The Reference Model
for Disease Progression
uses MIST to find data fitness
Jacob Barhak
Austin, Texas
http://sites.google....
Jacob Barhak
Disease Modeling - The Very Basics
• Disease models:
– Describe phenomena observed in past trials
– Attempt t...
Jacob Barhak
The Reference Model
• Built from literature references and hence the name: The Reference Model
• Designed to ...
Jacob Barhak
How Does it Work?
• Loop through Risk Equation/Hypothesis combinations
• Loop through populations
• Calculate...
Jacob Barhak
MIST Basics
• MIST stands for MIcro-Simulation Tool
– In a nutshell it is a Monte-Carlo simulation compiler
–...
Jacob Barhak
MIST Uses Computing Power
Here is Proof!
Fried after two year of
extensive use
Jacob Barhak
MIST Runs Over the Cloud!
Anaconda drives MIST to run over the Amazon cloud!
• Batch mode MIST utilities allo...
Jacob Barhak
Populations: Background
• The First Table in a Clinical Trial publication typically
contains Population Stati...
Jacob Barhak
INSPYRED MIST
• INSPYRED MIST can regenerate mock populations
from Table 1 in clinical trials
• Only publicly...
Jacob Barhak
MIST uses INSPYRED
• Bio Inspired computation Python library
– Evolutionary Computation
– Swarm Intelligence
...
Jacob Barhak
MIST
INSPYRED
INSPYRED Evolutionary Computation:
Population Generation & Objectives
• Generation Expressions:...
Jacob Barhak
INSPYRED Evolutionary Computation
Generator
Evaluator 3.1 7.5 4.2 5.2
Selector
Crossover Mutation
Variators
C...
Jacob Barhak
Population Generation Example
Skewed by Inclusion/Exclusion
• Generate 10 people with:
– Inclusion criteria i...
Jacob Barhak
Population Generation Example
With Objectives & INSPYRED
• Generate 10 people with objectives:
– Base distrib...
Jacob Barhak
The Reference Model Fitness Matrix
Method_A1c 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0...
Jacob Barhak
This Modeling Technology Opens
Possibilities
• The Reference Model for Disease Progression
– Participating in...
Jacob Barhak
Acknowledgments
• Deanna J.M. Isaman - who is the spirit behind the great ideas. She taught me my first steps...
Jacob Barhak
Questions?
MIST Jacob Barhak
https://github.com/Jacob-Barhak/MIST http://sites.google.com/site/jacobbarhak/
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The reference model for disease progression uses MIST to find data fitness by Jacob Barhak PyData SV 2014

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The Reference Model for Disease progression [1,2] is a league of disease models that compete amongst themselves to fit existing clinical trial results. Clinical Trial results are widely available publicly at the summary level. Disease models are typically extracted from a single trial and therefore may not generalize well to all populations. The Reference Model determines the fitness of multiple disease models for multiple populations and helps deduce better fitting scenarios. This is done using High Performance Computing (HPC) techniques that support Monte Carlo simulation at the Micro individual level. The MIcro Simulation Tool (MIST) [3,4] facilitates running those simulations in HPC environment using Sun Grid Engine (SGE) [5]. MIST can even run over the cloud using StarCluster [6] and an anaconda AMI [7]. Note, however, the public published data is summary data while simulations are conducted at the individual level. The individual population is reconstructed from summary data using the MIST Domain Specific Language (DSL) and is optimized using evolutionary computation using Inspyred [8]. This allows creating populations that conform to the clinical trial summary statistics and allow incorporating trial inclusion and exclusion criteria as well as cope with skewed population distributions. The Reference Model allows exploring new assumptions and hypothesis about disease progression and determines their fitness to existing population/model data. These virtual trials consider much more information than a single trial, using already available and public data. Links to relevant own publications: [1] The Reference Model video: http://youtu.be/7qxPSgINaD8 [2] The Reference Model short description: http://healtheconblog.com/2014/03/04/the-reference-model-for-disease-progression/ [3] MIST video presentation: http://www.youtube.com/watch?v=AD896WakR94 [4] MIST github repository: https://github.com/Jacob-Barhak/MIST Links to external free software tools relevant to this work: [5] SGE: http://gridengine.org/blog/ [6] INSPYRED github repository: https://github.com/inspyred/inspyred [7] StarCluster home page: http://star.mit.edu/cluster/ [8] B. Zaitlen, StarCluster Anaconda. Online: http://continuum.io/blog/starcluster-anaconda

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The reference model for disease progression uses MIST to find data fitness by Jacob Barhak PyData SV 2014

  1. 1. The Reference Model for Disease Progression uses MIST to find data fitness Jacob Barhak Austin, Texas http://sites.google.com/site/jacobbarhak/ PyData Silicon Valley 2014 Facebook Headquarters Menlo Park, CA 03 May 2014
  2. 2. Jacob Barhak Disease Modeling - The Very Basics • Disease models: – Describe phenomena observed in past trials – Attempt to predict future disease progression – Used to predict Costs / Quality of Life • Typically developed from a certain population • Current efforts attempt to generalize those models
  3. 3. Jacob Barhak The Reference Model • Built from literature references and hence the name: The Reference Model • Designed to serve as a reference for new equations and populations • A League / Consumers Report for disease models • Current version deals with diabetic populations MINo CHD Survive MI CHD Death StrokeNo Stroke Survive Stroke Stroke Death Alive Other Death Death Process CHD Process Stroke Process Competing Mortality
  4. 4. Jacob Barhak How Does it Work? • Loop through Risk Equation/Hypothesis combinations • Loop through populations • Calculate fitness of simulation outcomes to observed phenomena MINo CHD Survive MI CHD Death StrokeNo Stroke Survive Stroke Stroke Death Alive Other Death Death Process CHD Process Stroke Process Competing Mortality 1 2 34 1 2 34 Pop 3 Pop 2 Pop 1 Eq 1 1 1 1 1 … Eq 2 1 2 3 4 … Pop 1 4 6 2 1 … Pop 2 2 4 6 1 … Pop 3 2 3 9 2 … … … … … … … Fitness Matrix
  5. 5. Jacob Barhak MIST Basics • MIST stands for MIcro-Simulation Tool – In a nutshell it is a Monte-Carlo simulation compiler – Offers a Domain Specific Language – Reproducible simulations • MIST Supports Population Generation – Generating functions – Optimization towards objectives – Evolutionary computation with INSPYRED • MIST runs over the cloud! – And on Sun Grid Engine (SGE) clusters
  6. 6. Jacob Barhak MIST Uses Computing Power Here is Proof! Fried after two year of extensive use
  7. 7. Jacob Barhak MIST Runs Over the Cloud! Anaconda drives MIST to run over the Amazon cloud! • Batch mode MIST utilities allow: – Submitting jobs to Sun Grid Engine (SGE) – Running simulations – Generating reports – Combining reports from multiple repetitions/scenarios • Star Cluster creates an SGE cluster on the Amazon Elastic Compute Cloud • The Anaconda Amazon Machine Image (AMI) is used for the cluster master / nodes • Good for: – Cutting down computation time by renting computing power – Saving initial and maintenance costs associated with a cluster MIST Cloud
  8. 8. Jacob Barhak Populations: Background • The First Table in a Clinical Trial publication typically contains Population Statistics – Summary Data Only: Mean (SD) / Median (IQR) – Limited information about distribution – Inclusion/exclusion criteria skew the distribution – Example: Excerpt from Table 1 in UKPDS 33 Control Intervention Age 53.3 (8.6) 53.2 (8.6) % Male 61.9% 59.3% Smoke 31% 30% Systolic Blood Pressure (mmHg) 135(20) 135(20) Total Cholesterol (mmol/L) 5.4 (1.02) 5.4(1.12)
  9. 9. Jacob Barhak INSPYRED MIST • INSPYRED MIST can regenerate mock populations from Table 1 in clinical trials • Only publicly available summary data is used • No need to have access to restricted data MIST INSPYRED Table 1 Generate
  10. 10. Jacob Barhak MIST uses INSPYRED • Bio Inspired computation Python library – Evolutionary Computation – Swarm Intelligence – Neural Networks • Developed and Maintained by Aaron Garrett • Repository: https://github.com/inspyred/inspyred
  11. 11. Jacob Barhak MIST INSPYRED INSPYRED Evolutionary Computation: Population Generation & Objectives • Generation Expressions: – Define how to generate a single individual – Test if individual fits the inclusion/exclusion criteria – Define ties and correlations between characteristics • Objectives: – Define aggregate targets for the entire population – Reduce random generation error – Handle skewed distributions to fit target Expression Compiler Evolutionary Computation Monte Carlo ResultSelection Result Population Converges to Objectives
