Jacob Barhak Ph.D. http://sites.google.com/site/jacobbarhak/ IMAG Multiscale Modeling (MSM) Consortium Meeting 2013 - 2-3 October
The Reference Model for Disease Progression Sensitivity to Bio-Marker Correlation in Base Population The Reference Model Runs with MIST Over the Cloud! In a Nutshell: A League of Disease Models using High Performance Computing
Multiple Populations
Population Characteristics: Age, Male, Race, SBP, DBP, A1c, Smoke, BMI, HDL, LDL, Trig, TC, ACR, Lipid Ratio, Age At Diagnosis Of Diabetes, AF, Survive Stroke, Survive MI, MicroAlbuminuria, MacroAlbuminuria, Diabetes Type 2, Treated for Hypertension, Family History CHD, Rheumatoid Arthritis, Townsend Index, A1c Change, BMI Change, DBP Change, SBP Change, HDL Change, LDL Change, Trig Change, TC Change, Smoke Change, Year
Population 2
Population n
No CHD
MI
MIST Runs Over the Cloud!
CHD Death
Survive MI
MIST (MIcro Simulation Tool)
Process Stroke No Stroke
Stroke
Alive
Other Death
Survive Stroke
Death
Stroke Death
Sun Grid Engine (SGE) StarCluster Anaconda AMI (Amazon Machine Image) Amazon EC2 (Elastic Compute Cloud)
Process Competing Mortality
Multiple Risk Equations The Reference Model is good for: • Economic forecast: Cost/Quality of Life • Comparison amongst studies Reproducible!!! • Evaluation of models – “consumers report” • Better model development • Visualizing the bigger picture of our understanding of disease progression • MultiScale Modeling: individual to population to multi-population
Model Traits
No Model Correction
Possible Future Directions: • Optimizing MIST performance • Adding more populations • Adding more risk equations • Adding more disease processes • Additional analysis modes • Using Individual data • Formulating alternative fitness functions
1. Temporal Correction for Model Outdating / Treatment Improvement: Simulated Time Stamp
Model Data Time Interval
The Reference Model Accomplishments so far: 1. Disease models go out of date and need for temporal correction Adjustment 2. Identify models that behave better/worse Time 3. Using end of trial biomarkers in equations is beneficial 4. Identify which diabetic studies are easier / harder to explain 5. Bio-marker correlation is not the main reason for our gaps in understanding disease progression MODELS
Bio-Marker Correction
Time
New!!!
Model Outdating Correction
