This document summarizes a model for simulating lipoprotein profiles and fluxes based on kinetic parameters. It describes:
- Developing a multi-compartmental model to simulate lipoprotein production, lipolysis, uptake, and transport.
- Validating the model against experimental tracer data on lipoprotein fluxes in different subjects.
- Deriving novel markers from the model, such as ratios of lipoprotein production and clearance rates, and showing they improve prediction of cardiovascular risk over traditional markers.
- Concluding the model-based markers could help reclassify risk for over 1 million people in the US, but requiring independent validation in different cohorts before clinical use.
HDL is the smallest and densest lipoprotein particle, composed of proteins, phospholipids, free cholesterol, cholesterol esters, and triglycerides. HDL particles transport cholesterol from tissues like macrophages to the liver for processing or excretion. The liver synthesizes nascent HDL particles that acquire cholesterol through interactions with the ATP-binding cassette transporter A1 and other receptors on cells. Enzymes further process and enlarge HDL as it circulates, eventually returning mature HDL to the liver to offload cholesterol through the scavenger receptor class B type 1. This reverse cholesterol transport pathway is important for reducing atherosclerosis and is part of HDL's anti-inflammatory and antioxidant functions that provide protection against cardiovascular disease.
Lipoproteins are protein-lipid complexes that transport lipids between tissues. They have an outer surface containing proteins and phospholipids and an inner hydrophobic core containing triglycerides and cholesterol esters. The main classes of lipoproteins are chylomicrons, VLDL, IDL, LDL, and HDL. Chylomicrons transport dietary lipids from the intestine to tissues. VLDL is produced in the liver and transports triglycerides. Through the action of lipoprotein lipase, VLDL loses triglycerides to become IDL and LDL, which transports cholesterol. HDL transports cholesterol from tissues back to the liver in the reverse cholesterol transport pathway. Cholesterol homeostasis is maintained through hepatic
1) The site (Organs and subcellular localization)
2) Reactions including High quality diagrams showing the reaction with structures.
3) Pathway regulation (Key enzymes and allosteric effectors shown clearly on the pathway with different colors and/or fonts) and hormonal regulation.
Lipoproteins are particles that contain a core of cholesterol and triglycerides surrounded by a membrane containing apolipoproteins. There are several main types of lipoproteins: chylomicrons and VLDL deliver triglycerides to cells, LDL delivers cholesterol to cells, and HDL transports excess cholesterol from cells back to the liver. The primary apolipoproteins are apoB in chylomicrons, VLDL, IDL, and LDL, and apoA1 in HDL.
Minimal and maximal models of glucose metabolismyvonne0
This document summarizes Francesca Piccinini's presentation on minimal and maximal models of glucose metabolism. It discusses various minimal models used to measure parameters of glucose and insulin dynamics, including the intravenous glucose tolerance test (IVGTT) minimal model, oral glucose tolerance test (OGTT) minimal model, and beta-cell responsivity minimal model. It provides examples of applying these models to compare insulin sensitivity, beta-cell function, and other indices between young and elderly subjects. The document also discusses using tracers to validate the models and segregate glucose disposal from production, as well as applications of the models in pathophysiology.
Genome-Scale Metabolic Models and Systems Medicine of Metabolic SyndromeNatal van Riel
workshop on 'The interplay of fat and carbohydrate metabolism with application in Metabolic Syndrome and Type 2 Diabetes', December 12 and 13, 2013, Eindhoven University of Technology
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HDL is the smallest and densest lipoprotein particle, composed of proteins, phospholipids, free cholesterol, cholesterol esters, and triglycerides. HDL particles transport cholesterol from tissues like macrophages to the liver for processing or excretion. The liver synthesizes nascent HDL particles that acquire cholesterol through interactions with the ATP-binding cassette transporter A1 and other receptors on cells. Enzymes further process and enlarge HDL as it circulates, eventually returning mature HDL to the liver to offload cholesterol through the scavenger receptor class B type 1. This reverse cholesterol transport pathway is important for reducing atherosclerosis and is part of HDL's anti-inflammatory and antioxidant functions that provide protection against cardiovascular disease.
