII "' Clf~CK "' t ~C ~Ol Ll ' ~lOTTACU! >•OD" lA aL! l~OT PLOTT40L! rOT 140D. IPIHLI ,J IIA~t CO:lii!IIT ~ IIAIU \'ALl.'! CC<!•~eNT II"'' '·' ........ EEf,~~ ~~'.Uo J~•O.G)'O~•O II\ : ~1.: (!). UQ.1Z..!JI..!. Li..U.u .,!),3, K J ~ • h.!..L..li~~_; • 0 ( [-'.J 1 "ti7ITii'-J,;: 1~i.,c .!.l_" l !I ?t ~. liD 11..!..L2.l;UJ!.. .! ..'l ..!.1 ;jDfi-'nI- -'·d 11~-•--·L!...Ll-'tU.: • a q i..,l-1J H i;J...!l.!il 'I o4 .•lHOi!oOI f'-'j.B.L....._....;I±t±Q,.tl.~...!.2.Jf I u ,r :r ; · 'T l' 1 I n •:.LJI • • o- . 1 1 T 4 l 'Q I~· -; : t 0 t " 0 7 t j j ~ ": ~j'i (j •'! if ·1. t)~"if~i''tQ 'JJI ~ I ~I J JE~M ..tJ,.....__,J ~· ,~,_; i I II ~ \ ' W'-----~ ~ I II_ __,' • I~ !~ I I l+i!: m1 : II - I Fig.4-The model variables end parameters -· ' · .. · -13- r.lesf:ages. The time rl?t;.td .rcd for the tranr,l:,tion dcpcad.,; on the load on the (r.lultiprogrammcd) computer; gcncnllly it is about three minutcc. Our DRUGS n:odel trr:nslates successfully, so the form choHn in r'ie. 5 is displa)•ed on ~he screen, As in the other forms, softHare pushbuttons appear across the top. The centL·al area is for selecting numerical in tegration methods, modifying parameter vatuas, eY.t.illinin_g variable names and values, or plotting graphs. The areas to the left and below the central area are for specifying the y and x axes of the graphs. We expect the values of our model variubles to change smoothly and over several units to TIME, so we choose a simple ·integration method- Simpson's method \-lith step-size= 0,1. This is a fixed step-size method, so the infonnati·:>n regarding variable step-sizes disappears. Before studying how to '.JSe a multi-pellet capsule, we want to ensure proper model behavior w·:1en there is initially some drug in the gastrointes t inal tract, but no cap~ule. To eli~inate the capsule drug we push the Pf.i:tAHETERS button to display the list of modifiable parar..etcrs in the central area, then ovenrrite the value of DOSAGE, cha::tging it to 0. Next ._;.e display the list of plottable variables. Because \-!e are most interested in the amount of drug in the gastrointesti~al tract, blood, ·and udne, "'e drag the names DGI, DB, and DU to the y axis. We ~<lent to watch the model for several sic-.ulated hours, so to 0. Next ._;.e display the list of plottable variables. Because \-!e are most interested in the amount of drug in the gastrointesti~al tract, blood, ·and udne, "'e drag the names DGI, DB, and DU to the y axis. We ~<lent to watch the model for several sic-.ulated hours, so \-:e chsnge the upper range of TI!·ffi (in the small box at the lot·ler right of the central area) f'l."om 1. to 7. 'He push PLOT; now we are ready to plot OGI, DB, and DU from 0. to 1. against TIME from 0. to 7. hours. rle ?USh RESTART and the sit:1ulation begins running. He see (from the curves) that DB, and later DU, are being generated; the "NOW X .. " number changes continuously to indicate the current value of simulated TI~iE. Because tGI is plotted off scale al~ng the upper boundary, we· touch the pen dc-vm to stop the simulati,on. In order to determine the range of DGI, wa return to the display that lists the variables along ~o.•itn their currE.nt, minirr.um, c:nd maxi;,lum Vf•lues. The mc:x:tr.:um value of DGI is 5. (its initial value), so we write 5 over the 1 that specifies the t!?par y-axis vaJ •!e, then rcclispl.-:y the curves, The curve5 are now · . . · -14- <nq {IQ\FC· ' oIn, ' ' OI_<Pl H ' ' en T'l ,,t. ,,, F~ TF ~ qFqsqr Ctl\TI•l r P4q&~FTZ~~ rv.··~n1~~' 4'41 Hf <lnP "'qDCtlPY \Aqi&RI[~ MnOfl fOITn~ Pli\T Till~ ll I OAT~ rHI' TH I\ OATS I ~F:THnO< H&QT n, "n'"' t,..,, TFC !t.l T I 11-. ynq Rl ' I, OAt C ~ OOIZ1tfl lf·ot SET UP GRAI?H AND r t·I8THO D tl I OOF•OO I' TFC q Hill~ "fTIHlO I I qFcu•c• Laq I I fqH!flll Oll I I q,.r~n~·• qll" (1 I'!UJ I I z•o-nqorq I 0 I"'~ I I tTH·nqor.q Ill •CE ·KI TTl I. I , TH -tl~orq ql •CF ·1'1 TT4, ~aqi&BL~ HH•H1'- I I ~ TH .l)qOF 1\ "I L ~ F' ~HI 481 F <Tf:P·H1r I I Fn•lF.I\·14qTF.• "110 B .-o c • \41\ <TZP•'•'F. . y .......... ,. ql ' 10 .I.