ITRA
STRATEGY FORMULATION MEETING
for the initiative
ITRA-HUMAN: BUILDING A HUMAN SIMULATOR
BACKGROUND
A. SIMULATOR DEFINITION
1. The basic objective of the simulator will further the therapeutic options available to
clinicians.
2. The simulator would provide help clinicians obtain optimal answers to specific questions
more clearly and readily.
3. For a specific clinician, the simulator’s scope will be a specific type of disease or a family of
diseases D.
4. The initial focus of ITRA-Human Simulator will be on Amyloid misfolded proteins and the
disturbances they cause in the Brain, Liver, Pancreas and Kidney. Since these are important
factors in Alzheimer’s, Type II Diabete’s Steatohepatitis (i.e. Fatty liver disease that can lead
to cirrhosis) and Nephritis induced by dialysis (i.e. id-Nephritis), the focus will be in the
context of these diseases. While the simulator may include any and all organs as required, it
is anticipated that the prime focus of the simulator will include the roles of brain, liver, heart
and kidney, and the development of the related D = {Alzheimer’s Dementia, Diabetes,
Cirrhosis and Nephritis}, and intervention by drugs and novel agents.
5. Specifically, for a given set X of input parameters (independent variables: e.g., results of
pathological or biochemical tests, radiological images, drug-challenge tests, etc.), the
simulator will output the set Y, as a quantitative function of X, namely the set F(X) of
unknown values of output parameters (e.g., diagnostic/prognostic predictions, drug
combinations and their dose-time protocols, for a particular patient condition with a specific
disease from among D, etc.).
6. The input-output pair [X, F(X)] may represent one or more characteristics of the body
system relevant to D, comprised of components C such as:
a. Biophysical, biochemical, pharmacodynamic, pharmacokinetic, and other processes in
the body, e.g., the behaviors of certain proteins, enzymes and drugs;
b. Organs, as brain, liver, pancreas, kidney, blood vessels, etc.
c. At varying scopes, e.g., early marker pathway, diseases progression pathways, drugs
action pathway, pharmacological toxicity pathways, cell degeneration/cell regeneration
pathways, etc., and
d. At varying granularities or scale-levels, e.g., molecular, cell, tissue, organ, and/or
interlinked-multi-organ system (body) level.
Alternatively, X and F(X) may capture only a symbolic or numerical relationship, e.g., learned
from data, and may not have immediately or directly obvious correspondences with the
body.
Thus, an aim would be to find a causative quantitative, or a mathematical functional
relationship of observations X, with the results sought F(X).
7. X and F(X) for each simulator [X, F(X)] in a repertoire of simulators may be meant for a
different combination of a disease from D and components from C. These simulators may be
partitioned into focused groups, such that each simulator [Y, F(Y)] in a group is specific to a
component c from C, a disease d from D, etc. Thus, a C-Simulator is the set of [Y, F(Y)] such
that Y or F(Y) for each member [Y, F(Y)] pertains to c; a D-Simulator analogously is defined
by the sharing of a specific d from D; etc. As the number of disorders D increases, these
resulting C-Simulators (D-Simulators) more and more comprehensively capture the
behaviors of c (d).
To further illustrate, the input-output behaviors of the component liver that may be
relevant to diseases d1, d2, d3, … such as Alzheimer’s dementia, Diabetes-II, Nephritis (id), …
may be represented by simulators [X1, F(X1)], [X2, F(X2)], [X3, F(X3)] ….. These may be
regrouped to define a more comprehensive (not D-specific) Liver-Simulator [Y, F(Y)] where
each of Y and F(Y) is a union U of the individual X’s and F(X)’s, respectively, i.e., Y = X1 U X2 U
X3 … and F(Y) = F(X1) U F(X2) U F(X3)... As the number of diseases in D increases, the resulting
Liver-Simulator becomes an increasingly comprehensive simulator of liver (applying to an
increasing number of diseases.) Likewise, a Brain-Simulator, a Kidney-Simulator, and a
Pancreas-Simulator. Interconnecting these simulators with the intervening blood vessels
would yield a corresponding Human-Body-Simulator, whose capabilities will reflect those of
the simulators interconnected.
B. WORK METHODOLOGY
1. The specification of the first set of simulators to be targeted, namely the ones offering most
value, is to be done by clinicians.
2. Simulators are based on computational representation and all other aspects of processing
information pertaining to body components, diseases, etc. Such information processing
involves computing and all related aspects of engineering, and is denoted by Information
Technology, or IT.
3. There are well recognized limitations on how much the IT side understands the needs of
clinicians and how much the clinicians understand the potential IT holds for them.
Therefore, the process of designing the simulators will be seeded by clinicians presenting an
overview, e.g., by (i) going over their “time-and-work-flow” type of accounts, (ii) stating
what they see as possible sources of loss of quality, efficiency, cost and ease of operation,
and (iii) what they see as help IT could provide.
4. The interdisciplinary (IT, and science- and domain-level) ITRA teams, formed as a part of the
initiative, will develop the simulator design progressively during the initiative.
5. Clinicians will test the prototype designs as they are produced, and provide test and
validation data as corrective feedback to the ITRA teams as needed by them for refined
modeling and design.
6. Examples of the data that the clinicians will provide will be as deemed domain-relevant by
the clinician or as required by the design teams. The data may include, but is not limited to,
the results and intermediate stages of using the simulator for:
a. Early Diagnosis
b. Prognosis
c. Therapies
d. Drug Discovery
e. Understanding the Origination, Natural Progression and Spontaneous Remission of the
Disease,
f. Design of methods for intervention/modification of disease processes, by drugs/other
agents (“in-silico clinical trials”).
g. Teaching and Training (to compose a strategic series of questions such that the answers
teach and illustrate certain concepts to a student, help them test their knowledge, or
help a trainee (IT, scientific or clinical) to develop confidence in performing certain
practices.)
The data in (a- f) may pertain to an individual subject or to entire populations.
7. Aforementioned iterative design steps will be aimed at “guaranteeing” a design that would
deliver the maximal impact.
8. The teams will integrate the different related datasets, collected to develop a suitably
organized comprehensive dataset that will be made available for future experimentation,
developing new clinical treatment protocols, and studies for drug-discovery/medical
instrumentation
9. Given the nature of its objectives, the expected contributions of the work done will
inevitably span across the entire spectrum, from science and engineering to medicine and
industry. For example, the short term results may pertain to diagnosis/therapeutics,
medium term may significantly help clinicians for prognosis, toxicological and riskassessment aspects, and long term may lead to discoveries impacting epidemiological
aspects, health policy, drug/device-discovery and medical industry, etc.
C. SFM AGENDA
1. Will identify all clinical topics to cover as per the chosen definition and methodology.
2. For each topic, clinician(s) will give a summary including, e.g., (i) a “time-and-work-flow”
type of account of their activities, (ii) what they see as possible factors impacting efficiency,
cost and ease of operation, and quality, and (iii) what they see as help that IT could provide.
3. The topics will pertain to the four diseases related to amyloid or amyloid-like bodies [viz.
Alzheimer’s dementia, Diabetes-II, Fatty liver disease and Nephritis (id type)].
4. The challenges from the clinicians in each will be deliberated in breakout sessions to
determine a range of pre-specified parameters about the implementation of the initiative.
5. A comprehensive review of the implementation plans arrived at for each topic will then be
conducted to ensure all possible cross-topic synergy.
6. Care should be taken that there are balanced representation of the members from all the
disciplines [clinicians, basic science, industry and IT, and that there is also appreciable
representation from the different regions (north, west, east, south) in this country-wide
initiative.