Lipoproteins are protein-lipid complexes that transport lipids between tissues. They have an outer surface containing proteins and phospholipids and an inner hydrophobic core containing triglycerides and cholesterol esters. The main classes of lipoproteins are chylomicrons, VLDL, IDL, LDL, and HDL. Chylomicrons transport dietary lipids from the intestine to tissues. VLDL is produced in the liver and transports triglycerides. Through the action of lipoprotein lipase, VLDL loses triglycerides to become IDL and LDL, which transports cholesterol. HDL transports cholesterol from tissues back to the liver in the reverse cholesterol transport pathway. Cholesterol homeostasis is maintained through hepatic
1) The site (Organs and subcellular localization)
2) Reactions including High quality diagrams showing the reaction with structures.
3) Pathway regulation (Key enzymes and allosteric effectors shown clearly on the pathway with different colors and/or fonts) and hormonal regulation.
Lipoproteins are particles that contain a core of cholesterol and triglycerides surrounded by a membrane containing apolipoproteins. There are several main types of lipoproteins: chylomicrons and VLDL deliver triglycerides to cells, LDL delivers cholesterol to cells, and HDL transports excess cholesterol from cells back to the liver. The primary apolipoproteins are apoB in chylomicrons, VLDL, IDL, and LDL, and apoA1 in HDL.
Minimal and maximal models of glucose metabolismyvonne0
This document summarizes Francesca Piccinini's presentation on minimal and maximal models of glucose metabolism. It discusses various minimal models used to measure parameters of glucose and insulin dynamics, including the intravenous glucose tolerance test (IVGTT) minimal model, oral glucose tolerance test (OGTT) minimal model, and beta-cell responsivity minimal model. It provides examples of applying these models to compare insulin sensitivity, beta-cell function, and other indices between young and elderly subjects. The document also discusses using tracers to validate the models and segregate glucose disposal from production, as well as applications of the models in pathophysiology.
Genome-Scale Metabolic Models and Systems Medicine of Metabolic SyndromeNatal van Riel
workshop on 'The interplay of fat and carbohydrate metabolism with application in Metabolic Syndrome and Type 2 Diabetes', December 12 and 13, 2013, Eindhoven University of Technology
Mathematical modelling of disease progressionyvonne0
This document discusses using computational modeling to analyze the long-term effects of treatments on disease progression in type 2 diabetes. It presents a disease progression model to simulate glucose-insulin homeostasis and the effects of treatments over time. The model is compared to clinical trial data from diabetes patients on different drug therapies. The document also introduces the ADAPT modeling approach, which estimates time-varying parameter trajectories to model phenotype transitions. Applying ADAPT to the disease progression model suggests more dynamic representations of declining beta-cell function and insulin sensitivity compared to the original model.
This document provides an outline for a lecture on lipids and lipoproteins. It begins by defining key terms related to lipids and lipoproteins and describing the different classes of lipids and lipoproteins, including chylomicrons, VLDL, LDL, and HDL. It then discusses apolipoproteins and their functions. The document outlines the laboratory procedures for determining lipid and lipoprotein levels and interpreting the results. It also discusses the significance of lipids and lipoproteins in conditions like atherosclerosis.
This document provides information on various diagnostic tests including a complete blood count, serum electrolytes, liver function tests, lipid profile, blood glucose levels, urine tests, sputum culture, and radiologic procedures. It describes what each test measures, normal ranges, and conditions they can help screen for or diagnose. A complete blood count provides counts and percentages of red blood cells, white blood cells, platelets, and can screen for many disorders. Serum electrolytes commonly measure sodium, potassium, and chloride levels which can be abnormal in cases of fluid imbalance, kidney disease, or other conditions. Liver function tests evaluate liver health through measures of bilirubin and liver enzymes. A lipid profile assesses cholesterol and triglyceride levels
This document provides an overview of a pharmacology lecture on antihyperlipidemic drugs. It discusses the lipid hypothesis, pathophysiology of hyperlipidemia and atherosclerosis, mechanisms of action and side effects of various lipid-lowering drugs, and key topics on lipoproteins, cholesterol transport pathways, and the development of atherosclerosis.