Best Model Model Outdating and Bio-Marker Correction
A1c changes BMI changes BP changes Lipid change Smoke changes MI Equation # Stroke Equation # CHD Death Equation # Stroke Death Equation #
0 0 0 0 0 1 1 1 1
0 0 0 0 0 1 2 1 1
0 0 0 0 0 1 3 1 1
0 0 0 0 0 1 4 1 1
0 0 0 0 0 2 1 1 1
0 0 0 0 0 2 2 1 1
0 0 0 0 0 2 3 1 1
0 0 0 0 0 2 4 1 1
0 0 0 0 0 3 1 1 1
0 0 0 0 0 3 2 1 1
0 0 0 0 0 3 3 1 1
0 0 0 0 0 3 4 1 1
0 0 0 0 0 4 1 1 1
0 0 0 0 0 4 2 1 1
0 0 0 0 0 4 3 1 1
0 0 0 0 0 4 4 1 1
1 1 1 1 1 1 1 1 1
1 1 1 1 1 1 2 1 1
1 1 1 1 1 1 3 1 1
1 1 1 1 1 1 4 1 1
1 1 1 1 1 2 1 1 1
1 1 1 1 1 2 2 1 1
1 1 1 1 1 2 3 1 1
1 1 1 1 1 2 4 1 1
1 1 1 1 1 3 1 1 1
1 1 1 1 1 3 2 1 1
1 1 1 1 1 3 3 1 1
1 1 1 1 1 3 4 1 1
1 1 1 1 1 4 1 1 1
1 1 1 1 1 4 2 1 1
1 1 1 1 1 4 3 1 1
1 1 1 1 1 4 4 1 1
0 0 0 0 0 1 1 1 1
0 0 0 0 0 1 2 1 1
0 0 0 0 0 1 3 1 1
0 0 0 0 0 1 4 1 1
0 0 0 0 0 2 1 1 1
0 0 0 0 0 2 2 1 1
0 0 0 0 0 2 3 1 1
0 0 0 0 0 2 4 1 1
0 0 0 0 0 3 1 1 1
0 0 0 0 0 3 2 1 1
0 0 0 0 0 3 3 1 1
0 0 0 0 0 3 4 1 1
0 0 0 0 0 4 1 1 1
0 0 0 0 0 4 2 1 1
0 0 0 0 0 4 3 1 1
0 0 0 0 0 4 4 1 1
1 1 1 1 1 1 1 1 1
1 1 1 1 1 1 2 1 1
1 1 1 1 1 1 3 1 1
1 1 1 1 1 1 4 1 1
1 1 1 1 1 2 1 1 1
1 1 1 1 1 2 2 1 1
1 1 1 1 1 2 3 1 1
1 1 1 1 1 2 4 1 1
1 1 1 1 1 3 1 1 1
1 1 1 1 1 3 2 1 1
1 1 1 1 1 3 3 1 1
1 1 1 1 1 3 4 1 1
1 1 1 1 1 4 1 1 1
1 1 1 1 1 4 2 1 1
1 1 1 1 1 4 3 1 1
1 1 1 1 1 4 4 1 1
Treatment Improvement Correction
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
FITNESS MATRIX: LOW SCORE = GOOD FITNESS (GREEN) , HIGH SCORE = BAD FITNESS (RED) UKPDS
APSEN
ADVANCE
ACCORD
KP
NDR
UKPDS33 Conventional UKPDS33 Conventional Correlated UKPDS33 Intensive UKPDS33 Intensive Correlated UKPDS33 Full
25.4 23.0 22.9 25.1 23.1
25.2 23.5 23.4 24.1 22.1
25.6 22.6 20.2 23.8 21.9
26.4 23.6 20.9 26.4 22.9
42.8 38.9 34.1 32.1 33.1
37.3 36.8 35.8 32.1 34.6
41.8 40.7 33.8 32.5 36.1
39.6 42.1 33.9 31.1 35.1
39.9 36.2 33.5 29.6 32.1
37.9 33.0 32.4 30.3 35.1
41.8 35.6 31.2 28.7 34.8
36.7 36.0 30.5 28.6 33.7
38.4 41.8 44.7 51.3 42.6
32.8 39.4 41.4 47.3 40.1
35.7 43.7 44.3 44.7 42.3
35.2 43.5 46.2 51.4 40.6
26.6 22.7 27.6 25.7 22.9
28.8 23.6 23.6 25.0 23.8
25.2 23.5 23.1 26.1 23.5
26.7 22.9 22.6 26.4 24.2
40.6 37.1 35.4 34.3 34.4
38.2 39.8 32.7 32.1 34.7
39.5 37.8 34.8 28.9 32.7
40.8 38.2 35.3 33.5 35.4
37.9 35.1 34.5 28.7 33.6
41.1 36.0 31.5 31.9 34.9
39.0 33.1 30.9 30.0 32.7
37.0 38.0 32.0 30.5 33.5
34.6 40.1 41.4 50.3 40.2
