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Open-Systems-Pharmacology / PK-Sim

PK-Sim® is a comprehensive software tool for whole-body physiologically based pharmacokinetic modeling
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Too many parameters created for Individual #2656

Closed rwmcintosh closed 1 year ago

rwmcintosh commented 1 year ago

There are too many parameters added to individual building blocks when converting to a core building block.

Individual building block should only include species specific parameters.

rwmcintosh commented 1 year ago

These parameters are all excluded for being not species specific

Parameter name
SA proportionality factor
Specific clearance (endosome)
Surface area scaling exponent
Weight
Weight of blood organs
Weight of tissue organs
pH (blood cells)
pH (interstitial)
pH (intracellular)
pH (plasma)
Scaling exponent for fluid recirculation flow rate
Thickness (endothelium)
Fraction endosomal (global)
Protein ratio (interstial/plasma)
Vf (lipid, blood cells)
Vf (lipid, plasma)
Vf (neutral lipid, blood cells)-WS
Vf (neutral lipid, plasma)-RR
Vf (protein,blood cells)
Vf (protein,plasma)
Vf (water,blood cells)
Vf (water,interstitial)
Vf (water,plasma)
Surface/Volume ratio (blood cells)
Vf (neutral lipid, plasma)-PT
Vf (neutral phospholipid, blood cells)-WS
Vf (neutral phospholipid, plasma)-RR
Fraction of endosomal uptake from plasma (global)
Ontogeny factor (albumin)
Ontogeny factor (alpha1-acid glycoprotein)
Plasma protein scale factor
Vf (acidic phospholipids, blood cells)-WS
Vf (neutral lipid, blood cells)-RR
Vf (phospholipid, plasma)-PT
Vf (neutral phospholipid, blood cells)-RR
Vf (water,plasma)-PT
Fraction recycled to plasma (global)
Acidic phospholipids (blood cells) [mg/g] - RR
Vf (intracellular water, blood cells)-RR
Rate constant for endosomal uptake (global)
Rate constant for recycling from endosomal space (global)
Hematocrit
MeanBW
Percentile
Mean
Deviation
Weight (tissue)
Density (tissue)
Allometric scale factor
Fraction vascular
Volume
Initial concentration
Peripheral blood flow fraction
Fraction endosomal
Blood flow rate
Fluid recirculation flow rate
Lymph flow rate
Volume (endothelium)
Fraction intracellular
Fluid recirculation flow proportionality factor
Lymph flow proportionality factor
Organ volume mouse
Fraction of blood for sampling
Flow fraction via large pores
Hydraulic conductivity
Radius (large pores)
Radius (small pores)
Vf (lipid)
Vf (neutral lipid)-PT
Vf (phospholipid)-PT
Vf (protein)
Fraction interstitial
Albumin ratio (tissue/plasma)
Albumin ratio (tissue/plasma)-PT
Lipoprotein ratio (tissue/plasma)
Vf (water)
Vf (water)-PT
Vf (neutral lipid)-RR
Vf (neutral lipid)-WS
Vf (neutral phospholipid)-RR
Vf (neutral phospholipid, plasma)-WS
Vf (extracellular water)-RR
Vf (protein)-WS
Vf (intracellular water)-RR
Vf (water)-WS
Acidic phospholipids [mg/g] - RR
Vf (acidic phospholipids)-WS
Specific blood flow rate
pH
Fraction expressed basolateral
Relative expression
Fraction expressed at blood brain barrier
Fraction expressed brain tissue
GeometricDeviation
GFR (specific)
Renal aging scaling factor
fGFRpremat
Fraction expressed apical
Effective surface area variability factor
Geometric surface area
Volume (gut wall)
Fractional steady state fill level
pH in fed state
Thickness of gut wall
Inverse rate of inflow of liquid into stomach
pH in fasted state
Distal radius
Gastric emptying time
GET_alpha (Weibull function) variability factor
GET_beta (Weibull function) variability factor
Length
Proximal radius
Effective surface area
Intestinal transit rate
Microvilli factor
Effective surface area enhancement factor
Small intestinal transit time factor
Fluid recirculation flow rate (incl. mucosa)
Lymph flow rate (incl. mucosa)
Volume (mucosa)
Mucosa blood flow fraction
Small intestinal transit time factor intercept
Small intestinal transit time factor slope
Small intestinal transit time
Fraction mucosa
Fraction of regional blood flow rate
Large intestinal transit time factor
Large intestinal transit time factor intercept
Large intestinal transit time factor slope
Large intestinal transit time
Is liver zonated
Fraction of periportal zone
EHC continuous fraction
Microsomal protein mass/g tissue
Number of cells/g tissue
Kd (FcRn, endogenous IgG) in plasma/interstitial
kass (FcRn, endogenous IgG)
Kd (FcRn, endogenous IgG) in endosomal space
Radius (endogeneous IgG)
Start concentration of free endogenous IgG (plasma)
Start concentration of free FcRn (endosome)
Surface area (blood cells/plasma)
Surface area (interstitial/intracellular)
Surface area (plasma/interstitial)
Reference concentration
t1/2 (liver)
t1/2 (intestine)
Ontogeny factor GI
Ontogeny factor
Relative expression in blood cells
Relative expression in vascular endothelium
rwmcintosh commented 1 year ago