  12. 12. Jacob Barhak INSPYRED Evolutionary Computation Generator Evaluator 3.1 7.5 4.2 5.2 Selector Crossover Mutation Variators Candidates Parents + = → Repeat Terminator Best Solution Generations/Epocs
  13. 13. Jacob Barhak Population Generation Example Skewed by Inclusion/Exclusion • Generate 10 people with: – Inclusion criteria is 45< Age <90 – The base population distribution is: • Age for Male: Mean 53 SD 10 • Age for Female: Mean 52 SD 7 • Male: 50% • Generation Functions (Implementation): Age ~ Iif (Male,Gaussian(53,10) ,Gaussian(52,7)) Male ~ Bernoulli(0.5) Assert = And(Gr(Age,45),Ls(Age,90)) • Notes: – May not represent well what was intended – Assertion drops non qualifying candidates – The resulting Age is skewed Age Male 48.85785535 0 59.94741744 0 56.19039096 1 64.40825341 0 49.77582796 1 60.29975596 1 51.27571792 1 72.13820388 1 55.51746037 0 58.72574003 0 Final population that would have been reported in Table 1: Age Mean: 57.71366233 Age SD: 7.115024093 Male Mean: 0.5 Result to be Published Design is Subject to Constraints
  14. 14. Jacob Barhak Population Generation Example With Objectives & INSPYRED • Generate 10 people with objectives: – Base distribution & Inclusion criteria as before – Age : Mean 50, SD 5 – Male: 60% • Objectives (Implementation): Age Mean: 50 , Weight 1 Age SD: 5 , Weight 1 Male: 0.6 , Weight 10 • Notes: – Design matches results as much as possible – The designer can study effect of constraints – Table 1 can now be planned ahead! Age Male 50.8953429 0 53.71135174 1 52.86278825 0 46.021901 1 48.36662032 1 47.87355499 1 45.11370607 1 62.15347882 1 47.48350736 0 45.93131347 0 Final population selected out of 1000 generated candidates: Age Mean: 50.04135649 Age SD: 5.166548964 Male Mean: 0.6 Design = Desired + Constraints Result to be Published
  15. 15. Jacob Barhak The Reference Model Fitness Matrix Method_A1c 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Method_BMI 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Method_BP 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Method_Lipids 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Method_Smoke 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Method_MI 1 1 1 1 1 1 1 1 2 2 2 2 2 3 3 3 3 3 3 3 4 4 4 4 4 4 4 4 5 5 5 5 5 6 6 6 6 6 6 6 7 7 7 7 7 8 8 8 8 8 1 1 1 1 1 1 1 1 2 2 2 2 2 3 3 3 3 3 3 3 4 4 4 4 4 4 4 4 5 5 5 5 5 6 6 6 6 6 6 6 7 7 7 7 7 8 8 8 8 8 Method_Stroke 1 2 3 4 5 6 7 8 1 2 3 4 6 1 2 3 4 5 7 8 1 2 3 4 5 6 7 8 1 3 4 5 6 1 2 4 5 6 7 8 1 3 4 6 7 1 3 4 6 8 1 2 3 4 5 6 7 8 1 2 3 4 6 1 2 3 4 5 7 8 1 2 3 4 5 6 7 8 1 3 4 5 6 1 2 4 5 6 7 8 1 3 4 6 7 1 3 4 6 8 Method_DeathCHD 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Method_DeathStroke 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Method_TimeImprove -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 FITNESS: LOW SCORE = GOOD FITNESS UKPDS33 Conventional 13.845 20.743 15.914 21.72 25.441 25.36 28.089 18.589 14.877 20.577 14.15 22.322 26.799 29.021 32.342 18.513 28.939 28.647 34.265 42.527 19.646 24.438 25.212 32.941 29.175 23.545 23.493 37.46 30.928 35.489 26.746 31.944 44.571 37.471 44.368 38.836 39.246 37.899 48.124 42.4 8.7074 19.295 22.161 15.355 13.49 21.597 27.906 28.312 32.555 36.855 18.076 16.406 19.626 23.232 16.078 22.236 12.856 32.593 21.405 21.905 20.199 18.307 21.999 31.123 33.52353 35.19492 30.07539 40.29552 26.23041 38.48692 22.66249 22.58756 19.19884 34.47119 34.58814 37.09544 29.17024 35.44334 26.99075 13.22095 32.83443 34.01337 33.75026 42.34086 41.60634 46.24915 38.83031 40.82201 45.0277 40.20789 17.25467 18.23899 13.5631 21.80644 18.25077 33.22091 27.01441 27.52192 24.4146 26.18002 UKPDS33 Intensive 9.9209 11.567 8.9666 7.3778 22.481 16.845 13.75 20.252 21.469 5.9306 18.021 8.3755 13.62 25.523 13.279 21.563 16.842 25.693 29.859 27.102 48.374 53.194 46.236 49.011 43.378 30.947 39.597 45.211 22.309 22.092 28.781 24.337 32.361 33.461 35.164 30.958 33.267 29.412 30.243 29.072 14.004 18.4 5.882 15.535 11.593 13.378 19.551 16.665 23.987 23.567 11.089 6.6215 11.106 10.896 18.277 12.87 16.757 19.121 16.311 10.836 14.716 12.052 8.723 22.66 22.18713 22.81032 23.29195 17.52691 19.83347 19.68946 36.78836 48.66079 44.88712 46.76087 40.41662 46.68597 46.10053 42.76746 18.27661 27.01638 18.27117 20.07734 23.78032 31.59603 29.50407 26.57366 35.80162 29.12223 31.625 41.31305 7.454333 16.49486 10.37217 20.75803 10.40375 20.34087 19.93435 14.67622 15.87331 25.40965 UKPDS33 Full 13.801 17.379 20.605 13.518 21.071 15.365 15.861 22.986 30.024 21.303 21.534 14.49 21.363 26.102 15.306 19.029 28.894 34.46 29.271 28.788 28.99 39.663 24.09 43.844 36.598 49.925 45.689 43.035 25.162 22.559 26.797 28.137 33.903 35.026 36.421 34.474 36.6 32.841 36.58 36.107 12.334 10.827 10.081 15.849 15.338 22.875 20.415 27.372 35.901 30.882 19.788 18.288 22.66 16.893 23.216 12.458 11.861 24.485 14.27 8.7388 14.332 16.798 14.124 20.251 19.20442 15.91239 25.02071 27.55646 28.15635 27.43958 33.53995 46.68913 32.88769 40.90189 47.05068 30.89849 39.74441 41.77824 19.99875 21.32849 27.91905 34.23523 30.27157 37.70196 37.64045 30.13108 38.18436 35.20906 32.40403 44.60335 13.89977 14.31121 9.882864 9.315511 15.0712 17.62772 16.87899 21.94292 25.44539 33.54797 ASPEN All Placebo 18.728 14.958 19.71 6.8007 19.742 15.033 8.544 17.059 25.169 16.271 23.617 19.767 22.55 19.352 20.791 14.612 11.214 21.777 23.071 20.463 34.627 18.412 16.748 20.803 27.523 15.898 19.812 25.947 11.336 13.5 11.853 10.794 12.942 8.6603 9.9121 11.478 17.734 11.895 8.2614 16.039 17.958 19.666 20.408 27.618 22.028 16.583 15.851 9.0277 13.647 17.479 15.443 14.916 13.388 11.597 18.848 20.67 18.615 19.526 15.305 13.73 14.807 15.264 16.837 15.78 9.987492 11.67262 19.94367 18.01388 14.74788 24.5 25.71964 24.5255 22.07374 25.64664 26.33913 21.13646 22.61637 27.3633 8.930286 14.77329 15.17399 13.87444 19.9374 12.41974 15.04992 13.17194 13.00961 16.9632 11.68332 16.7556 16.36307 15.40292 20.2608 14.75635 21.87464 9.785193 14.18626 14.45683 15.34601 14.45683 ASPEN All Atorvastatin 18.276 25.426 23.717 19.033 41.707 30.533 24.515 25.03 23.606 30.004 21.989 24.094 25.758 25.681 20.827 23.345 19.824 28.64 20.821 18.255 27.263 32.152 28.134 31 44.931 38.22 33.534 33.756 16.225 20.18 10.025 17.769 21.817 16.47 16.837 18.987 19.429 15.141 15.74 21.743 26.707 24.804 23.329 27.322 24.31 15.322 17.168 21.196 21.668 18.426 15.732 16.078 23.098 12.155 17.861 17.044 17.139 18.788 12.278 17.671 21.668 15.708 18.782 15.922 15.94522 18.46619 11.0227 10.79352 13.50926 21.17782 23.97916 25.68073 24.25387 25.89401 26.65521 19.27434 26.07202 21.0891 16.77796 11.7686 9.246621 13.81123 13.36039 10.12423 14.36141 13.38843 9.759611 15.37856 17.0147 12.10372 12.82576 17.29884 16.31717 17.38534 28.28869 12.4298 9.578622 13.87444 14.02676 19.48076 ASPEN Primary Placebo 28.262 21.829 13.379 23.351 17.168 21.477 15.969 23.452 24.723 22.023 34.673 17.93 24.026 21.136 18.574 19.222 17.678 22.051 18.534 25.952 35.071 32.734 40.109 37.809 26.429 37.928 37.37 33.604 19.602 16.568 15.256 22.187 18.828 16.132 11.958 11.64 21.207 18.628 14.891 18.007 34.471 23.318 23.377 25.48 30.976 15.508 18.615 22.544 21.937 24.688 24.97 23.817 15.313 30.36 26.311 26.566 27.902 23.843 32.222 30.716 35.882 29.069 28.627 21.184 20.57304 17.03673 13.02881 17.05872 22.16416 22.78706 30.42614 33.45893 37.35974 36.4863 34.18333 39.83403 31.51587 28.46928 18.06239 15.19046 16.89675 18.01388 21.80023 20.5548 14.73092 14.79865 15.59647 14.05347 12.09339 15.10794 17.60682 22.43881 27.04626 33.84893 26.1247 19.65324 29.71952 14.07125 21.36586 26.73013 ASPEN Primary Atorvastatin 25.055 19.761 31.619 25.065 27.051 30.927 25.788 27.249 28.723 18.561 20.676 24.31 30.471 18.069 18.049 20.056 28.557 19.526 26.201 21.886 36.946 30.615 24.885 35.658 48.047 35.054 40.611 34.623 27.937 20.255 18.514 18.419 19.634 15.867 15.289 14.95 20.457 12.39 13.124 23.659 25.323 22.045 23.728 37.977 31.405 17.428 19.786 17.578 19.039 30.765 13.36 16.666 14.44 13.62 19.532 14.824 21.743 18.574 19.118 15.182 21.943 18.152 16.279 24.218 16.57558 10.12423 19.51922 16.5 20.21757 17.95828 20.70024 33.74167 35.26684 20.6942 18.8016 25.83602 27.17996 20.76656 13.41641 17.61391 15.70828 23.77499 15.24795 9.656604 15.01666 14.48275 19.66596 15.83509 14.5 14.13329 25.03498 19.98124 28.95255 10.98863 28.79236 14.62019 12.57975 18.73499 17.47856 19.43579 ASPEN Secondary Placebo 36.435 21.628 18.987 18.392 21.407 32.384 16.332 25.402 22.738 19.856 22.858 28.539 28.465 21.645 11.247 16.477 25.564 22.433 15.564 23.617 21.389 17.464 18.748 18.432 20.39 31.788 15.867 26.944 39.291 30.307 