•.I.T I H 1\Tf.G~~TIIl• HEP•<I7C I I 00'-•OA ~·- &LltlllBlf 1\TF(:;qiTin• <TfP .q 7F • I OH•IO Hl rqqo~ I• I\UCRlTIH Ill TPI T ~ ' I OH •Ot 1'1114 '\ • A B' fl\111'11\ I• I' TFC 1\t TI'IQ I'll TPI r• The document page contains a typed text that includes mathematical notation and chemical equations in a diagrammatic format. The text describes the PILL function and its implementation within a system called BIOMOD. The diagrams depict relationships between variables like P, MEAN, PI, SIGMA, and DOSAGE, as well as chemical equations showing drug flow through the body with rate coefficients. There is no photographic content, handwritten annotations, official stamps, or filled-in forms visible on this page. . y .......... ,. ql ' 10 .I.•.I.T I H 1\Tf.G~~TIIl• HEP•<I7C I I 00'-•OA ~·- &LltlllBlf 1\TF(:;qiTin• <TfP .q 7F • I OH•IO Hl rqqo~ I• I\UCRlTIH Ill TPI T ~ ' I OH •Ot 1'1114 '\ • A B' fl\111'11\ I• I' TFC 1\t TI'IQ I'll TPI r• • I OOF •0 I . ill[ •TfP•<IH I < 10 II <f[O q CH T~IT F<TI,.4TFO ,q~l')q • I A•IIH8<1YI •HF.I\F y • F<TIUITFO nt . . T PI T ~• t • H V E 7C C I t F ri t F r O O . ~ . " H &A • l n •r n n r r r P r l t \ ~ 1\ q 1 n 1 q - H c OO ;> P •O n O ? O OF•n2::J r.:i'!"tiiJ .,. ::· ;-oo ,. ~a <I j~"+NI '., '""' .[!! .. ~ _:J .. ' • 0 OOP•OO .,, •\1 PlnTTI•C I•TPII> AI •lo,....~_H•Hl I' l , • , m I OH = - Fig. 5-The simulation control form with Integration Methods -1.)- We assume, from the curve's reasonable appearance (Fig. 6), that He described at least the body cor.1pone:nt of the model corr('.Ctly, and our choice of integration mcd1od is adequate. We sec fron the curve labeled D3 that, as expected, the drug rer.1ains in the blood for only a short time. We reintroduce the capsule drug by chaneing DOSAGE back to 3 .• then restart simulation and vatch the curves being continuously th~ updated as it runs. Once it becomes apparent that the capsule is not effective, i.e., tha.t the value of DB drop's too loi<, we stop the simu lation. Apparently (Fig. 7), the drug is not releas~d from the pellets in time to replace the drug that leaves the blood. To correct this, change the mean times of release from 2., 4., 6., and 8. to 1., 2., ~e 3., and 4. We then rerun the simulation and get much better resu~ts. The amount of drug in the blood should be greater than 2.5. In order I to determine if this is achieved, we place the pen down in the cen'tral area to establish an x-y meter, then drag this metet to a place where Y (corresponding to DB·as well as DGI and DD) is eq~al to 2.5 (Fig. 8), Our choice of oeans good, but they need The document page contains primarily text, formatted as a list and paragraphs, with no images, stamps, forms, diagrams, or handwritten annotations. The text outlines parameters and variables for a simulation model called BIOMOD, discussing drug release into the gastrointestinal tract and the input of values for parameters. Notably, there are no visual elements that would indicate experimental procedures, facilities, or subjects. The page appears to be a technical description of a computational model. determine if this is achieved, we place the pen down in the cen'tral area to establish an x-y meter, then drag this metet to a place where Y (corresponding to DB·as well as DGI and DD) is eq~al to 2.5 (Fig. 8), Our choice of oeans good, but they need to be ad jus ted to roaxhlize ~"as the total duration of capsule effectiveness. ~bile changing the means for further trials we realize that rather than controlling four means, we would prefer to dea: only with the first r:.ean and the interval bet'l-:een mean times of release, To reformulate the model in this way, we return to its description and add another box to the definition of the capsule component. In this box.we write M2 = Hl + INTVAL and similar equations for X3 and H4, This replaces the par~meters }12, '!-13, and W1 with the single parameter I};TVAL, t-lhich t-:e• set to 1. and car~ modifi~ble. Once this is accomplished, we retranslate the model, then cor.tinue to resiuulate it and p<lrameters until we have chang~ established a saticfactory drug fonmlation and adrr.inistration policy. • . . -16- 1--'-"-·; .:..,.