34.1 38.7 46.2 46.0 38.1
33.0 37.9 45.1 47.8 42.7
34.1 42.0 43.2 47.2 39.9
25.3 26.4 21.6 29.3 21.6
31.0 29.5 25.3 29.4 26.0
33.6 35.4 30.6 33.6 29.7
30.5 29.6 26.9 30.8 28.0
26.8 30.7 31.9 40.0 29.6
30.3 38.8 32.5 40.4 34.0
32.2 42.7 36.8 42.1 37.9
31.5 33.3 34.3 40.7 33.3
32.3 39.2 36.3 49.0 37.9
40.1 45.6 44.5 48.9 41.0
41.3 48.2 45.2 55.5 46.9
35.0 45.4 43.2 51.2 43.0
21.8 22.8 22.2 26.1 21.6
30.8 28.2 29.8 31.4 26.5
34.9 34.1 31.9 32.7 31.4
30.7 28.7 28.4 26.5 29.7
22.2 23.8 21.8 27.8 22.8
30.8 32.3 26.1 31.0 29.5
34.9 36.2 30.2 33.5 30.9
29.8 31.5 28.0 30.0 27.4
26.5 26.9 32.1 35.6 29.0
32.2 34.9 35.2 37.9 35.1
33.0 40.4 37.1 44.6 40.0
31.1 32.9 33.0 37.7 35.3
30.5 40.2 37.5 50.3 37.5
37.9 46.4 42.2 53.1 44.7
38.1 51.4 46.2 57.0 41.1
38.9 42.8 42.3 51.4 41.6
22.2 24.2 23.7 24.9 21.6
28.6 31.1 27.0 30.2 26.1
33.1 36.4 28.4 35.2 31.1
28.9 28.0 27.2 28.4 25.9
UKPDS33 Full Correlated ASPEN All Placebo ASPEN All Placebo Correlated ASPEN All Atorvastatin ASPEN All Atorvastatin Correlated ASPEN Primary Placebo ASPEN Primary Placebo Correlated ASPEN Primary Atorvastatin ASPEN Primary Atorvastatin Correlated ASPEN Secondary Placebo ASPEN Secondary Placebo Correlated ASPEN Secondary Atorvastatin ASPEN Secondary Atorvastatin Correlated ASPEN Full
22.8 13.6 37.7 18.6 40.4 21.3 39.8 22.2 41.0 23.2 29.3 14.7 33.3 9.8
24.9 13.1 33.4 17.1 38.0 22.3 40.1 21.4 38.8 23.7 18.0 8.4 26.2 7.4
22.6 13.4 32.2 16.8 37.6 20.1 43.3 23.3 40.3 20.9 22.5 13.7 31.1 8.2
24.7 12.4 31.4 16.6 37.3 22.6 38.2 20.1 39.0 20.9 20.9 14.6 26.8 8.0
33.5 17.7 24.7 20.7 26.8 23.2 30.3 25.7 30.0 21.4 23.1 14.4 26.0 9.5
34.9 12.0 22.1 18.5 27.1 23.5 29.3 23.7 29.8 20.2 17.9 11.6 16.3 11.4
34.5 14.0 18.1 21.0 28.6 25.0 29.7 24.4 26.8 18.7 19.5 13.9 21.5 12.4
30.8 14.2 21.8 20.6 24.4 24.7 28.3 24.1 27.1 19.1 19.8 14.7 19.0 9.1
30.6 12.5 22.9 19.8 26.2 16.9 23.6 17.6 24.4 19.0 23.7 24.6 42.3 7.7
31.3 12.6 18.2 20.6 22.7 14.5 26.1 19.7 24.8 14.0 17.0 24.8 38.9 6.7
30.1 10.7 20.8 17.7 25.8 15.8 24.7 17.5 24.6 15.3 22.0 23.6 35.8 7.7
31.1 12.6 21.2 15.8 27.0 16.0 23.2 15.4 23.4 12.3 21.6 26.5 37.4 7.0
48.8 21.2 36.8 30.6 42.6 34.4 48.3 34.5 46.1 19.8 25.1 19.0 35.8 18.8
47.7 20.9 36.8 28.2 43.2 31.7 45.6 35.4 42.7 14.8 17.5 17.5 27.8 17.3
51.1 23.1 34.6 28.9 40.9 29.1 43.6 33.6 47.5 18.1 21.8 20.4 29.5 16.1
50.4 24.3 34.0 29.9 42.5 33.1 41.5 32.1 44.3 15.8 17.7 16.0 28.9 15.9