30.042 28.883 38.347 20.218 21.737 20.609 17.464 29.125 19.416 18.534 26.725 20.603 22.282 29.908 17.241 31.678 31.643 24.031 27.785 33.249 23.796 21.29 21.972 17.923 21.142 31.377 24.587 21.869 28.627 20.062 18.708 21.72 31.639 20.694 19.94367 18.05547 16.66583 22.67157 14.57738 30.21589 15.53222 17.21191 15.90597 19.05256 25.87953 34.0551 18.50676 22.54994 33.84524 37.10795 29.87892 25.87953 37.3497 21.03568 23.29163 19.39716 25.224 33.58943 20.70628 16.80774 21.37756 23.64847 19.8809 28.90069 14.55163 21.48837 31.72932 24.38237 32.85575 23.25403 ASPEN Secondary Atorvastatin 20.292 24.845 24.89 22.444 16.023 20.421 19.261 20.261 18.358 15.508 12.227 12.669 27.595 34.18 24.91 29.466 45.044 36.159 26.472 32.427 25.164 17.132 25.676 23.838 28.718 36.565 21.296 25.632 14.37 17.4 12.99 21.731 32.5 14.124 6.9821 20.555 23.2 24.094 13.509 16.823 24.955 19.384 26.847 29.026 23.011 16.263 21.628 14.23 28.262 21.703 21.178 7.9057 15.108 13.955 16.837 22.622 7.7298 19.609 9.6437 10.283 15.411 15.652 25.431 24.31 19.36492 41.91658 30.02499 24.64244 10.97725 27.66315 9.513149 9.013878 17.57128 14.7394 11.09054 27.79838 12.90349 16.46967 16.74067 14.00893 10.06231 24.5204 28.11583 17.0147 7.5 15.47579 15.67642 19.48076 7.36546 27.43173 11.86381 19.38427 23.33452 25.01 16.62077 11.80042 10.87428 15.52417 34.49275 17.30607 ASPEN Full 15.186 6.4129 10.302 12.966 14.427 13.053 8.8388 18.224 16.458 12.384 22.575 9.3608 16.602 17.281 7.673 9.6631 9.1173 21.439 18.698 16.051 23.883 19.586 13.505 13.148 19.548 24.599 24.731 18.183 13.233 13.091 5.534 16.617 17.752 14.921 14.392 5.2321 9.5851 19.439 8.3141 17.871 15.285 14.366 13.346 15.012 25.615 14.031 10.398 6.093 7.5416 12.821 9.9058 14.659 17.084 14.987 18.169 12.545 21.251 20.625 8.0545 16.9 16.96 10.788 15.776 16.237 7.945124 8.696264 9.829802 13.41175 16.15163 11.09617 18.944 25.09233 20.6791 23.74605 23.577 12.83063 22.48611 17.36016 9.931012 11.77391 7.27152 18.07968 14.44386 7.721723 9.387492 11.69936 11.12991 12.46495 9.585145 18.27909 17.11359 6.661456 14.67566 20.75753 18.36096 11.46189 12.17066 16.09736 18.87127 13.62443 ADVANCE Standard 47.506 57.988 55.213 54.352 64.557 51.108 59.33 57.614 33.671 51.022 40.267 29.328 48.277 41.595 43.5 55.843 38.253 52.773 46.383 55.319 69.632 56.87 70.452 67.819 67.419 60.455 46.695 62.493 32.628 14.687 18.902 32.344 20.736 17.259 34.469 21.709 41.6 36.251 25.422 25.391 41.407 33.528 32.118 47.371 51.608 21.223 14.852 26.189 24.951 41.778 29.554 38.68 43.227 29.079 39.106 42.117 38.569 47.829 33.827 33.774 25.051 32.768 40.302 34.709 39.47694 37.53475 30.78265 39.23737 30.67572 42.79686 46.01397 35.55479 44.60141 44.5357 42.0272 55.69304 41.42808 64.11597 18.92466 14.11686 21.28715 25.57622 35.41388 16.42298 11.79588 7.416198 21.25021 20.17424 6.77179 33.56869 41.18252 30.90076 36.63722 33.97478 25.55945 9.561829 6.279217 20.6778 39.58174 27.16353 ADVANCE Intensive 64.295 49.845 76.751 62.371 57.927 60.38 56.294 62.628 23.299 41.756 40.859 40.1 50.396 41.158 42.017 56.967 44.878 59.781 42.509 47.038 54.492 50.357 52.811 66.874 62.457 56.731 62.054 63.265 24.991 20.973 31.129 34.507 22.447 34.178 12.101 25.671 47.933 41.725 20.73 30.458 40.485 38.502 46.222 53.195 45.006 31.085 22.662 26.899 38.892 34.084 35.333 35.543 24.116 31.471 41.326 35.507 29.13 47.073 25.837 27.888 31.516 28.224 38.737 28.777 25.60134 23.25019 37.95862 35.80902 36.85493 41.90124 42.61288 36.5904 46.86759 48.12038 50.39416 57.54874 42.65309 36.86462 20.26256 13.03293 20.36103 21.18962 12.74475 8.518887 14.74061 24.12764 21.02719 22.8567 16.5702 18.9473 32.14921 29.3355 29.3355 31.90163 35.08968 32.92632 19.02254 19.84223 18.89444 20.02498 ADVANCE Asia Standard 66.355 58.244 41.785 43.722 68.608 63.073 53.692 47.367 23.829 21.312 30.695 26.298 15.862 37.481 38.168 39.24 32.462 37.374 31.912 39.136 63.567 70.606 60.198 62.567 50.569 72.643 59.149 65.328 18.363 11.082 11.645 9.757 24.008 19.89 19.606 30.338 18 38.314 29.234 32.274 25.152 26.833 16.565 26.42 20.577 8.3785 9.9599 13.993 13.327 12.681 38.701 31.645 38.629 50.468 41.864 35.676 35.892 29.786 16.267 22.32 16.205 16.535 30.939 39.696 34 33.94702 34.44706 25.20317 34.44996 52.72381 45.65742 45.46647 41.64373 41.2068 59.29081 43.90444 44.79062 39.33192 15.11952 10.92703 12.48199 10.82589 24.07904 17.32051 23.16031 23.16031 26.79552 26.85889 15.94992 25.54604 14.66288 19.77372 13.38656 25.56951 20.83747 12.00833 9.476286 4.538722 11.82371 5.366563 ADVANCE Asia Intensive 53.918 58.964 63.998 56.296 68.148 54.858 52.148 73.71 27.961 36.105 35.688 17.407 33.193 40.272 36.412 32.23 56.921 56.91 43.188 41.4 61.33 69.482 61.8 66.342 71.103 68.833 58.164 59.716 15.199 19.391 11.305 12.239 16.118 37.561 23.622 48.079 31.806 27.419 19.657 34.511 31.768 42.112 33.091 37.515 30.496 7.7846 15.434 11.305 23.264 15.792 42.546 42.995 27.893 27.287 30.312 43.474 24.091 31.847 21.114 16.358 22.694 24.69 29.634 33.211 31.28578 31.97812 46.13675 40.89254 33.58273 38.50195 46.98936 44.92438 41.20437 52.08839 36.58688 51.57519 38.87673 46.68833 22.48555 11.41928 7.014271 12.86079 24.91184 15.06652 18.85206 19.02104 23.68966 13.73317 24.68603 11.48042 22.44103 33.06962 23.61356 26.14957 19.0683 15.76705 15.20526 11.97497 24.75884 1.788854 ADVANCE EME Standard 62.2 56.706 57.29 65.003 76.042 83.53 55.415 66.351 55.4 76.085 77.162 58.554 64.067 57.46 56.127 44.933 47.274 62.849 49.771 71.311 72.746 73.207 80.652 77.612 100.8 76.202 79.755 87.843 46.02 41.9 27.528 60.544 56.793 33.592 41.068 47.487 44.797 57.815 49.169 66.927 77.226 69.275 54.938 76.341 67.543 54.329 53.907 36.434 62.698 67.073 57.651 56.84 57.131 60.055 54.297 58.294 48.409 72.558 48.559 46.562 55.105 44.627 61.304 47.318 46.42629 44.71241 45.87374 59.36834 39.77688 57.87918 72.03471 66.90142 64.21682 74.64449 77.05323 57.8256 57.66281 65.96969 33.76389 42.65443 26.16486 43.4304 51.15076 46.34221 24.4663 23.74447 41.67253 38.04997 31.02902 46.10206 59.96832 57.04384 58.47906 69.16936 61.28948 41.65093 38.20733 41.12907 40.58325 52.32017 ADVANCE EME Intensive 86.633 69.307 70.818 70.419 69.997 68.257 70.061 94.739 79.637 66.756 56.189 61.563 77.227 57.682 50.933 71.574 65.24 76.003 54.975 75.693 76.438 72.378 84.907 77.178 96.653 85.255 84.976 107.04 50.709 43.327 42.956 59.516 65.109 50.752 40.8 25.179 60.934 56.512 43.69 59.558 75.986 71.681 70.566 89.269 71.602 49.808 62.044 50.214 68.724 65.529 48.293 53.17 42.939 38.771 46.122 57.214 46.426 61.444 56.909 61.649 53.572 49.169 68.179 39.054 39.31158 35.72954 44.58251 56.31696 48.52834 54.98182 60.33904 49.38623 65.24722 53.36291 72.58512 79.54998 38.28316 82.81787 40.69644 40.26661 43.71727 46.18225 40.08491 37.82063 27.79209 36.18563 42.06186 30.94188 35.08276 40.10985 72.65122 61.4817 62.71682 65.59726 54.70283 42.96277 33.53207 36.20773 40.67677 55.75661 ADVANCE Eastern Europe Standard 44.423 46.964 52.09 56.764 60.727 53.192 40.447 61.91 54.659 61.926 49.342 41.711 67.692 42.207 39.189 32.367 36.219 57.99 27.041 55.986 62.346 63.203 44.123 51.348 71.663 57.616 48.475 65.838 14.142 11.705 18.778 43.442 51.728 11.933 16.535 17.983 35.819 30.189 30.659 36.905 55.391 52.492 51.763 67.738 61.995 29.333 30.223 24.633 42.176 36.761 35.808 55.611 32.212 17.292 47.083 35.816 30.848 56.784 59.395 33.767 35.443 31.238 52.663 31.174 31.69543 40.6694 32.08115 44.20633 31.00645 41.93567 34.99429 49.45301 41.36182 52.40801 56.23878 69.34119 46.24284 66.30988 10.87198 12.05819 15.9875 31.70489 27.7092 8.988882 16.41341 18.6494 30.09651 19.32356 20.02498 24.61707 52.43472 35.28739 33.09381 54.65711 46.5532 18.17691 16.04369 15.78607 25.34956 29.27798 ADVANCE Eastern Europe Intensive 63.465 54.345 46.219 59.095 65.839 65.746 48.757 65.786 55.998 24.352 39.704 50.381 60.414 28.723 42.071 58.689 54.452 66.866 45.943 41.002 63.422 47.168 64.786 66.135 83.41 60.065 73.547 80.207 26.9 16.697 28.046 49.394 48.726 29.117 34.044 18.493 29.98 35.93 40.696 57.893 55.688 54.834 44.089 65.854 65.408 25.448 35.457 18.601 48.734 62.645 20.533 26.161 23.778 28.217 41.161 29.725 28.719 42.783 28.26 32.299 38.613 33.281 45.372 32.769 33.51119 30.25558 19.00526 43.63026 41.97857 35.52745 48.63538 53.7829 44.40045 39.9975 58.68219 31.72381 62.89038 60.58052 18.89974 21.07131 15.44668 38.60311 27.50273 9.97998 13.60882 6.244998 25.27845 14.22674 21.73937 32.64966 27.20662 18.55802 56.77147 50.16373 52.72191 16.04992 14.29685 24.08734 36.35932 28.32314 ADVANCE Full 37.867 49.677 44.613 51.244 56.625 43.77 42.639 72.98 56.567 45.178 46.879 49.65 66.593 46.829 50.379 50.004 42.919 53.893 56.067 58.076 70.32 79.124 70.971 51.276 71.669 75.489 66.505 73.266 37.587 19.2 28.699 42.094 40.842 32.119 35.576 43.092 42.819 45.278 42.62 58.696 54.271 60.871 51.511 56.636 55.428 28.454 30.927 14.214 41.208 