Lipoproteins are complexes of protein and lipids that transport lipids in the bloodstream. There are four main types of lipoproteins: chylomicrons, very low-density lipoproteins (VLDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL). Each type has a specific function in lipid transport and metabolism. Chylomicrons transport dietary lipids from the intestine to other tissues, VLDL transports endogenous lipids from the liver, LDL delivers cholesterol to tissues, and HDL transports cholesterol from tissues back to the liver. The apolipoproteins associated with each lipoprotein complex help determine its structure and function in lipid transport and metabolism.
This document summarizes cholesterol, including its structure, functions, sources, and regulation. Cholesterol is a sterol present in animal tissues and transported in the blood. It has four fused carbon rings with an eight-carbon side chain and performs essential functions like forming cell membranes and acting as a precursor for bile acids, hormones, and vitamin D. Cholesterol comes from both diet and synthesis in the body, mainly the liver and intestine, and high levels can indicate medical conditions like diabetes or familial hypercholesterolemia.
Lipoprotein introduction, their general characteristics, exogenous and endogenous metabolism focusing on chylomicron and vldl metabolism, ldl metabolism and HDL metabolism , reverse cholesterol transport.
Cardiac function tests are used to determine if there has been damage to cardiac tissue by measuring certain enzymes, proteins, lipids, and ratios that are released after a cardiac event. The tests outlined in the document include creatine kinase (CK), CK-MB, lactate dehydrogenase (LDH), aspartate transaminase (AST), cardiac troponins I and T, myoglobin, lipid profile measurements of cholesterol, triglycerides, HDL, LDL, VLDL and their ratios, and apolipoproteins A1 and B. These markers provide information to help diagnose conditions like myocardial infarction, coronary artery disease, and atherosclerosis.
This document discusses lipoproteins, their classification, metabolism, and management guidelines. It defines lipoproteins as biochemical assemblies containing both proteins and lipids that enable fats to be transported in the bloodstream. Lipoproteins are classified based on their density and include chylomicrons, very low density lipoproteins, low density lipoproteins, and high density lipoproteins. Their metabolism involves exogenous and endogenous pathways for transporting triglycerides and cholesterol. The document also identifies four major statin benefit groups for whom statin therapy is recommended to reduce cardiovascular risk based on extensive evidence from clinical trials.
Lipids are insoluble in water, the problem of transportation in the aqueous plasma is solved by associating nonpolar lipids (triacylglycerols and cholesteryl esters) with amphipathic lipids (phospholipids and cholesterol) and proteins to make water-miscible lipoproteins.
Lipoproteins: Structure, classification, metabolism and significanceenamifat
This document discusses lipoproteins and their role in transporting lipids like triglycerides and cholesterol in the body. It describes the different types of lipoproteins, including chylomicrons, VLDL, LDL, and HDL. Chylomicrons transport dietary lipids from the intestine to tissues, while VLDL transports endogenous lipids from the liver. VLDL is converted to LDL as it delivers lipids to tissues. HDL transports cholesterol from tissues back to the liver in a process called reverse cholesterol transport. The document provides details on the composition and metabolism of each lipoprotein class and their role in lipid transport.
lipoproteins transfer lipids such as triacylglycerol, cholestryl ester, fat soluble vitamins in the body. there are 5 categories of lipoproteins which includes chylomicrone, VLDL, IDL, LDL and HDL. LDL-cholesterol is called bad cholestrol while HDL-cholesterol is called good cholesterol.
This document outlines the key points about lipids and lipoproteins that will be covered in the chapter. It defines important terms, classifies lipids and lipoproteins, and describes the roles and properties of chylomicrons, VLDL, LDL, and HDL. It also discusses apolipoproteins and the clinical significance of abnormalities in lipid and lipoprotein metabolism, including their role in atherosclerosis. Laboratory methods for analyzing lipids and lipoproteins are summarized, including quality control procedures. Reference ranges for lipid results are also provided.
1. High-density lipoprotein (HDL) transports cholesterol from tissues like arteries back to the liver, helping to reduce atherosclerosis.
2. HDL has protective effects including inhibiting oxidation, inflammation, and endothelial activation which contribute to atherosclerosis.
3. Lifestyle factors like exercise and diet can help raise HDL levels, while medications like niacin and fibrates are also used to increase HDL.