25.8 15.7 33.6 13.4 29.2 23.7 42.4 15.8 28.6 23.6 28.3 12.7 21.1 8.5
23.8 11.5 34.5 10.0 29.7 19.9 40.6 15.2 31.5 18.1 18.7 6.5 18.9 8.6
21.9 14.2 31.1 13.2 28.4 22.4 40.6 15.3 32.0 21.3 23.0 11.2 22.2 8.5
24.7 16.0 34.8 13.2 29.1 22.6 38.4 16.1 31.0 21.2 20.7 12.2 20.0 9.2
36.1 14.6 21.6 15.8 24.5 24.5 29.5 19.8 27.0 21.4 24.6 11.9 15.6 7.3
31.4 15.8 22.0 16.3 24.4 24.8 29.6 18.9 25.9 21.4 16.0 6.1 9.3 10.1
34.2 19.2 23.4 19.1 22.4 22.9 27.7 18.3 25.8 20.6 20.7 10.4 18.0 8.3
33.4 14.1 20.1 16.9 22.7 19.5 30.0 19.2 25.7 20.4 18.9 12.2 12.7 9.4
30.0 13.9 20.7 14.3 22.2 16.3 23.3 14.6 20.4 17.8 24.9 19.3 35.6 7.4
30.2 13.4 20.9 13.1 21.2 17.0 22.0 14.7 20.9 13.3 20.1 17.4 27.0 7.4
28.9 12.8 20.1 16.4 21.9 15.9 21.5 15.9 20.0 14.2 24.2 20.7 30.9 9.3
26.9 15.5 17.5 14.9 20.9 16.8 22.5 14.5 19.7 14.0 19.6 20.0 30.6 7.7
49.3 21.0 41.3 18.3 36.4 31.4 46.3 23.6 34.6 21.0 27.4 12.1 20.9 17.5
45.7 21.6 36.9 22.0 27.4 31.6 44.0 24.6 34.3 14.5 16.7 6.7 17.7 17.7
47.2 22.0 34.1 17.5 29.9 35.3 47.2 21.8 37.2 19.2 20.7 10.9 19.7 16.4
47.8 21.3 35.9 18.1 32.3 34.0 45.7 25.3 33.2 16.9 17.6 10.9 19.6 19.9
29.6 11.1 9.3 9.5 15.6 8.9 18.4 11.4 18.7 39.9 26.9 17.8 7.7 12.1
36.4 10.6 10.9 9.9 20.2 11.8 19.1 11.9 20.3 40.6 28.7 19.6 12.8 10.9
35.4 10.5 12.3 11.5 22.4 8.8 18.3 12.5 18.7 43.3 31.9 25.1 27.8 10.8
31.6 9.5 8.4 8.5 16.7 7.6 18.0 12.8 18.8 39.2 24.4 19.9 14.5 10.8
33.3 21.1 26.1 30.6 37.0 30.1 35.8 30.1 35.5 9.5 7.7 18.9 23.5 16.7
40.5 22.9 29.4 27.6 36.4 34.0 34.6 30.9 38.4 10.0 9.8 20.0 28.8 21.6
41.8 23.7 29.7 27.1 35.1 32.2 33.7 32.7 35.7 18.8 20.4 28.2 33.8 16.8
35.5 20.8 25.9 28.8 37.0 31.9 37.0 33.8 38.8 9.3 8.7 23.4 26.1 14.4
46.6 21.5 29.7 27.6 35.3 23.6 32.5 26.1 34.6 19.4 26.2 43.2 50.0 15.0
50.6 24.4 29.4 28.6 41.5 25.8 33.3 25.5 36.2 17.0 30.1 40.3 48.9 16.5
56.5 18.2 29.1 28.5 38.6 25.1 31.2 23.7 35.3 20.7 36.4 42.6 54.3 15.4
52.0 20.5 29.4 25.7 38.2 22.1 32.8 25.1 33.7 20.8 28.1 45.3 52.5 14.7
25.6 14.1 10.2 9.5 6.1 8.7 9.3 10.2 11.7 46.7 41.7 25.8 23.7 18.2
31.0 12.5 11.6 12.4 12.1 7.7 11.2 12.2 12.4 48.5 44.0 24.5 24.9 18.1
34.7 12.8 9.7 12.3 13.9 7.3 12.1 9.3 12.2 50.6 46.1 32.2 33.0 17.6
29.3 13.6 8.9 10.1 8.2 8.0 9.5 10.1 11.0 48.6 44.0 28.0 24.3 14.9
29.3 9.8 9.7 9.3 10.2 9.5 18.0 10.5 15.1 37.9 25.8 21.7 10.6 15.0
30.9 10.8 12.0 8.5 11.6 9.7 18.7 8.9 15.7 39.7 24.4 23.4 15.0 14.8
36.7 10.0 13.1 11.1 11.2 9.1 21.9 9.3 13.9 43.4 31.9 28.8 23.2 13.1