50.778 27.264 42.821 33.854 32.758 46.981 40.581 36.796 47.464 62.579 40.2 44.376 50.924 42.893 36.108 48.25903 43.66677 40.81227 55.13304 39.03017 55.35414 50.60992 49.97506 45.13079 34.78393 45.85928 58.47172 48.43484 51.85082 32.6703 30.1293 17.44112 50.36938 38.42889 19.16231 14.89645 27.38196 27.70865 49.04304 24.69643 37.80676 50.05219 56.15232 55.37351 53.66902 42.2991 32.94898 31.79945 39.99551 31.54456 43.85439 ACCORD BP Standard Therapy 39.663 52.236 62.209 44.658 46.8 64.068 45.7 58.773 41.106 41.27 49.68 41.207 59.746 54.324 50.431 48.797 51.67 59.437 59.228 67.685 55.698 52.765 60.915 53.715 51.831 63.254 66.038 67.187 36.625 41.478 40.649 50.946 57.773 45.713 45.214 47.461 50.573 56.187 47.86 42.414 53.129 46.29 47.197 60.286 51.965 41.016 39.679 39.189 57.188 44.842 43.846 42.803 49.054 53.79 50.254 61.599 38.95 51.836 43.567 44.279 49.557 41.636 60.357 59.068 63.09756 53.36588 59.82507 57.74548 56.0604 60.37507 53.84697 61.18766 58.7087 56.85903 42.95179 60.83377 53.91216 54.68165 34.52606 31.39912 45.46286 45.06671 54.48609 37.43555 44.03754 49.0809 46.50134 55.2022 37.24087 50.62645 41.95631 54.11239 45.08539 57.92412 52.0882 39.2801 33.37011 40.92891 66.97515 43.16264 ACCORD BP Intensive Therapy 38.501 43.179 54.278 43.943 57.022 53.488 56.192 52.165 44.685 36.752 35.563 49.113 67.268 46.258 45.203 61.914 54.686 58.258 42.979 63.509 59.398 48.095 53.454 57.366 71.858 58.294 48.656 62.344 31.294 35.084 39.695 38.368 44.263 35.475 45.243 41.116 42.575 53.884 33.434 59.392 43.848 56.944 35.498 58.071 37.212 31.657 41.148 32.422 55.309 42.579 34.195 35.936 42.994 42.236 50.318 47.706 38.588 53.055 43.258 23.619 38.273 40.841 50.831 34.015 41.93353 41.16953 49.84724 56.41206 44.71246 51.65144 28.53475 30.80471 42.06139 40.17586 45.10157 38.25995 29.39693 42.37776 37.1113 37.02059 33.71171 46.15297 46.54236 31.02187 27.62513 36.91642 36.33782 44.57518 38.64834 50.55192 35.25795 38.71664 37.54194 52.34051 29.30084 29.83799 30.41647 34.52754 42.78197 37.83079 ACCORD BP Full 48.886 43.179 57.444 53.715 54.137 55.247 51.351 49.873 39.712 32.433 51.586 46.156 61.969 55.743 63.368 48.76 47.809 61.252 56.582 65.174 55.413 54.565 55.061 61.874 75.485 67.907 42.005 69.109 36.565 33.807 35.651 45.268 58.277 37.577 38.037 41.21 42.037 64.119 53.349 51.238 41.723 40.63 48.983 68.612 49.145 36.79 42.953 40.149 55.794 44.361 39.127 41.785 44.754 46.915 56.293 62.027 45.988 39.103 41.036 31.67 55.298 47.771 52.262 47.047 50.63383 52.22284 56.61367 53.90855 42.96476 58.48467 41.75387 44.97807 42.94205 43.66469 51.05981 53.11276 47.6859 54.55997 37.36272 35.50154 38.90312 44.96484 44.26273 42.36062 38.45213 36.47209 48.9023 46.39214 39.77541 44.48023 43.95849 46.38778 46.49311 50.12646 39.69487 28.72887 33.16661 38.21615 51.11573 45.28257 KP 20-34 9.5786 6.2249 16.21 12.43 11.091 10.416 8.6891 10.782 9.5 11.158 9.2601 12.99 12.835 11.158 14.44 13.647 15.827 11.822 13.666 9.7211 14.569 15 22.226 9.6825 14.824 16.34 12.47 12.58 8.7034 9.2601 13.332 14.448 12.42 12.52 11.068 12.669 13.248 10.954 14.62 12.43 7.5993 11.214 12.43 10.886 9.8362 8.6891 11.5 13.802 12.369 10.332 9.9373 12.61 15.124 9.1241 12.268 15.419 12.073 8.7034 6.6895 7.746 10.571 11.034 11.906 10.025 9.246621 18.88121 10.21029 11.21383 14.30909 12.8355 10.79352 17.14643 17.13184 16.25577 13.51851 19.32615 14.90805 13.83835 5.894913 12.78671 11.81101 8.660254 9.823441 6.946222 16.88935 9.721111 16.26346 16.14001 12.5996 17.72005 6.30476 12.09339 9.513149 12.68858 7.449832 12.4298 16.17869 18.85471 11.06797 9.287088 KP 35-50 18.641 25.283 22.147 18.661 22.011 28.452 26.405 24.213 22.913 29.24 27.143 32.07 27.152 24.088 22.793 24.729 22.344 26.641 26.125 23.335 42.039 43.937 38.714 43.442 41.161 49.952 34.081 36.589 25.303 27.848 25.357 22.31 25.52 21.101 33.023 21.018 24.346 17.059 27.477 27.875 20.579 34.081 30.85 25.005 25.593 20.555 26.851 23.103 23.13 28.062 17.84 28.377 33.47 27.897 24.693 26.972 27.825 29.787 24.713 22.528 20.037 27.032 17.168 18.561 27.75788 18.12457 21.43012 21.47673 26.35337 19.57039 50.88959 40.06557 46.12212 38.75564 47.26256 40.73082 39.59482 44.88597 21.43595 17.75528 19.98124 20.79663 24.82942 25.20417 17.25543 30.37269 17.63519 30.4836 26.73948 30.52048 25.76335 28.82707 36.15591 29.6395 24.5153 31.47221 30.83018 27.39526 24.80423 21.87464 KP 50-65 41.479 56.323 59.064 50.085 64.37 51.337 47.718 59.405 44.975 59.435 45.632 51.442 54.014 46.489 42.65 47.568 66.972 53.81 47.233 54.268 68.536 80.47 82.526 77.618 84.364 90.579 74.751 78.202 42.314 32.646 41.225 47.755 46.179 28.346 38.292 34.565 50.302 46.193 46.749 50.929 54.429 48.629 44.623 64.861 53.061 46.163 49.028 43.903 44.866 46.837 50.779 49.015 46.699 50.381 53.638 57.775 52.721 54.502 44.187 49.93 58.647 55.464 61.589 46.419 49.26967 49.33052 42.92435 57.12705 55.13166 62.80923 80.63343 77.26092 65.73622 74.44125 81.23577 80.68147 87.00862 77.41608 29.80352 43.00872 31.73326 51.83387 49.82469 29.79513 40.92371 39.13758 45.8503 38.87801 40.62635 52.86303 48.56439 61.4451 52.31396 63.16051 55.96651 37.52999 42.64094 51.74456 45.11375 60.79062 KP 65-75 72.827 75.849 79.961 90.978 81.59 108.21 80.425 87.172 74.748 91.699 83.561 100.96 114.25 87.918 92.058 95.082 96.446 96.781 100.15 109.53 94.939 97.117 87.079 109.82 92.349 109.08 75.791 98.871 67.829 59.002 84.27 84.898 90.069 58.004 65.856 81.655 80.553 93.113 73.469 85.131 74.128 90.264 88.935 115.47 90.678 67.088 71.99 82.623 73.012 82.175 68.982 78.278 89.758 90.768 93.611 90.838 75.13 106.81 72.248 76.821 86.481 93.531 110.93 85.087 78.24002 70.42372 115.5617 103.5833 91.90892 112.8317 90.25381 78.09289 108.2335 98.55709 82.21314 105.0274 85.65337 88.0284 62.91065 55.03181 79.39616 70 99.0568 65.09224 55.07268 88.73697 81.5935 98.30437 68.15424 77.66756 99.77475 95.13937 112.5722 113.5859 94.04919 69.57909 74.47483 88.38835 101.3435 84.91614 KP 75+ 125.89 119.96 120.64 152.26 136.99 138.95 110.35 107.62 148.9 130.45 126.73 170.14 143.28 154.28 142.26 139.66 176.27 158.43 156.34 171.77 109.8 90.313 89.489 120.88 101.63 133.03 100.44 106.52 122.97 117.85 153.37 120.47 126.57 131.61 129.12 156.63 133.9 139.23 111.68 139.46 139.45 148.37 149.09 160.29 131.96 124.41 106.28 139.15 133.82 121.07 125.93 109.5 102.42 139.18 149.56 156.13 105.79 133.78 153.2 133.37 137.64 150.85 148.53 173.32 134.6737 146.8954 176.8198 162.4731 150.6469 148.0827 111.5572 94.94472 84.39194 123.2933 101.7571 119.6296 88.03124 107.9641 126.7655 121.064 143.7167 127.6626 141.0496 140.9264 129.1878 152.4238 126.7902 144.8249 113.6299 145.6082 149.6554 136.9881 158.1977 161.6184 136.2011 121.9436 103.3671 144.0477 123.8134 125.994 KP Total 57.085 58.401 54.534 69.42 78.841 73.695 60.805 75.375 61.475 66.652 71.69 75.757 73.092 64.721 72.795 69.085 73.101 75.673 68.943 67.68 67.982 64.475 81.102 79.379 69.721 77.445 66.857 79.507 52.126 56.335 59.948 61.502 70.301 49.907 51.387 68.454 58.994 58.079 58.963 70.252 67.038 52.455 73.321 70.269 79.325 59.195 50.997 64.484 62.938 64.22 59.028 58.718 63.266 67.215 79.844 64.63 60.243 78.549 64.648 51.796 69.535 69.223 79.969 75.301 71.16356 75.05354 72.07208 74.00638 61.02019 67.64988 54.75018 78.0044 58.47601 88.21379 81.51017 93.02931 68.20729 85.44532 49.03401 52.99232 64.16167 52.61954 71.75664 61.78986 52.43389 56.15554 60.05512 66.66797 57.01654 62.61913 57.27068 75.70524 66.4619 85.21527 58.09295 46.77928 64.36105 61.24258 65.59108 66.11525 NDR 20-34 8.5147 9.2195 10.124 12.59 13.892 11.068 10.817 14.089 14.16 10.607 19.455 14.714 11.853 8.6023 13.21 11.511 12.349 10.512 17.335 12.083 20.518 20.555 20.591 17.464 27.613 15.264 20.591 14.916 19.092 15.652 10.512 20.809 10.63 12.903 11.853 14.577 11.18 10 16.155 15 9.9247 13.946 12.083 9.6177 16.447 19.144 18.028 13 14.318 14.983 12.104 15.443 18.385 5.1478 15.443 14.422 12.349 13.21 10.817 13.601 12.207 15.182 13.416 10.607 17.39253 10.63015 10.5119 10.29563 10.19804 14.57738 23.33452 24.18677 20.70024 19.30026 20 21.27205 19.03943 22.63846 14.1598 13.94633 11.42366 13.0384 8.944272 16.98529 12.34909 13.60147 13.28533 16.55295 19.45508 12.04159 16.32483 19.96246 14.76482 12.90349 10.81665 11.51086 15.89025 16.55295 17.73415 13.94633 NDR 35-50 20.159 11.67 14.327 15.871 9.5373 11.002 16.474 6.8789 15.914 26.202 21.13 19.285 18.698 7.3993 9.8939 5.8152 12.333 4.9747 10.147 11.469 37.78 25.326 37.389 36.788 35.593 32.871 35.301 42.487 17.285 16.095 22.385 15.477 17.474 10.91 8.5583 20.782 18.85 11.933 17.862 10.168 13.674 13.674 16.805 20.987 23.512 14.446 27.487 14.006 20.83 26.651 11.015 19.024 24.853 13.904 12.078 6.3776 14.645 14.327 9.5861 17.939 16.69 15.537 19.496 4.5471 13.66562 7.002231 13.51855 12.69828 14.60538 9.147472 39.21621 34.25398 38.3459 24.45347 29.43588 29.55218 28.38336 27.36869 