This document summarizes research on lipoproteins and their role in transporting lipids like cholesterol and triglycerides through the bloodstream. It discusses that lipoproteins are composed of lipids and proteins that form complexes to carry fatty substances. It classifies major lipoproteins like LDL, HDL, and VLDL according to their density and predominant lipids. High LDL and low HDL are risk factors for heart disease as they influence cholesterol levels and plaque buildup in arteries. The document also outlines advantages and disadvantages of cholesterol as well as effects of different fatty acids on serum cholesterol levels.
Lipoproteins are complexes of lipids and proteins that transport hydrophobic lipid molecules in blood plasma. They play key roles in lipid absorption, transport, and reverse cholesterol transport. Lipoproteins are classified based on their density and include chylomicrons, VLDL, LDL, IDL, and HDL. They contain characteristic amounts of triglycerides, cholesterol, phospholipids, and apolipoproteins such as Apo B, Apo E, and differ in size, density, and function. Abnormal lipoprotein metabolism can lead to dyslipidemias and diseases like atherosclerosis.
This document defines and classifies different types of lipoproteins. It discusses lipoproteins' roles in transporting lipids like triglycerides and cholesterol through the bloodstream. The main lipoproteins described are chylomicrons, VLDL, IDL, LDL, and HDL. Chylomicrons and VLDL transport lipids from the intestine and liver to tissues. Their triglycerides are broken down by lipoprotein lipase, forming chylomicron/VLDL remnants taken up by the liver. LDL transports cholesterol to tissues, while HDL transports excess cholesterol from tissues back to the liver in reverse transport.
What are lipoproteins?
Structure of lipoprotein complex.
Classification of lipoproteins.
Important enzyme and protein involved in lipoprotein metabolism.
Apolipoprotein.
Lipoprotein metabolism.
Clinical disorders
Importance of lipoprotein.
Conclusion
Reference.
Fueling AI with Great Data with Airbyte WebinarZilliz
This talk will focus on how to collect data from a variety of sources, leveraging this data for RAG and other GenAI use cases, and finally charting your course to productionalization.
HCL Notes and Domino License Cost Reduction in the World of DLAUpanagenda
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The introduction of DLAU and the CCB & CCX licensing model caused quite a stir in the HCL community. As a Notes and Domino customer, you may have faced challenges with unexpected user counts and license costs. You probably have questions on how this new licensing approach works and how to benefit from it. Most importantly, you likely have budget constraints and want to save money where possible. Don’t worry, we can help with all of this!
We’ll show you how to fix common misconfigurations that cause higher-than-expected user counts, and how to identify accounts which you can deactivate to save money. There are also frequent patterns that can cause unnecessary cost, like using a person document instead of a mail-in for shared mailboxes. We’ll provide examples and solutions for those as well. And naturally we’ll explain the new licensing model.
Join HCL Ambassador Marc Thomas in this webinar with a special guest appearance from Franz Walder. It will give you the tools and know-how to stay on top of what is going on with Domino licensing. You will be able lower your cost through an optimized configuration and keep it low going forward.
These topics will be covered
- Reducing license cost by finding and fixing misconfigurations and superfluous accounts
- How do CCB and CCX licenses really work?
- Understanding the DLAU tool and how to best utilize it
- Tips for common problem areas, like team mailboxes, functional/test users, etc
- Practical examples and best practices to implement right away
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This document provides an outline for a lecture on lipids and lipoproteins. It begins by defining key terms related to lipids and lipoproteins and describing the different classes of lipids and lipoproteins, including chylomicrons, VLDL, LDL, and HDL. It then discusses apolipoproteins and their functions. The document outlines the laboratory procedures for determining lipid and lipoprotein levels and interpreting the results. It also discusses the significance of lipids and lipoproteins in conditions like atherosclerosis.
This document provides information on various diagnostic tests including a complete blood count, serum electrolytes, liver function tests, lipid profile, blood glucose levels, urine tests, sputum culture, and radiologic procedures. It describes what each test measures, normal ranges, and conditions they can help screen for or diagnose. A complete blood count provides counts and percentages of red blood cells, white blood cells, platelets, and can screen for many disorders. Serum electrolytes commonly measure sodium, potassium, and chloride levels which can be abnormal in cases of fluid imbalance, kidney disease, or other conditions. Liver function tests evaluate liver health through measures of bilirubin and liver enzymes. A lipid profile assesses cholesterol and triglyceride levels
This document provides an overview of a pharmacology lecture on antihyperlipidemic drugs. It discusses the lipid hypothesis, pathophysiology of hyperlipidemia and atherosclerosis, mechanisms of action and side effects of various lipid-lowering drugs, and key topics on lipoproteins, cholesterol transport pathways, and the development of atherosclerosis.