Integration tests are showing that if we exclude all these from an Individual Core building block then there's issues creating the simulation

OneTimeSetUp: PKSim.Core.Services.CannotCreateSimulationException

I won't list the whole message, but a few issues where the parameter appears to be excluded from both the Individual and Spatial Structure

Observer 'Whole Blood' with path 'Whole Blood' references an entity with path '..|..|Plasma|Inhibitor|Concentration' that cannot be found
Observer 'Whole Blood' with path 'Whole Blood' references an entity with path 'simulation|Organism|Hematocrit' that cannot be found
Observer 'Interstitial Unbound' with path 'Interstitial Unbound' references an entity with path '..|..|Interstitial|Inhibitor|Partition coefficient (water/container)' that cannot be found
Observer 'Tissue' with path 'simulation|Organism|Bone|Specific blood flow rate|Drug|Tissue' references an entity with path '..|..|Fraction interstitial' that cannot be found
Distributed Parameter 'Age of aging onset' with path 'simulation|Organism|Kidney|Age of aging onset' references an entity with path 'Mean' that cannot be found
Distributed Parameter 'Aging half-time' with path 'simulation|Organism|Kidney|Aging half-time' references an entity with path 'Mean' that cannot be found
Distributed Parameter 'Hill coefficient for aging GFR' with path 'simulation|Organism|Kidney|Hill coefficient for aging GFR' references an entity with path 'Mean' that cannot be found
Distributed Parameter 'Maximal decreasing rate factor' with path 'simulation|Organism|Kidney|Maximal decreasing rate factor' references an entity with path 'Mean' that cannot be found
Distributed Parameter 'GFRmat' with path 'simulation|Organism|Kidney|GFRmat' references an entity with path 'Mean' that cannot be found
Distributed Parameter 'GFRmat' with path 'simulation|Organism|Kidney|GFRmat' references an entity with path 'Deviation' that cannot be found

CannotCreateSimulationException.txt

msevestre commented 1 year ago

Observer 'Whole Blood' with path 'Whole Blood' references an entity with path 'simulation|Organism|Hematocrit' that cannot be found

Looks for hematocrit and it should be there. It's in the list of not being species specific. Too many parameter are filtered out

msevestre commented 1 year ago

@Yuri05 The implementation of the common parameters is wrong, or at least not complete

Yuri05 commented 1 year ago

"Common parameters" are those which are present for every species, not necessarily with the same value or the same formula. That was the idea.

msevestre commented 1 year ago

Then this concept is missing something because how do we decide where to export ? Right now, we duplicate a lot of stuff

The mean parameter however is still a bug I think

Yuri05 commented 1 year ago

Something like this, no?

Yuri05 commented 1 year ago

Regarding the Mean/STD parameters: they are not part of the PK-Sim DB and are created on the fly. They should always get the same "common" state as their "parent" parameter?

msevestre commented 1 year ago

Ok so this repository returns true where it should return false or vice versa for parameters that it does not know. Probably the logic for unknown parameter should be it's NOT common

msevestre commented 1 year ago

Common parameters should be created both in the spatial structure and in the individual-BB In the spatial structure with NaN value In the Individual-BB: with their value or formula

I don't know. Do we want to create the formula for BW = Sum of all organs weight as sum formula in ALL individuals? I thought this would be defined in the SP structure. Then it's ok but the individual really is huge and the spatial structure has only NaNs lol

Yuri05 commented 1 year ago

Ok so this repository returns true where it should return false or vice versa for parameters that it does not know. Probably the logic for unknown parameter should be it's NOT common

hmm, need to check this...

Do we want to create the formula for BW = Sum of all organs weight as sum formula in ALL individuals?

yes!

I thought this would be defined in the SP structure.

yes! BW is common parameter, right?

msevestre commented 1 year ago

Then I don't understand what we are trying to do lol What's the point of defining BW in the individual with a formula that is the same for all species?

And why adding parameters with NAN in your structure?

Yuri05 commented 1 year ago

And why adding parameters with NAN in your structure?

That's something we have discussed some time ago... But I also don't see a problem, if we export individual parameters with their current value/formula to the spatial structure instead of NaN. @PavelBal

msevestre commented 1 year ago

I understand when there is a parameter with different formulas. But with the same formulas, I am just highly confused about what we are trying to do

PavelBal commented 1 year ago

21.06.2023: Proposal to put all parameters that are defined by a formula AND the formula is identical for all species - put the parameter into the spatial structure.

PavelBal commented 1 year ago

Is this clear by now, or do we need additional discussion?

rwmcintosh commented 1 year ago
Yuri05 commented 1 year ago

I have created another issue for the DB query which is required for this one: https://github.com/Open-Systems-Pharmacology/PK-Sim/issues/2699 Once the PR for that issue is merged - this one can be fixed (not by me then 😉 )