22.93099 10.28699 20.38132 23.638 24.18175 8.886183 11.97169 8.789212 11.01137 12.76853 12.24309 17.67066 19.14153 12.5883 17.05149 15.74463 26.51496 26.50964 15.66273 21.09095 18.88609 16.35877 NDR 50-65 27.464 25.24 32.149 39.106 39.603 36.312 36.675 43.955 42.059 22.874 34.109 37.39 48.659 29.336 38.989 32.594 22.042 37.859 31.492 36.663 69.625 60.495 51.273 57.485 61.333 63.057 55.483 57.363 25.144 26.859 43.823 26.408 28.946 19.791 23.185 24.528 29.253 30.548 30.132 36.104 38.092 51.033 40.286 51.688 47.14 22.984 24.69 30.446 35.596 45.816 44.183 36.312 30.083 31.2 31.778 40.673 21.208 42.686 30.388 41.599 42.757 42.982 36.312 29.944 34.58592 22.80899 27.03121 26.69528 34.01209 25.46955 63.99014 60.0405 53.98828 52.96337 67.8316 46.99389 56.17193 65.09545 18.74721 29.58604 22.94772 36.02541 27.57394 12.3563 21.73242 15.98456 31.14563 32.1081 11.93558 32.78759 53.37024 44.89016 37.01878 46.38627 39.92931 38.70041 32.87945 20.72684 33.6892 38.8159 NDR 65-75 48.969 54.641 49.87 52.465 60.983 59.206 54.176 61.995 51.756 45.731 50.73 59.507 53.613 39.775 46.802 35.556 49.885 47.098 36.201 55.371 51.793 45.946 36.96 51.994 60.983 61.341 60.307 45.059 25.149 31.541 24.332 38.787 36.397 28.799 21.356 25.447 31.469 24.788 24.22 45.631 49.679 55.291 58.956 42.152 51.05 32.35 42.691 31.557 39.677 44.184 48.403 51.624 55.645 54.116 58.389 54.684 51.523 64.37 60.446 57.693 44.705 49.235 56.756 47.853 53.18656 43.4053 48.67042 49.4842 29.83149 48.48 56.74367 61.66596 53.24671 58.47037 70.5535 54.54072 57.06495 48.73299 33.07733 28.54992 29.67609 44.41802 39.80292 31.14055 18.86478 16.46311 35.65743 42.717 25.64258 43.54979 64.77998 72.99386 64.34338 58.45462 68.85726 38.63154 25.63158 37.48485 44.1598 35.07652 NDR 75+ 79.257 69.089 48.495 66.785 57.625 73.422 64.07 65.018 58.343 32.814 44.617 64.086 58.731 77.955 73.614 65.029 59.828 72.571 54.051 69.506 35.259 26.639 27.274 28.345 31.874 24.817 18.766 25.763 50.641 25.623 33.76 18.296 23.97 69.796 34.202 34.752 39.359 40.324 29.886 49.327 57.044 57.662 63.179 64.086 77.834 62.73 45.997 29.042 41.185 41.158 53.201 64.771 66.278 73.475 59.183 64.43 71.781 75.524 62.175 58.887 55.595 61.069 53.89 68.037 43.16874 59.87061 53.0076 68.36969 62.62931 54.75427 47.29655 24.06217 25.84697 28.82683 32.59724 23.81732 17.09605 25.4538 47.25227 22.46586 23.31581 25.26206 28.24011 46.88137 34.15898 31.26004 41.6844 34.03686 32.1957 50.25222 73.55645 65.69882 66.53402 63.96304 62.6571 53.55895 27.12506 37.29167 36.35419 32.32709 NDR Total 43.058 33.218 35.984 57.078 43.44 42.686 41.011 43.592 48.115 57.335 43.142 38.225 51.922 28.286 37.019 33.12 39.395 45.236 40.763 48.533 54.574 43.726 52.222 47.499 56.767 53.111 47.645 60.571 37.408 28.898 18.092 24.592 32.091 19.857 16.759 19.705 26.788 23.697 19.287 31.315 52.783 32.555 40.46 50.881 54.017 34.612 40.938 33.218 35.738 23.592 41.281 40.288 47.288 40.898 38.619 42.793 43.679 47.254 50.797 34.544 39.76 60.118 33.081 46.489 39.9059 34.5062 35.98985 45.87663 40.30553 42.48057 42.90356 48.70174 38.19072 54.02893 59.8035 59.69498 40.22242 46.33394 19.67315 26.18659 31.15969 38.90535 29.33038 17.73669 16.36056 17.733 23.68099 24.67766 16.8942 34.26302 51.53954 50.82945 55.12317 55.2249 53.2442 37.24369 33.96317 23.097 32.53607 48.23595 AHEAD Control 70.932 69.883 64.859 60.769 83.678 72.747 58.605 79.179 61.43 79.018 87.756 72.878 81.876 76.02 74.346 75.75 93.065 94.463 78.257 93.743 88.669 89.833 89.627 115.91 108.45 102.07 106.46 106.01 56.887 53.129 53.061 58.073 53.141 79.005 60.02 61.866 65.754 82.103 56.247 66.421 76.79 77.66 76.686 79.947 77.866 52.557 53.307 65.963 72.402 62.851 47.012 48.351 60.868 66.883 68.954 60.66 63.293 62.003 61.525 59.203 75.383 71.2 68.384 82.207 77.2744 75.4214 83.20829 95.01568 55.13534 83.31883 86.41313 69.70303 88.80189 101.2906 81.20946 101.5044 92.80234 102.551 52.64744 59.14396 73.70755 57.16382 65.409 58.91981 53.53396 66.66848 74.52231 73.31617 48.78896 68.91542 52.12094 80.11895 65.31537 64.85177 69.89072 51.00029 53.17066 51.74519 73.57255 71.56379 AHEAD Intervention 77.084 62.48 66.244 70.609 73.371 96.76 71.308 86.411 78.272 75.02 79.306 77.785 91.082 71.852 77.128 95.205 83.222 100.32 82.891 97.524 102.34 82.17 88.294 98.961 110.65 108.44 106.19 93.998 55.146 42.788 62.615 51.57 65.672 57.577 58.031 63.883 58.084 74.08 45.382 68.206 67.866 70.503 81.605 97.552 61.673 61.048 58.164 58.253 70.921 66.385 53.284 58.972 64.362 57.024 72.45 66.132 47.796 65.18 61.916 65.724 61.68 76.571 77.42 56.819 57.97596 76.33954 78.06035 77.3327 72.93919 86.25006 99.93964 90.07775 80.81177 90.83674 77.15249 99.07846 94.00278 86.30873 39.24546 55.61202 52.14535 51.22253 62.70044 55.52815 66.29899 52.4305 82.52974 64.20305 66.64922 55.59278 57.27973 68.46805 87.63542 76.96896 73.35495 55.93869 56.68382 56.99322 55.29891 58.03291 AHEAD Full 71.284 74.857 73.654 75.615 76.566 82.247 73.587 82.891 77.795 83.698 72.813 79.59 84.991 84.123 90.289 71.723 79.82 94.327 72.427 85.081 102.45 105.6 108.63 104.75 115.52 132.97 97.908 107.75 55.549 55.445 70.58 62.043 73.802 55.767 63.702 72.162 79.177 75.443 74.76 67.729 76.631 85.119 99.892 82.779 80.587 59.625 59.196 64.208 69.774 71.871 62.661 69.248 60.194 61.244 68.8 77 52.06 84.247 70.451 74.563 68.133 77.641 82.609 81.567 72.83978 73.17806 73.00988 78.37396 62.73755 74.57664 88.25704 72.79475 81.82338 81.38222 93.73673 89.99672 89.99018 92.01466 48.13727 52.18478 51.30918 58.77476 74.86892 65.82568 47.85216 61.3031 62.95515 63.03293 55.75211 61.89969 78.8821 67.45445 74.9856 70.09205 75.48924 70.07004 47.38219 67.88298 69.38271 65.09727 ADDITION Routine 41.803 48.485 61.486 50.205 63.02 51.24 53.505 57.151 43.399 52.242 53.35 54.615 57.232 36.949 38.949 39.462 28.836 41.743 42.997 47.297 92.903 96.946 79.546 85.917 79.955 85.905 72.744 90.608 27.622 33.053 38.965 46.556 49.409 26.462 31.949 26.472 39.316 24.362 29.034 36.773 52.398 51.786 42.793 61.247 56.582 38.125 45.667 41.911 43.491 47.26 17.27 27.308 22.517 18.289 37.33 23.822 23.179 31.329 29.013 40.488 37.091 35.415 47.789 14.79 28.19574 24.09876 18.91428 25.41161 23.02173 38.14446 54.32541 59.10584 54.28398 59.10584 50.97794 61.84658 54.307 47.66288 25.23391 28.95686 31.233 28.24447 39.22053 13.22876 19.18984 19.37782 23.17865 18.47972 13.72953 17.55705 41.17645 32.14032 33.95217 36.89851 42.24038 18.30301 31.83159 31.97264 39.53479 39.35416 ADDITION Intensive 48.036 46.707 44.931 53.645 53.607 49.772 56.013 60.254 56.749 51.032 51.218 43.076 49.216 36.817 45.708 35.784 36.8 50.926 55.709 56.646 81.532 89.803 93.404 81.837 94.11 93.136 80.737 98.395 36.79 41.527 46.704 48.14 38.775 29.043 26.977 21.201 38.613 35.718 35.627 40.725 59.205 50.274 60.287 77.685 58.425 39.303 46.027 35.623 52.835 55.322 24.088 31.918 35.658 28.062 31.674 28.588 30.112 37.36 43.191 36.5 44.334 37.346 35.461 21.506 31.87868 25.56854 21.77728 33.35041 42.95637 50.26927 63.14665 56.59284 64.70317 48.09626 61.54267 57.81652 62.98016 64.04881 36.10402 26.49056 29.16762 36.44859 28.25774 15.19046 15.07481 18.20714 30.6635 28.32402 34.0147 28.52192 44.39313 44.37623 41.2977 45.10543 48.05726 28.8184 38.72015 47.326 36.18011 34.11744 ADDITION Full 35.644 45.747 58.691 59.592 59.096 46.046 52.037 60.706 49.131 58.102 47.682 53.356 54.088 38.045 27.214 33.219 31.026 47.646 33.916 44.67 94.656 84.679 77.888 86.753 102.93 88.553 95.466 100.96 35.565 40.019 38.522 53.161 42.855 20.733 35.936 21.304 37.132 35.932 28.013 47.624 46.064 48.261 54.968 60.867 48.195 40.934 53.757 45.137 52.941 50.793 26.683 27.648 28.799 28.142 37.058 31.893 26.095 33.456 33.77 45.811 26.623 43.331 46.583 22.275 20.24825 18.05351 21.73631 41.78521 24.84483 28.12747 56.99514 49.9509 50.53629 54.40331 62.83326 53.58532 53.83199 62.30456 29.92634 28.6043 35.14352 30.07006 35.85275 14.73212 20.32227 18.57066 30.33172 25.60018 22.30238 33.64528 32.95458 41.48538 40.83987 43.0981 50.13957 33.31616 33.32031 36.23743 33.7911 35.88 UKPDS33 Conventional Correlated 25.045 35.017 29.24 31.782 41.778 38.2 29.777 46.879 14.656 18.466 16.524 15.451 21.38 15.477 20.774 21.087 21.206 44.867 25.113 36.785 67.057 63.527 65.243 67.976 66.818 62.605 63.007 75.907 20.076 19.36 22.985 35.261 29.451 32.363 27.763 29.438 40.486 33.573 27.943 39.681 15.251 10.461 17.164 27.631 20.637 10.782 12.93 16.641 21.007 37.987 27.212 37.122 34.794 39.19 43.591 33.615 34.259 43.218 11.957 17.888 20.694 13.731 29.196 19.395 23.0559 19.58786 12.08705 36.65801 21.28382 42.06195 65.88564 58.02905 66.05837 58.80761 74.29599 72.82883 63.51251 66.33521 18.73379 16.35771 17.31018 30.2672 20.60576 22.26462 34.73846 28.64703 30.5385 40.46111 34.26707 37.62484 14.55782 16.57807 19.91043 28.32552 22.58707 19.19956 22.54955 14.59012 28.08197 28.41862 UKPDS33 Intensive