Lipoproteins are complexes of protein and lipids that transport lipids in the bloodstream. There are four main types of lipoproteins: chylomicrons, very low-density lipoproteins (VLDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL). Each type has a specific function in lipid transport and metabolism. Chylomicrons transport dietary lipids from the intestine to other tissues, VLDL transports endogenous lipids from the liver, LDL delivers cholesterol to tissues, and HDL transports cholesterol from tissues back to the liver. The apolipoproteins associated with each lipoprotein complex help determine its structure and function in lipid transport and metabolism.
This document summarizes cholesterol, including its structure, functions, sources, and regulation. Cholesterol is a sterol present in animal tissues and transported in the blood. It has four fused carbon rings with an eight-carbon side chain and performs essential functions like forming cell membranes and acting as a precursor for bile acids, hormones, and vitamin D. Cholesterol comes from both diet and synthesis in the body, mainly the liver and intestine, and high levels can indicate medical conditions like diabetes or familial hypercholesterolemia.
Lipoprotein introduction, their general characteristics, exogenous and endogenous metabolism focusing on chylomicron and vldl metabolism, ldl metabolism and HDL metabolism , reverse cholesterol transport.
Cardiac function tests are used to determine if there has been damage to cardiac tissue by measuring certain enzymes, proteins, lipids, and ratios that are released after a cardiac event. The tests outlined in the document include creatine kinase (CK), CK-MB, lactate dehydrogenase (LDH), aspartate transaminase (AST), cardiac troponins I and T, myoglobin, lipid profile measurements of cholesterol, triglycerides, HDL, LDL, VLDL and their ratios, and apolipoproteins A1 and B. These markers provide information to help diagnose conditions like myocardial infarction, coronary artery disease, and atherosclerosis.
This document discusses lipoproteins, their classification, metabolism, and management guidelines. It defines lipoproteins as biochemical assemblies containing both proteins and lipids that enable fats to be transported in the bloodstream. Lipoproteins are classified based on their density and include chylomicrons, very low density lipoproteins, low density lipoproteins, and high density lipoproteins. Their metabolism involves exogenous and endogenous pathways for transporting triglycerides and cholesterol. The document also identifies four major statin benefit groups for whom statin therapy is recommended to reduce cardiovascular risk based on extensive evidence from clinical trials.
Lipids are insoluble in water, the problem of transportation in the aqueous plasma is solved by associating nonpolar lipids (triacylglycerols and cholesteryl esters) with amphipathic lipids (phospholipids and cholesterol) and proteins to make water-miscible lipoproteins.
Lipoproteins: Structure, classification, metabolism and significanceenamifat
This document discusses lipoproteins and their role in transporting lipids like triglycerides and cholesterol in the body. It describes the different types of lipoproteins, including chylomicrons, VLDL, LDL, and HDL. Chylomicrons transport dietary lipids from the intestine to tissues, while VLDL transports endogenous lipids from the liver. VLDL is converted to LDL as it delivers lipids to tissues. HDL transports cholesterol from tissues back to the liver in a process called reverse cholesterol transport. The document provides details on the composition and metabolism of each lipoprotein class and their role in lipid transport.
lipoproteins transfer lipids such as triacylglycerol, cholestryl ester, fat soluble vitamins in the body. there are 5 categories of lipoproteins which includes chylomicrone, VLDL, IDL, LDL and HDL. LDL-cholesterol is called bad cholestrol while HDL-cholesterol is called good cholesterol.
This document outlines the key points about lipids and lipoproteins that will be covered in the chapter. It defines important terms, classifies lipids and lipoproteins, and describes the roles and properties of chylomicrons, VLDL, LDL, and HDL. It also discusses apolipoproteins and the clinical significance of abnormalities in lipid and lipoprotein metabolism, including their role in atherosclerosis. Laboratory methods for analyzing lipids and lipoproteins are summarized, including quality control procedures. Reference ranges for lipid results are also provided.