30.2 7.5 12.2 8.5 11.3 9.0 15.5 10.9 15.0 39.4 23.8 26.1 18.5 12.5
34.9 20.1 27.0 21.2 29.4 31.5 34.2 26.1 31.6 10.0 7.1 14.7 14.2 18.4
39.4 21.2 27.8 26.1 32.0 28.7 36.2 28.7 30.1 10.4 11.7 13.8 19.6 15.5
42.5 23.3 27.6 25.4 30.8 29.6 34.1 27.5 31.4 20.3 23.8 21.2 28.3 17.3
37.5 19.7 28.8 25.8 29.8 29.1 35.5 26.1 28.3 12.4 9.5 17.5 21.0 17.2
46.8 20.6 31.7 22.0 32.8 22.1 34.9 20.8 31.5 17.6 34.3 32.8 46.2 16.9
48.1 23.1 31.1 23.7 31.5 25.1 31.3 23.3 29.4 20.7 31.4 34.2 44.8 16.1
52.1 20.8 33.5 23.8 34.6 23.2 31.9 22.4 31.1 23.1 36.9 38.7 49.1 15.7
48.5 19.8 31.2 25.5 35.2 21.9 32.5 22.6 29.9 18.3 29.7 37.5 46.9 17.0
24.7 14.8 8.2 11.8 8.7 9.5 9.4 11.6 10.0 48.2 42.6 30.7 24.0 16.7
32.4 12.3 11.5 13.9 10.2 9.0 11.8 9.7 12.6 47.9 43.9 32.1 27.9 16.3
34.6 11.6 12.0 12.3 12.7 5.7 9.8 10.5 11.2 50.6 46.2 34.7 34.2 17.3
27.6 12.6 9.3 12.8 7.5 8.4 10.0 12.3 9.2 47.8 42.1 34.1 31.1 15.1
ASPEN Full Correlated ADVANCE Standard ADVANCE Standard Correlated ADVANCE Intensive ADVANCE Intensive Correlated ADVANCE Asia Standard ADVANCE Asia Standard Correlated ADVANCE Asia Intensive ADVANCE Asia Intensive Correlated ADVANCE EME Standard ADVANCE EME Standard Correlated ADVANCE EME Intensive ADVANCE EME Intensive Correlated ADVANCE Eastern Europe Standard ADVANCE Eastern Europe Standard Correlated ADVANCE Eastern Europe Intensive ADVANCE Eastern Europe Intensive Correlated ADVANCE Full
26.2 60.0 120.2 66.9 127.4 66.6 147.1 75.2 147.1 88.0 151.9 93.8 161.5 71.7 149.3 72.3 149.2 53.9
27.6 55.6 117.9 61.4 117.8 54.1 133.0 65.2 140.0 75.2 147.7 82.9 156.2 69.1 142.7 69.1 147.6 53.5
25.7 59.6 122.2 59.8 128.9 64.2 139.6 73.1 151.4 72.6 144.6 89.9 152.5 72.1 146.1 74.6 147.4 59.3
29.0 16.2 60.0 36.5 121.8 66.5 68.7 45.0 128.9 68.7 61.3 29.3 144.2 55.6 67.9 35.9 152.0 60.8 83.0 73.1 147.7 104.2 93.3 80.9 150.5 109.0 68.5 61.8 142.2 96.5 72.1 72.6 144.1 100.1 54.3 55.3
16.6 29.5 41.3 33.5 45.5 27.5 38.0 34.5 41.8 68.0 86.6 73.2 89.8 60.2 73.5 54.2 81.6 58.4
15.0 32.1 54.3 38.0 56.0 30.7 40.6 36.0 51.9 67.0 90.6 69.9 92.1 60.1 78.5 54.7 76.9 53.2
15.4 36.8 49.0 35.0 52.3 24.1 45.2 35.2 52.7 67.2 82.7 77.7 87.7 58.7 79.2 58.7 82.7 55.5