Correlated 50.133 44.224 50.879 45.578 43.554 50.664 46.206 45.002 11.193 19.134 20.554 20.723 21.678 9.5029 18.384 15.375 14.287 29.95 16.176 31.852 66.06 71.948 78.917 77.151 79.939 76.491 68.262 78.752 15.176 10.647 14.293 31.278 24.575 15.16 19.314 20.303 33.296 20.499 22.94 37.002 16.231 25.284 19.582 24.58 21.928 7.4727 8.1061 8.1968 19.346 29.784 44.587 49.312 45.417 41.514 55.945 51.529 30.225 57.041 19.173 20.18 21.132 16.891 22.159 17.168 18.16631 9.126913 13.3797 23.27935 17.57847 37.65385 69.66731 75.92333 68.42288 65.67099 73.38624 75.63363 71.84168 78.851 12.31341 14.59015 10.48435 32.94067 24.1628 14.99384 20.29269 19.0969 37.93925 32.26874 30.32533 36.98932 15.93075 28.68016 23.85006 24.99085 23.68968 11.78643 4.292813 14.21463 21.94744 32.25956 UKPDS33 Full Correlated 40.928 34.87 47.177 43.355 56.058 45.647 49.234 53.315 9.9239 13.371 12.21 17.386 29.491 9.9451 11.932 15.437 11.776 28.657 17.635 30.162 74.527 64.982 72.065 70.939 69.203 67.86 66.368 69.77 17.591 19.098 13.712 32.085 18.859 23.076 29.512 18.335 39.336 16.63 21.559 35.046 20.25 17.776 20.994 30.877 29.345 9.1406 16.278 8.8659 25.631 33.47 33.331 47.137 41.53 35.897 52.656 39.445 33.865 54.065 8.9625 22.232 11.778 9.2474 26.137 15.751 13.91752 15.44127 10.42857 38.35831 23.51628 26.89665 54.26978 66.6063 75.60898 63.5061 80.63836 69.66938 59.80273 71.08688 15.38244 10.53476 12.04383 34.26308 27.80266 15.01448 24.717 29.22879 37.03304 28.65065 29.52574 39.35585 24.24074 14.43726 15.82083 19.83764 31.10288 12.1353 13.77509 13.64712 20.60466 31.33154 ASPEN All Placebo Correlated 45.875 49.066 43.041 39.869 50.351 51.875 46.511 49.792 34.304 32.829 30.008 32.098 36.708 37.128 26.225 26.125 23.89 32.133 28.592 28.539 52.436 49.186 48.772 40.666 43.94 43.414 47.721 49.115 27.78 15.969 22.254 20.094 21.296 30.749 14.739 15.66 13.775 18.908 10.428 27.884 35.69 39.538 34.893 31.725 29.202 23.157 15.223 20.815 30.891 33.365 55.489 46.06 40.611 51.839 52.856 59.962 45.415 46.559 28.018 29.504 35.795 26.561 31.468 34.979 31.08456 33.52238 20.21757 41.84196 33.93376 30.58594 54.75856 48.53349 39.03524 44.50281 47.71268 40.70319 41.51205 58.50855 22.41093 21.23087 20.16185 27.59529 30.52048 24.56115 12.49 19.9875 20.35927 23.98437 21.85749 36.43487 24.5815 29.09897 35.74213 36.84427 45.65906 31.58718 19.05256 29.43213 28.34167 27.27178 ASPEN All Atorvastatin Correlated 54.923 56.42 51.344 50.51 63.101 58.801 49.825 60.733 37.865 33.845 45.686 28.853 40.401 29.762 37.699 33.612 43.766 36.756 33.478 39.099 41.842 54.143 52.628 46.677 54.884 52.17 50.826 44.054 16.263 24.845 20.676 30.781 31.165 20.457 16.47 18.187 28.513 33.384 27.409 23.885 49.267 39.793 32.226 37.36 28.909 24.109 25.705 26.467 32.346 30.025 48.515 41.806 50.946 37.383 50.022 44.255 43.629 44.908 24.693 39.506 26.462 30.054 39.221 31.448 35.21008 32.94313 25.68073 30.18692 21.37756 26.8235 39.98125 36.42458 43.41947 40.15595 45.11652 47.56049 42.08919 48.54379 19.55761 20.70024 22.88012 22.09638 22.52776 24.23324 16.38597 16.03901 24.92489 18.79495 18.04162 18.37798 24.87971 38.42525 21.78302 33.23778 38.48376 22.5 24.36186 17.73415 21.43012 24.18677 ASPEN Primary Placebo Correlated 61.437 51.405 62.121 55.944 60.519 64.85 56.085 60.92 39.781 35.809 43.442 36.038 39.601 37.871 37.888 33.716 33.856 35.539 47.122 38.643 58.764 61.956 49.401 48.099 59.864 66.996 63.847 57.955 29.891 25.328 23.043 29.783 29.753 23.569 21.249 21.61 31.788 28.614 24.95 31.165 32.415 37.875 36.177 55.195 41.94 29.749 33.738 38.056 32.585 34.446 70.742 57.708 61.786 58.393 71.655 61.284 61.551 53.28 41.533 31.824 36.763 37.769 42.232 35.847 23.05428 27.16155 19.84313 39.16312 31.64253 36.36276 56.3427 57.79057 54.22177 52.57851 66.33438 60.79885 46.62885 50.0025 28.59196 26.05283 27.59529 27.35416 33.66749 24.01041 23.14627 34.7491 25.43128 28.08469 21.25441 26.83747 41.94639 43.14221 49.68652 41.00305 46.0923 31.13278 34.56154 30.51229 29.57195 22.41651 ASPEN Primary Atorvastatin Correlated 59.552 65.198 59.044 66.144 63.902 61.029 65.843 57.528 33.667 32.411 34.154 39.392 39.592 26.669 27.102 29.47 36.349 38.558 27.884 47.077 64.393 48.875 43.494 50.316 55.675 55.168 54.21 59.163 26.41 18.432 30.467 25.734 28.408 24.187 24.723 28.736 28.697 23.356 18.131 29.458 46.144 31.867 35.85 39.972 35.843 31.504 22.616 23.292 20.652 37.845 39.437 39.922 40.367 45.117 42.72 51.887 46.859 41.067 30.992 31.044 25.234 26.636 36.125 37.057 28.53507 29.62685 26.98611 34.82815 32.14809 30.91116 44.87204 47.58676 48.64925 44.84696 55.09537 39.84658 56.62155 44.32832 32.93175 20.4817 25.54408 31.18894 26.35337 15.73213 11.46734 21.03568 18.88783 30.29026 15.40292 23.98437 38.43826 32.81768 27.19375 46.76003 35.14612 20.0624 24.47958 27.64959 22.24298 26.83282 ASPEN Secondary Placebo Correlated 28.469 33.422 25.348 35.263 46.583 42.991 24.031 38.542 28.714 19.912 26.94 25.583 34.857 35.567 29.279 36.235 29.095 38.856 35.093 28.531 30.631 18.594 40.826 22.683 28.588 28.697 14.95 25.189 30.042 28.022 23.638 36.187 34.954 26.387 20.081 18.615 22.666 33.996 17.958 24.062 34.007 17.882 22.655 30.733 18.848 37.706 25.894 19.615 39.449 30.042 37.343 28.275 28.434 32.989 41.277 43.396 25.426 33.189 30.008 15.612 24.92 25.475 35.651 37.97 30.78149 31.91786 30.92329 39.2492 20.89258 33.13986 34.86402 26.65521 22.75961 22.50555 19.83683 45.13037 17.19011 34.85685 41.77918 28.80538 26.32964 27.48181 41.18859 31.69779 22.91288 18.24144 26.43861 31.42849 17.97915 25.0699 31.37276 16.92631 20.71232 37.89789 17.05139 32.58834 33.30916 24.91486 41.4367 28.5 ASPEN Secondary Atorvastatin Correlated 50.693 43.592 47.085 51.227 45.615 55.286 49.684 46.266 34.619 39 27.299 31.627 42.924 51.098 33.151 50.227 48.997 49.412 47.069 48.278 40.945 36.118 30.895 40.481 32.265 45.853 39.994 42.03 30.212 21.249 16.636 27.762 40.231 45.158 14.534 35.341 30.455 40.583 19.685 33.593 34.713 27.861 25.01 43.362 24.3 27.641 21.272 14.335 43.099 32.488 37.878 38.856 27.942 38.409 34.993 58.784 32.234 33.489 34.853 12.01 21.095 15.017 33.481 53.512 35.58792 48.24158 34.67348 52.12965 42.13668 41.27651 32.38055 28.08024 22.43881 32.31099 26.11034 35.17812 19.67867 31.10466 20.30394 20.26697 20.03746 19.84313 34.16504 31.71356 14.22146 24.86463 31.33289 45.43677 27.07859 25.0699 31.12073 21.09502 18.77498 32.87096 16.57558 22.39978 18.41874 11.18034 41.25227 18.8016 ASPEN Full Correlated 41.375 51.508 34.44 38.028 38.391 56.878 48.085 46.461 20.14 20.041 23.693 16.819 29.94 26.441 21.474 22.291 24.246 23.835 22.943 39.867 43.438 32.926 42.108 45.151 41.933 51.138 46.703 49.073 16.534 8.8388 13.005 20.673 23.203 23.305 16.458 11.264 20.497 14.987 18.162 23.057 47.206 32.317 21.246 33.588 27.652 17.688 21.051 18.911 21.694 23.476 37.012 43.109 31.351 30.568 43.254 40.378 35.565 43.097 30.465 23.31 15.839 11.974 34.269 28.985 32.79291 24.49235 22.26264 23.5876 17.02572 26.88169 46.62483 38.65715 34.53802 28.55039 33.38974 35.61425 46.65699 51.10651 17.39612 23.21368 13.34635 23.0353 25.08735 13.01442 10.0312 14.20827 19.67549 18.9374 13.00481 21.73419 22.12182 31.77853 22.90469 33.78794 21.83174 16.72947 11.25278 9.387492 22.80077 31.79819 ADVANCE Standard Correlated 77.644 70.806 77.936 69.963 68.62 79.464 73.629 79.925 29.27 35.124 33.698 22.69 43.854 50.704 38.628 47.295 36.768 42.697 50.438 42.942 63.241 56.455 58.559 63.812 60.522 72.597 75.548 63.765 24.08 14.243 24.375 27.594 30.496 31.834 19.712 35.163 33.63 45.073 29.326 32.816 49.93 42.844 30.09 56.008 39.826 30.04 26.433 23.065 29.311 43.963 48.465 51.275 50.875 51.636 61.386 76.265 55.014 55.306 25.629 25.467 20.567 24.71 30.554 30.701 30.56375 30.93542 34.32617 43.30622 39.58355 44.16042 39.35371 37.05016 54.88039 51.62502 53.10636 52.96225 43.41001 56.70097 17.72005 11.11627 18.63177 16.83109 35.75112 25.90091 14.02039 16.59174 27.54736 32.08694 21.04757 29.0566 34.77684 31.61148 34.22405 34.11116 33.43223 26.25425 17.95232 27.57069 32.92199 33.16194 ADVANCE Intensive Correlated 63.604 77.39 65.727 71.557 85.706 79.682 90.396 84.923 46.773 29.123 42.036 45.233 48.48 46.912 54.141 42.104 45.645 47.722 43.599 56.497 73.958 64.581 77.746 79.571 76.085 81.242 66.837 92.794 48.14 21.125 23.549 25.876 30.896 35.325 25.324 43.994 35.942 50.581 43.533 55.527 42.482 44.373 39.301 47.233 45.125 38.665 28.621 27.923 30.982 37.388 66.911 52.564 62.917 49.007 53.792 58.406 48.753 60.992 39.889 33.276 20.833 42.825 42.574 34.986 38.71877 37.48714 43.40671 49.50036 23 35.35534 50.29484 40.7466 51.31833 57 55.73919 59.34163 47.48383 45.12997 18.73881 12.32303 20.36453 37.70184 33.91376 26.88069 13.83577 17.58652 28.89884 43.73622 25.2728 24.35452 45.49254 36.89173 36.81421 36.67619 40.50749 28.95563 34.34489 17.70391 29.99762 29.19393 ADVANCE Asia Standard Correlated 