1. High-density lipoprotein (HDL) transports cholesterol from tissues like arteries back to the liver, helping to reduce atherosclerosis.
2. HDL has protective effects including inhibiting oxidation, inflammation, and endothelial activation which contribute to atherosclerosis.
3. Lifestyle factors like exercise and diet can help raise HDL levels, while medications like niacin and fibrates are also used to increase HDL.
This document summarizes research on lipoproteins and their role in transporting lipids like cholesterol and triglycerides through the bloodstream. It discusses that lipoproteins are composed of lipids and proteins that form complexes to carry fatty substances. It classifies major lipoproteins like LDL, HDL, and VLDL according to their density and predominant lipids. High LDL and low HDL are risk factors for heart disease as they influence cholesterol levels and plaque buildup in arteries. The document also outlines advantages and disadvantages of cholesterol as well as effects of different fatty acids on serum cholesterol levels.
Lipoproteins are complexes of lipids and proteins that transport hydrophobic lipid molecules in blood plasma. They play key roles in lipid absorption, transport, and reverse cholesterol transport. Lipoproteins are classified based on their density and include chylomicrons, VLDL, LDL, IDL, and HDL. They contain characteristic amounts of triglycerides, cholesterol, phospholipids, and apolipoproteins such as Apo B, Apo E, and differ in size, density, and function. Abnormal lipoprotein metabolism can lead to dyslipidemias and diseases like atherosclerosis.
This document defines and classifies different types of lipoproteins. It discusses lipoproteins' roles in transporting lipids like triglycerides and cholesterol through the bloodstream. The main lipoproteins described are chylomicrons, VLDL, IDL, LDL, and HDL. Chylomicrons and VLDL transport lipids from the intestine and liver to tissues. Their triglycerides are broken down by lipoprotein lipase, forming chylomicron/VLDL remnants taken up by the liver. LDL transports cholesterol to tissues, while HDL transports excess cholesterol from tissues back to the liver in reverse transport.
What are lipoproteins?
Structure of lipoprotein complex.
Classification of lipoproteins.
Important enzyme and protein involved in lipoprotein metabolism.
Apolipoprotein.
Lipoprotein metabolism.
Clinical disorders
Importance of lipoprotein.
Conclusion
Reference.
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10. Cholesterol and heart disease
From: Keith Frayn, “Metabolic Regulation - A Human Perspective”.
Wiley-Blackwell, Third Edition, 2010
11. Stable isotope studies: lipoprotein classes
correspond to kinetically different pools
Multicompartmental model for apoB
metabolism in VLDL1 (Sf 60400), VLDL2 (Sf 20-60), IDL (Sf 1220), and LDL (Sf 0-12).
Tracer data time range 0-250h !!!
Gaw A et al. 1996 Arterioscler Thromb Vasc Biol 16:236-249
12. Our vision …
LPD kinetic model
development
Model-based LPD analysis
Lipoprotein flux ratio
biomarkers
13. Advantage of our concept
From one single plasma measurement to rates of processes
Process rates are closer to functional activity than concentrations!
better resolution to pick up risk-associated variation in lipoprotein
metabolism ?
New cardiovascular risk markers?
New diagnostic?
Otherwise, determination of process rates is only possible with costly
stable-isotope studies
15. Background of model
Model
development
=> Particle size-dependent rate constants => fluxes of different lipoprotein
processes:
-
Hepatic production
Peripheral lipolysis
Liver attachment (ApoE- and ApoB-mediated)
Hepatic uptake (annihilation of particle)
Hepatic lipolysis
Applied to each e.g. 0.1 nm subclass in the range 100 – 10 nm
17. Lipolysis cascades - 2
The ApoB LPD size range is divided into 11 cascade
fractions
Each cascade has e.g. 1000 particle subfractions
(pools).