-:.~.:.~-:-\.:.•-~-·- +--q-~-(,..T,..•-~-T.,..-...:.._o_,,_n...:.c_,.n-•-:r"'r-,-~-,:---+....:~,..•-:~::: ~:: '1 I?Z "! o~ 7 q ; o c~ PY ••• ' 1 ' n Y1 r F THr• <T • I r 1 L P n•r• rHI I • < AQ T O t< C f O ( P Y o •r• • • • w ~ p I r A ~ C < L O P O • ( Ht "O ~ O T ! L n ' ! O"InToOt~L PEN DOWN ,.,, --, 1 -.-0-~---o-o--., • TOP I, '& Fig. 6--The simulation run with no capsule drug • -17- I •n~Clii\EC· IDIC~l&Y~ ICflTflf E•TF.R AF.ST£RT cn•rt~lE PlRAUETfl\~ lrc>4POR4.RY COPY &•&LYZ£ ~TOP "ARDCOPY VlAilSlE~ ~CDEL POITOR PlOT THI~ 4tl OAT4 THI~ TII!C O£T£ I ~!Tt<llD~ ~T&~T 0' NOOH ~--P-l-OT- -C-\-IIV-F-C~ 'F-O-il -R-L-' -~I.~ -Q-R~l-C-' ------~--~--~~;•- ------·0 6/l!/11- 14·0~ 'f'·llrt:I."'E ~l ' I 0 Q<il ••• oq Q~ •••• 11~ I Ql• •••• {/l_: f. ' ~ <) 0! • 0 0 ~no l • 4 &0!•00 Fig. 7 -The simulation run with the parameter volues shewn in Fig. 4 .. -13- .,~Ciq\F~· 0~ ''OIHI1Y1 ICOT~f r----E~~-T~F.~.~~----~-~R~E~~~T-4~~~T~---,--~C~O~,~T~I-~-l~F.----I--~P~1~q~.-M~F~.T~re.:p~~A~r COPY 4'4LY7f \TOP "4ROCOPY VAq~•aL!~ ~norL FOITO~ J ~PT"~O~ ~T~~T OF ~<lOFt X 4.49E+OO Y= 2.50E+OO ~1,-----0-0-,-.-Q-Q-~~~r-----------~~--------~--------~ 8 PUITT I ~(l I~ TV, RV ll t l.~~.;.;;..__,_r_n_P_I_P_l_::r. Fig. 8 -The The image displays a declassified page, likely from a technical document or report, featuring a large table of technical data. The table is divided into "VARIABLES" and "PARAMETERS" sections, each with columns for "NAME", "VALUE" and "COMMENT". This structured data seems to list parameters and variables with numerical values assigned to them. There are also various header sections with labels such as "STORE", "RECALL", "MODEL EDITOR", "HANDCOPY", and "ROLL". No photographs, handwritten annotations, stamps, or redactions are visible on this specific page. The visual presentation is predominantly that of a computer-generated or printed data log. The document is a single page of typewritten text, numbered "13" at the top. There are no photographs, handwritten annotations, stamps, forms, diagrams, tables, or redactions visible on the page. The text discusses a "DRUGS model" and its simulation, referencing figures and parameters within what appears to be a scientific or technical report. The visual content is limited to the text of the report itself. Fig. 7 -The simulation run with the parameter volues shewn in Fig. 4 .. -13- .,~Ciq\F~· 0~ ''OIHI1Y1 ICOT~f r----E~~-T~F.~.~~----~-~R~E~~~T-4~~~T~---,--~C~O~,~T~I-~-l~F.----I--~P~1~q~.-M~F~.T~re.:p~~A~r COPY 4'4LY7f \TOP "4ROCOPY VAq~•aL!~ ~norL FOITO~ J ~PT"~O~ ~T~~T OF ~<lOFt X 4.49E+OO Y= 2.50E+OO ~1,-----0-0-,-.-Q-Q-~~~r-----------~~--------~--------~ 8 PUITT I ~(l I~ TV, RV ll t l.~~.;.;;..__,_r_n_P_I_P_l_::r. Fig. 8 -The simulation run with means = 1., 2., 3., and 4. This image displays a declassified CIA document, likely a report or a form, with a page number -14- at the top. The majority of the page is filled with a complex form, likely a "Simulation Control Form," detailing various settings and parameters for a simulation, including integration methods, step sizes, and error tolerances. The form features boxes for input and selection, with some fields appearing to be filled with handwritten entries like "TIME" and numerical values. There are also section headings such as "SET UP GRAPH AND METHOD," which are clearly printed. The overall impression is of a technical document with highly specific data entry and configuration options. This page contains a single block of text with a page number "-15-" at the top. There are no photographs, handwritten annotations, signatures, official stamps, forms, diagrams, tables, or redactions visible on this page. The content consists solely of typed text, which appears to be a continuation of a report or technical document. The image is a screenshot of a computer display showing a graph with two curves, labeled "01" and "02", and several input fields. The graph appears to be a simulation output, with labels such as "LINEAR" and "TEMPORARY COPY MODEL EDITOR" suggesting a scientific or technical context. Below the graph, there are fields