90.327 88.441 95.526 107.34 98.072 84.478 89.293 96.987 20.876 25.577 35.864 37.924 33.974 68.468 54.054 42.926 48.931 53.896 37.17 62.159 64.347 63.519 84.239 73.479 81.799 86.272 89.868 84.779 33.719 12.704 7.5631 19.975 25.04 21.886 40.085 40.482 47.108 37.36 24.339 29.189 32.444 23.524 31.837 47.94 24.323 16.625 11.278 6.7676 13.491 5.8652 56.461 65.646 64.96 76.318 72.007 85.033 71.903 59.79 20.469 15.944 18.52 22.865 26.918 48.479 47.78284 43.97044 41.59567 43.49713 50.63003 41.833 45.6377 55.16521 59.82642 50.87829 49.683 56.79084 52.93014 63.71499 9.143304 11.89117 8.342661 11.04536 4.939636 37.44863 30.74411 30.47294 36.94049 21.76695 26.64958 31.2666 21.2132 25.44799 21.84949 34.54562 18.05547 12.77498 13.98571 11.89117 6.723095 10.13903 ADVANCE Asia Intensive Correlated 111.28 81.794 83.132 98.4 92.52 90.082 96.726 95.211 23.074 32.775 33.326 32.833 35.592 50.06 54.107 52.6 64.946 51.297 57.976 53.256 77.527 66.934 50.418 66.569 78.483 91.78 60.594 84.704 25.597 22.93 18.963 17.539 36.058 42.818 33.199 40.603 38.181 49.703 38.846 36.837 36.775 34.17 35.066 45.991 25.231 14.22 10.139 7.2388 28.865 27.637 63.74 56.53 62.319 68.79 55.667 58.619 59.484 72.96 36.008 26.092 25.788 28.545 32.119 58.643 47.69486 38.23349 44.85309 39.52468 44.04316 54.90902 65.96666 53.20338 60.29594 60.67949 53.34604 54.56922 47.02765 46.8615 6.033241 14.87279 12.22293 11.01817 20.61068 25.48725 24.82338 26.49906 22.07261 22.71563 23.09978 22.56546 28.16381 21.85864 21.61018 18.85736 22.88668 17.21627 19.19896 7.823043 21.3682 13.53514 ADVANCE EME Standard Correlated 82.684 93.358 82.888 64.034 115.41 91.899 85.303 96.922 62.556 63.337 62.14 50.886 63.114 70.355 67.155 66.854 41.26 67.325 68.5 74.154 80.082 78.238 90.437 97.536 103.6 82.158 83.518 97.182 47.588 34.598 43.499 53.303 54.56 44.993 44.497 36.97 54.697 44.808 51.164 44.141 70.437 59.968 74.359 55.007 63.307 56.379 31.016 30.578 47.074 47.745 81.358 56.879 70.427 57.543 83.223 74.377 67.226 62.806 59.511 50.281 47.793 63.503 62.492 55.685 46.52741 42.48058 39.00256 68.7968 59.88656 66.3988 63.44289 68.29788 56.22277 52.63459 75.18776 65.56066 66.36415 69.14767 42.88823 38.8973 46.38965 67.20417 43.89533 32.02187 32.10607 27.81367 39.94496 55.73688 39.8748 50.018 55.44186 59.72604 46.70546 61.73168 49.3518 46.54031 30.28861 39.1561 39.91491 53.6973 ADVANCE EME Intensive Correlated 69.03 102.48 78.579 86.909 92.864 91.993 88.88 95.439 71.402 72.507 57.002 63.691 72.985 72.191 72.523 64.645 74.309 84.092 62.887 91.62 95.572 84.8 105.72 95.571 83.046 82.689 94.421 99.477 42.596 51.231 49.002 58.677 42.433 43.25 37.963 45.609 59.245 52.604 48.943 57.435 75.125 60.731 64.365 71.372 67.655 47.64 45.701 47.233 50.874 56.838 56.241 65.08 55.6 72.58 60.481 62.153 41.241 67.304 66.346 57.338 57.763 61.272 71.162 65.955 37.72797 82.26664 42.43112 64.73175 64.3506 56.81197 65.54083 81.38182 56.03749 71.49406 65.62164 75.50629 71.99861 83.23941 38.55905 55.69919 33.68679 34.59191 44.47696 40.53147 25.23886 25.05195 48.94691 34.31326 30.17284 37.34434 70.17122 52.93581 65.00769 70.22535 58.28207 40.09489 44.24251 39.88734 52.29914 57.92754 ADVANCE Eastern Europe Standard Correlated 85.726 90.926 79.317 82.884 91.539 98.558 88.135 87.519 69.52 53.833 42.055 52.347 61.465 51.43 39.243 37.35 36.924 46.161 55.163 53.006 66.863 69.059 59.738 81.406 81.632 65.933 66.597 89.076 34.788 21.772 20.616 39.138 40.494 37.855 18.968 24.429 39.299 47.722 31.818 26.721 71.28 47.802 45.957 56.187 53.213 43.021 27.434 31.138 38.887 34.658 61.221 44.75 68.606 67.206 79.159 74.675 66.378 81.505 42.697 24.306 39.669 43.033 53.081 53.072 37.73857 35.98611 38.98974 47.4173 35.98889 39.90238 59.654 53.39288 64.3133 62.89674 72.27724 68.80552 48.70113 68.68479 18.27019 21.29319 13.01538 25.88049 29.66142 20.24846 12.17374 18.25377 36.50479 29.41088 15.8619 42.23979 39.47911 39.09476 46.05866 57.26605 27.5971 33.34367 25.37321 24.78306 35.01143 37.66431 ADVANCE Eastern Europe Intensive Correlated 83.908 77.843 91.647 85.872 95.874 91.337 79.791 91.411 63.325 53.158 50.776 57.039 77.057 59.377 52.553 52.169 39.558 68.145 60.985 60.559 85.61 59.319 52.494 51.433 82.071 80.011 68.558 78.427 39.764 29.329 53.584 33.124 47.445 26.495 22.082 38.275 45.288 40.388 29.003 25.683 72.886 63.178 67.574 59.193 62.605 41.792 30.345 29.903 47.493 36.829 59.291 44.562 38.387 45.115 66.243 73.346 58.559 68.901 47.047 41.974 34.214 38.518 39.487 36.409 46.8807 32.08738 32.80854 48.21411 37.97368 52.07111 51.06662 53.30103 58.60887 54.10545 60.26608 51.34783 52.87911 59.18953 28.56921 14.49828 8.843076 41.83061 31.49921 34.68141 14.99333 16.72722 34.45287 34.34822 15.99375 38.64971 57.40906 45.24157 30.49918 55.51576 38.41354 36 10.45945 21.52673 32.96058 41.28196 ADVANCE Full Correlated 92.386 85.034 103.18 75.538 95.827 87.727 88.481 103.43 65.245 55.95 50.105 59.896 73.478 77.104 67.396 59.363 63.477 79.917 74.954 71.59 76.548 77.712 71.564 81.305 87.115 96.398 79.019 84.847 52.458 52.832 51.301 57.675 46.133 52.974 36.36 45.514 56.873 66.063 44.287 53.806 61.125 59.341 53.307 82.989 50.416 41.539 34.112 39.472 43.143 49.611 68.712 68.408 72.461 69.157 80.644 86.017 70.277 85.042 60.379 58.164 63.114 60.335 79.093 57.324 50.84648 64.36461 62.7542 56.84764 62.09166 70.2187 83.63505 68.07733 61.23796 63.8465 77.52023 69.75022 65.41476 79.85943 49.47228 28.04694 29.74277 43.49959 45.49018 34.07649 29.80754 27.59506 45.39116 45.92305 37.69515 47.57026 41.47718 50.78885 57.42149 69.29199 58.61813 38.76205 42.2129 30.02956 49.67972 48.77136 ACCORD BP Standard Therapy Correlated 74.296 71.869 65.973 63.429 80.292 89.338 70.57 87.007 53.858 65.235 52.059 45.972 69.432 58.729 62.792 71.287 64.566 75.406 55.046 71.671 73.541 67.939 66.991 78.316 91.187 94.901 59.389 89.569 47.55 52.113 45.006 48.552 66.139 55.164 42.295 51.129 58.203 75.463 47.601 57.716 52.944 61.302 57.254 61.572 57.425 48.724 44.751 44.065 58.925 55.671 63.237 68.045 71.195 69.435 71.032 84.317 60.537 73.723 60.656 59.548 53.202 64.226 63.29 70.531 72.52215 58.54797 67.82487 86.51173 68.07878 73.72404 62.27132 67.84098 68.38756 54.65185 69.02843 78.30387 59.29385 78.6532 46.05515 47.626 39.86562 47.73633 52.00224 46.49896 44.91775 41.23435 56.20179 61.85257 55.58498 47.44403 54.98303 62.10443 51.06118 62.21982 55.23042 42.21571 50.99447 47.47472 56.70182 55.98693 ACCORD BP Intensive Therapy Correlated 82.016 73.423 86.957 73.702 73.788 90.6 81.732 86.871 58.372 51.955 72.398 44.083 65.846 60.977 58.823 71.794 55.967 57.887 75.698 68.857 79.073 63.884 71.029 60.004 77.79 86.883 66.565 70.092 37.939 38.5 44.563 61.575 64.641 54.034 40.244 43.529 53.082 68.944 40.044 52.274 56.97 56.945 48.933 78.007 51.509 56.919 45.345 44.381 64.442 53.258 69.006 58.119 65.735 50.369 77.335 68.828 60.999 70.847 46.018 44.091 59.855 38.869 67.304 58.264 53.9951 63.04109 51.1597 66.16038 50.41728 63.6746 51.07424 44.62567 57.46056 47.82925 50.54818 56.73 55.85227 63.42404 29.90023 38.28347 40.45682 46.05863 55.8218 44.67576 41.06567 44.31425 53.82613 56.86185 47.9141 56.48717 41.47728 41.68698 56.41195 61.946 44.60033 38.17652 40.33538 38.86472 57.40778 51.68197 ACCORD BP Full Correlated 78.132 75.553 79.028 88.19 91.855 90.717 71.135 80.905 67.474 64.444 72.621 51.74 67.539 71.765 70.195 66.14 70.295 79.638 68.845 84.386 66.329 73.181 74.43 75.348 77.927 82.63 78.441 87.763 49.177 43.947 43.518 56.657 72.515 46.496 47.307 53.258 53.389 72.708 53.518 60.882 62.042 75.191 56.039 71.1 66.613 56.203 55.179 39.466 62.037 53.093 75.971 60.862 68.863 64.464 79.333 77.922 63.311 90.403 52.764 52.874 60.592 49.087 67.517 60.228 60.49518 58.10243 58.14058 74.35935 57.94247 67.32869 59.05167 53.59443 63.66799 48.28172 67.23709 61.74021 55.82206 64.3326 45.89693 40.29929 42.71524 53.45227 64.16985 44.45149 44.23524 49.14979 52.59231 61.45166 50.89269 53.96361 41.20191 44.92455 51.03905 61.96513 45.58232 39.89546 35.40417 39.34315 60.36107 52.93222 KP 20-34 Correlated 23.184 18.344 26.8 16.837 20.694 20.899 19.164 22.428 10.464 10.747 13.519 9.7211 13.086 15.636 18.655 17.664 12.787 15.058 18.875 18.398 13.435 17.428 22.55 22.051 12.52 25.353 17.248 15.78 9.6047 14.133 15.748 14.204 11.811 14.195 15.922 17.226 18.055 14.925 16.681 17.015 8.6168 14.722 12.894 11.937 13.638 7.7782 14.265 14.68 13.847 11.99 14.414 17.909 20.748 21.926 22.897 14.748 22.951 18.007 11.292 11.554 11.587 9.7211 11.683 9.6825 14.61164 25.70992 14.25658 14.66288 19.44865 17.0147 7.141428 15.6365 19.9374 14.08013 20.8866 22.01136 14.5688 14.1598 7.599342 13.64734 9.912114 9.124144 14.3788 12.30853 15.32155 20.59733 18.98684 18.53375 20.5061 16.02342 8.616844 17.53568 9.565563 13.22876 14.66288 9.407444 13.7659 12.35921 18.04162 16.68083 KP 35-50 Correlated 51.877 