Model
development
Each subsequent cascade has smaller size ranges of
itself and of all its subfractions
Each lipolysis step transfers particles from a given
cascade to the next cascade
The other processes can add or remove particles
from each cascade
For every subfraction a particle mass
balance is set up
The computer solves the 11000 mass
balances for steady state simultaneously
The result is a simulated LPD whose
appearance depends on the process
parameter settings
The simulated LPD is compared to a
measured LPD
A parameter optimization algorithm
searches the best parameter settings
18. Lipolysis steps - decreasing particle size
apoB apoE
uptake uptake
HL - lipolysis
LPL - lipolysis
Production
Liver attachment
Model
development
19. Lipoprotein production process model
Production flux (particles / min)
Model
development
VLDL1
VLDL2
IDL
Lipoprotein diameter (nm)
LDL
20. Lipolysis and uptake process models (single particle rates)
0.02
process rate (1 / min)
Model
development
Each subfraction particle P flux component F is modeled as F =
k(r).P with k(r) explicitly depending on particle subfraction
diameter according to a 1- or 2- paramer function
liver attachment
extrahep. lipolysis
uptake
hepatic lipolysis
0.015
0.01
0.005
0
100
80
60
40
lipoprotein diameter (nm)
20
21. Flux Data for model testing
Packard et al. 2000, human study
Model validation
stable isotope fluxes analyzed with multi-compartment model
Three groups of subjects, healthy men
Large LDL peak size (>26 nm)
Intermediate LDL peak size (25 – 26 nm)
Small LDL peak size (<25 nm) – risk group
Data on flux of lipoproteins input to our model.
22. Example output (main classes) compared
to stable isotope study
Particle Pools
Uptake Flux
0.2
400
number of particles fl-1 min-1
Simulated
Data
300
200
100
0
LDL
Simulated
Data
0.15
0.1
0.05
0
IDL
VLDL2 VLDL1
lipoprotein class
Lipolysis-Induced Influx
IDL
VLDL2 VLDL1
lipoprotein class
Fitted Lipolysis and Uptake Rates
Simulated
Data
0.1
0.05
0
LDL
0.025
0.15
process rate min-1
N.B. The LPD is
simulated as
particle
concentration
profiles. These
can be converted
to TG and
cholesterol
concentration
profiles
number of particles fl-1 min-1
Model validation
number of particles fl-1
500
LDL
IDL
VLDL2
lipoprotein class
0.02
Lipolysis rate
Uptake rate
0.015
0.01
0.005
0
10
20
30
40
50
lipoprotein particle size
60
23. Flux Data for model testing
4 results that give credibility to our model
Model validation
Model can reproduce particle concentration & flux data
The model qualitatively reproduces a separately measured
LDL peak size shift
The model can simulate genetic deficiencies
The changed processes the model detected
are biologically plausible
Journal of Lipid Research, Vol. 50, 2398-2411,
December 2009
25. What are we doing?
Derive
model-based
markers
Derive ratios between processes
For instance:
VLDL lipolysis outside the liver / VLDL production
See whether that helps to improve Risk prediction
Better risk prediction will help to give
the right therapy to the right people
28. Reclassification analysis
You have three risk categories
Validate markers
People are treated based on their category
Low risk – no treatment
Medium risk – some treatment
High risk – intensive treatment
Reclassification analysis compares diagnostics
for their classification ability
For those people whom we know will NOT have an event
How many move to lower risk categories?
For those people whom we know WILL have an event
How many move to higher risk categories?
29. Validation CVD risk prediction
The Framingham Heart Study Offspring cohort (FOS)
Validate markers
Inclusion criteria:
no history of cardiovascular disease
gave written informed consent for general research use
had complete NMR lipoprotein profiles recorded
had a complete record of classical cardiovascular risk factors.
Cardiovascular events 10 years after baseline measurement
Population size
Events (true positives)
No event (true negatives)
1981
145
1836
31. Best predicting ratios
Validate markers
In the VLDL size range
VLDLH – VLDL Hepatic turnover indicator
Liver
functional status indicator
VLDLE – VLDL Extrahepatic lipolysis indicator
How well do extrahepatic tissues absorb fat?
32. Predictor variables
Conventional
markers
LDLp
LDLp + HDLp
LDLp + HDLp +
VLDLE + VLDLH
Age
Age
Age
Age
Age
Sex
Sex
Sex
Sex
Sex
Cigarettes per
day
Cigarettes per
day
Cigarettes per
day
Cigarettes per
day
Cigarettes per day
Blood pressure
medication
Blood pressure
medication
Blood pressure
medication
Blood pressure
medication
Blood pressure medication
Systolic blood
pressure
(nurse)
Systolic blood
pressure
(nurse)
Systolic blood
pressure
(nurse)
Systolic blood
pressure
(nurse)
Systolic blood pressure (nurse)
Glucose
Glucose
Glucose
Glucose
Glucose
Total
Cholesterol
Validate markers
Conventional
markers
without
cholesterol
LDL particle
number
LDL particle
number
LDL particle number
HDL particle
number
HDL particle number
HDL
cholesterol
VLDL Extrahepatic lipolysis
indicator
32
VLDL Hepatic turnover
indicator
33. Area under the ROC-curve statistics for general CVD
Validate markers
Framingham Offspring Study
* Significantly better than conventional, no cholesterol p<0.05
** Significantly better than LDLp, p<0.05
† Significantly better than LDLp+HDLp, p<0.05
Model
AUC
SE
AUC improvement
from random
% incremental AUC
improvement from random
Conventional, no cholesterol
0.759
0.0204
0.259
0.0
Conventional
0.795
0.0193
0.295 (*)
12.2
LDLp
0.791
0.0192
0.291 (*)
11.0
LDLp + HDLp
0.797
0.0192
0.297 (*)
12.8
LDLp + HDLp +
VLDLE + VLDLH
0.812
0.0192
0.312 (*,**, †)
17.0
35. What is happening? An ‘average’ person.
A - no blood pressure medication
Validate markers
B - no blood pressure medication
0.35
male
female
0.25
10 year risk
10 year risk
0.3
0.4
0.2
0.15
0.1
male, low-med LDLp
female, low-med LDLp
male, med-high LDLp
female, med-high LDLp
0.3
0.2
0.1
0.05
0
50
100
150
200
250
0
300
0
20
40
LDLp
C - with blood pressure medication
100
0.25
male
female
male
female
0.2
10 year risk
0.8
10 year risk
80
D - no blood pressure medication
1
0.6
0.4
0.2
0
-14
60
HDLp
0.15
0.1
0.05
-12
-10
-8
-6
VLDLE
-4
-2
0
0
-6
-5
-4
-3
VLDLH
-2
-1
36. Conclusions
Lipoprotein metabolic ratios derived from Particle Profiler
significantly improve CVD risk prediction
As measured by area-under-the-ROC-curve
4% of the total population is positively reclassified by these markers
In Framingham Offspring Cohort
If we assume Framingham is a good representation of the US
population (it is not, it is generally healthier) then:
Given that approx. 32 million people in the US use statins,
this could help more than 1 million people improve their treatment
regime in the US alone.
“
“
37. But…
Clinicians & customers require an independent validation.
Different cohort e.g. MESA (Multi Ethnic Study of Atherosclerosis)
data would be needed
MESA has slightly different data type (e.g. “Diabetes Y/N” instead of
“plasma glucose”)
Simulating this different data type in Framingham did not result in
better risk prediction using Particle Profiler- derived flux ratio markers
MESA was not analyzed and the project was stopped by TNO
(we might have considered EPIC, but didn’t)
38. Lessons learned
SVM and binary variables – take care!
Introducing new diagnostics in the current clinical setting
is a all-or-nothing business.
Nothing is certain until the last statistical analyses come in,
the final success is highly unpredictable.
Because this is a high-risk enterprise, companies do not easily invest
in early development stages, but are willing to collaborate with data
sharing etc.
39. Towards linking carbohydrate and fat metabolism
Lipoprotein metabolism as a central node for interplay of
glucose, TG and NEFA metabolism
VLDL
Prod
Chylo
microns
-
VLDL
LDL
glucose
41. Collaborators
TNO
Daan van Schalkwijk
Evgeni Tsivtsivadze
Bianca van der Werff
Ben van Ommen
Albert de Graaf
(Andreas Freidig)
LACDR
Jan van der Greef
TUFTS university Boston
Laurence D. Parnell
José M. Ordovás
Financial support
The official Framingham
investigators were not involved in
the analysis nor commented on
the conclusions drawn