52.607 50.185 51.834 61.229 46.43 43.669 56.866 34.253 46.462 34.921 38.383 34.486 26.182 41.812 39.045 29.176 36.763 25.933 35.795 54.461 60.791 67.017 53.446 66.708 67.22 57.953 54.587 30.802 41.623 24.865 32.5 38.594 29.39 28.745 28.125 39.462 40.509 49.852 50.666 35.857 39.781 37.616 41.373 42.656 29.373 33.027 39.44 41.788 36.844 46.508 56.73 46.257 46.872 51.425 51.308 58.34 50.326 30.012 45.244 38.881 38.144 46.165 38.442 41.6143 38.2034 35.83643 48.01302 39.19503 45.50824 60.38833 68.4087 64.53875 50.92887 61.23316 51.25427 50.12484 58.51923 35.75612 31.99609 40.53702 46.03531 44.18993 30.6635 25.59785 24.995 34.17967 26.67864 38.11168 37.3497 32.01562 38.91979 27.40894 36.72193 34.24909 30.84639 37.61981 31.85122 34.42383 37.61316 KP 50-65 Correlated 77.822 82.506 89.987 82.272 100.3 97.341 90.497 103.5 60.986 57.734 62.552 62.231 81.383 52.49 62.51 71.084 55.794 78.789 50.087 81.783 94.888 104.87 104.78 99.027 103.03 106.32 96.339 104.47 51.505 50.671 52.564 64.659 72.232 45.346 58.922 51.578 60.659 55.505 60.908 73.121 54.208 76.776 58.792 73.372 60.758 52.086 46.637 58.724 73.14 60.087 70.523 77.721 93.747 75.773 104.99 97.241 89.121 94.012 67.615 74.271 64.121 70.244 79.632 61.553 63.90031 56.59064 70.41129 65.69817 64.02148 75.4586 96.38594 96.74838 96.92136 94.39942 104.7306 104.324 103.2945 104.0216 37.67957 57.97198 55.02499 62.0665 65.92609 38.1248 69.87489 49.97499 62.19727 61.09214 44.14465 66.22877 66.23254 71.07215 72.34984 83.49551 65.28017 46.89616 49.64121 50.9436 60.08328 47.31807 KP 65-75 Correlated 123.21 108.21 121.29 115.23 124.15 121.38 116.15 135.03 83.46 87.103 93.714 107.39 117.32 115.03 108.78 116.12 123.64 121.52 111.64 130.41 120.34 94.128 92.933 97.494 103.4 125.86 94.177 111.56 69.471 81.017 78.054 78.838 84.592 85.894 69.266 87.049 103.83 103.04 91.801 82.485 110.65 107.35 114.93 111.63 92.915 63.411 80.785 97.779 104.73 96.893 120.6 104.59 100.06 131.69 118.5 117.63 110.79 133.97 102.99 100.75 110.39 101.22 128.98 111.42 95.31264 117.6977 118.311 125.862 120.0927 131.5076 87.05889 89.57399 104.0973 110.8388 122.9837 116.6244 104.8642 120.1863 75.28944 72.59132 79.15491 91.5833 104.3528 83.68244 80.88881 72.83715 104.2809 100.307 81.39564 94.63086 99.66695 99.95749 106.9871 132.632 102.5171 96.20551 80.07809 82.49394 98.27004 93.63493 KP 75+ Correlated 166.68 149.46 142.69 173.54 165.56 167.94 144.18 143.89 157.74 153.89 133.28 170.43 145.94 177.97 147.52 163.05 190.05 150.45 134.78 180.34 122.6 89.72 100.17 138.44 115.63 125.13 95.292 121.68 143.68 121.36 146.51 135.01 137.55 155.19 136.99 149.19 152.21 159.18 127.52 149.51 163.58 137.73 164.35 166.42 163.6 140.78 119.64 139.03 150.6 139.4 169.44 148.61 155.75 185.27 158.23 158.13 130.71 141.27 167.86 119.99 128.33 154.6 160.29 180.77 145.2265 162.3499 188.8333 171.1184 131.9782 165.3133 127.1908 106.8352 99.47613 145.4381 129.244 118.1196 105.513 127.3283 148.2068 115.8555 144.6807 127.6215 146.9132 156.305 136.9033 167.4074 143.2925 152.6663 128.6954 143.8011 178.6246 145.4089 180.5443 173.8606 159.1674 148.0616 136.6885 144.8206 149.6713 137.0711 KP Total Correlated 146.38 134.33 145.46 129.98 123.38 137.77 137.69 144.67 87.163 79.817 95.51 90.373 104.39 110.59 95.926 108.9 82.699 112.81 96.354 120.08 120.86 110.73 113.36 99.172 98.165 120.49 95.3 120.91 85.889 76.413 73.454 80.119 100.39 93.187 84.6 89.358 90.437 84.098 70.382 85.222 95.882 105.33 99.61 115.72 94.927 69.716 72.526 76.286 89.081 93.513 115.28 127.26 137.7 136.82 148.67 160.32 139.14 123.9 98.881 80.023 103.43 99.551 102.44 118.78 105.2121 103.6874 101.3986 109.4736 114.7082 107.3657 114.0517 95.07103 86.53523 108.3453 115.23 107.5457 93.80628 103.2313 84.84961 75.65107 68.52665 93.45176 88.62128 100.9992 80.40919 72.75474 103.091 102.7207 80.60832 82.77928 92.60953 91.62098 86.7396 111.5541 87.00623 80.39023 71.23042 78.5985 111.8787 84.55756 NDR 20-34 Correlated 26.249 20.591 20.616 19.723 20.616 23.505 16.688 28.302 13.601 19.925 19.609 15.89 18.788 10 14.142 15.508 18.868 13.342 20.616 16.14 26.315 24.352 37.443 28.018 20.797 22.902 22.192 26.618 15.62 18.358 20.125 19.416 28.018 10 19.723 16.155 19.039 13.601 14.983 14.56 19.105 20.261 23.717 25 22.192 19.105 16.808 21.691 27.722 25.06 17.029 27.83 24.87 25.544 23.033 18.868 18.507 18.561 16.401 20.125 18.868 19.912 21.633 11.336 13.92839 13.92839 7.615773 16.14001 15.70032 14.31782 26.95366 27.10166 18.56071 26.31539 26.23928 21.96588 25.94224 25.34758 27.6134 19.72308 21.09502 20.0125 20.80865 21.26029 18.43909 17.49286 12.74755 17.02939 17.72005 16.76305 21.26029 20.61553 18.56071 27.01851 22.7706 27.58623 19.55761 31.40064 21.09502 25.387 NDR 35-50 Correlated 32.83 35.037 34.692 25.059 30.708 32.168 34.411 32.224 31.688 28.222 27.166 23.02 32.516 15.287 18.774 19.142 18.374 23.746 18.66 20.272 43.572 58.257 48.992 40.116 44.627 45.628 47.019 47.68 25.086 21.73 21.946 24.145 26.907 15.537 15.146 19.024 18.281 14.819 19.715 18.66 37.803 24.453 25.823 30.112 33.749 33.713 21.101 24.695 30.987 27.341 26.466 32.003 12.243 35.12 31.367 16.739 27.757 31.561 21.532 28.222 26.243 30.673 26.879 10.927 19.72403 18.28645 25.52676 24.65553 12.76853 23.739 47.75744 44.30636 45.38942 44.69083 44.36115 46.9177 37.38 57.70979 25.66073 21.78069 31.65401 31.61669 26.50961 10.3596 19.72403 23.5123 17.68472 19.30687 29.77363 21.26622 37.07785 26.65067 26.54329 27.44684 40.08716 25.82306 31.48999 25.39211 23.0009 29.68237 NDR 50-65 Correlated 49.132 56.155 44.513 56.598 48.87 63.415 51.533 54.05 42.757 41.295 52.902 42.933 55.431 39.688 26.087 29.252 35.796 41.891 49.204 44.256 63.994 56.435 62.784 68.289 66.774 71.383 62.256 82.755 29.899 33.561 24.373 45.235 34.039 28.293 25.075 24.432 49.472 26.534 25.847 39.119 47.011 47.772 45.387 56.145 58.791 29.586 34.39 27.966 32.74 37.43 61.874 60.316 40.219 62.145 70.948 58.128 60.286 74.258 51.273 52.217 45.387 46.587 45.628 36.606 31.20048 32.02402 33.88543 50.58267 43.47098 40.72407 75.35178 72.13663 62.39361 65.81047 81.64838 65.60587 85.45119 69.42975 39.69506 40.21888 35.77432 36.46195 41.37035 22.58641 18.57014 27.96594 31.54771 35.45231 37.80336 37.03482 43.49462 56.21969 44.23395 46.09809 55.48263 43.58337 30.85719 48.28994 34.54652 40.76202 NDR 65-75 Correlated 97.757 81.827 94.204 96.889 100.33 91.862 87.888 92.127 62.087 77.605 65.503 61.096 51.495 63.267 53.245 49.883 61.754 52.651 56.219 68.839 65.514 75.21 62.425 73.843 70.156 76.29 59.036 81.428 40.725 41.857 28.16 51.342 38.803 45.119 24.187 38.325 43.154 40.552 37.036 56.644 64.226 60.446 66.345 61.872 63.168 50.906 39.095 43.41 44.129 53.151 88.339 86.475 90.075 102.38 96.077 96.524 87.827 100.12 65.357 59.5 Date Correction Raw Models BioMarker Correction Date+BioMarker Correction Biomarkers Independent Fully Correlated 8Populations=40cohortsx2 50 Models x 4 Assumptions Biomarkers Independent Fully Correlated Unexplained BestModel Vers on 22 - MIST_RefMode _2014_04_29_MATRIX_TraceBack.z p
  16. 16. Jacob Barhak This Modeling Technology Opens Possibilities • The Reference Model for Disease Progression – Participating in the Mount Hood Challenge 2014 – Non diabetic populations? • Population Generation - Unexplored Potential: – Planning Recruitment Efforts? • Clinical Trials? • Other Recruitment Efforts? – Other population modeling?
  17. 17. Jacob Barhak Acknowledgments • Deanna J.M. Isaman - who is the spirit behind the great ideas. She taught me my first steps in disease modeling • Morton Brown & William H. Herman – for guidance, critical feedback, and growth environment • Aaron Garrett – for his responsiveness and help with starting with Inspyred – he saved me at least a months work if not two by sending me solution code within one day. • Continuum Analytics and specifically: – Benjamin Zeitler for creating the cloud AMI – Ilan Schnell for his work on Anaconda. • All those who developed free software used and supported it: including Python, Anaconda, Spyder, numpy, SciPy, nose, winpdb, Star Cluster, Ubuntu, Sun Grid Engine • The legacy IEST modeling framework was supported by the Biostatistics and Economic Modeling Core of the MDRTC (P60DK020572) and by the Methods and Measurement Core of the MCDTR (P30DK092926), both funded by the National Institute of Diabetes and Digestive and Kidney Diseases. The modeling framework was initially defined as GPL and was funded by Chronic Disease Modeling for Clinical Research Innovations grant (R21DK075077) from the same institute. MIST is based on IEST. • The Reference Model and MIST were developed independently without financial support
  18. 18. Jacob Barhak Questions? MIST Jacob Barhak https://github.com/Jacob-Barhak/MIST http://sites.google.com/site/jacobbarhak/

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