17.8 14.4 14.5 15.4 28.4 32.6 32.4 52.8 42.3 46.7 50.7 65.4 63.2 62.1 95.4 80.5 84.3 81.2 99.8 85.5 94.2 61.9 51.4 51.4 52.3 68.4 62.2 69.0 99.2 78.1 85.7 87.7 107.7 90.8 102.1 52.3 49.2 47.2 51.4 74.4 65.5 70.3 93.6 85.3 92.9 91.8 113.2 98.3 103.4 60.2 56.5 55.3 58.7 76.1 66.6 72.1 104.1 89.7 97.1 93.5 115.3 106.4 113.1 74.7 71.8 71.6 71.8 85.4 89.9 83.0 124.1 104.7 105.7 104.6 136.1 123.1 119.1 83.4 79.3 78.0 78.3 97.0 83.3 87.5 128.0 110.4 115.5 110.6 138.2 122.0 128.1 62.2 53.8 60.0 55.5 77.2 74.9 73.7 116.2 97.7 99.8 95.5 122.6 105.1 107.4 63.6 53.7 61.7 56.7 79.6 78.3 76.2 117.1 96.6 103.6 97.2 120.3 108.8 108.0 54.2 54.5 58.5 53.7 58.4 60.9 64.4
33.0 65.1 95.3 71.6 93.9 67.9 98.9 71.8 112.4 80.7 110.7 87.1 122.6 70.4 104.7 76.1 105.9 60.5
26.0 45.0 108.1 38.9 98.5 40.5 121.2 44.0 116.9 64.4 128.8 58.4 126.9 54.5 122.4 46.1 116.3 35.6
25.4 41.6 98.1 35.9 90.4 50.0 111.3 41.6 110.2 57.2 119.5 58.2 113.2 50.4 121.3 43.5 105.0 40.5
27.8 40.5 99.2 38.5 96.7 50.6 115.9 43.6 113.0 58.8 127.2 48.3 109.3 47.8 120.4 39.0 113.1 37.1
29.0 42.6 98.8 39.0 94.4 48.7 114.2 44.5 110.8 56.8 125.5 54.8 115.1 52.4 121.6 45.0 107.6 37.4
15.1 33.8 54.1 28.5 55.6 23.2 48.0 28.4 45.3 68.0 94.6 68.8 96.1 59.1 86.5 53.4 81.2 46.1
16.4 22.4 31.8 25.4 41.0 21.7 29.1 25.3 33.6 53.9 72.4 64.1 82.0 47.9 60.7 47.8 67.1 46.7
15.7 24.3 40.6 28.5 43.8 21.9 38.9 21.9 41.7 63.5 80.2 60.9 80.5 50.0 72.5 44.6 75.0 44.5
15.7 19.7 29.4 45.9 40.9 80.1 27.6 39.9 44.1 76.8 23.6 40.6 37.5 80.6 30.1 48.1 42.3 81.5 59.4 62.0 76.7 110.7 62.0 61.4 78.9 105.3 53.3 54.4 67.7 104.8 47.8 44.1 66.6 97.4 46.2 46.0
16.3 35.9 67.7 36.2 69.4 36.9 72.1 38.1 74.9 62.4 91.0 56.0 94.5 49.3 84.5 40.1 80.3 43.4
11.9 40.7 74.6 40.7 71.8 39.7 80.3 41.0 80.9 58.2 96.2 54.7 90.0 47.3 85.3 39.6 85.6 45.5
13.0 31.0 29.4 42.6 51.2 45.6 74.3 88.6 76.4 39.6 48.1 44.6 70.4 91.6 79.9 41.7 50.8 47.2 79.7 91.8 80.8 43.8 52.9 54.8 79.3 92.3 82.0 57.2 67.3 63.6 90.4 114.1 97.2 53.8 72.4 73.6 87.1 109.4 101.8 45.7 58.1 55.1 81.9 97.9 84.2 42.1 59.8 54.0 79.9 101.7 87.6 44.7 50.6 47.3
27.3 45.6 80.3 41.7 79.6 53.2 87.7 50.9 90.0 67.3 99.3 59.9 99.1 49.4 88.7 52.8 83.8 46.1
27.4 47.4 74.1 47.9 74.5 51.8 80.6 57.3 87.5 71.9 99.8 68.7 99.3 58.2 81.8 49.1 89.3 48.4
5.3 9.3 39.1 12.0 48.1 19.2 49.5 19.3 49.7 10.7 51.9 18.0 58.8 15.4 45.0 10.0 51.3 10.4
8.6 10.1 39.6 12.5 43.3 16.2 43.3 17.9 48.8 21.9 53.9 27.3 58.3 17.4 47.6 17.4 54.1 12.7
11.5 16.4 51.1 17.9 58.9 12.5 57.9 16.9 57.1 25.8 62.8 27.3 70.1 19.3 53.3 19.7 57.0 16.6
8.0 15.0 44.2 16.0 47.8 16.9 51.5 18.0 54.2 21.2 56.1 23.1 59.1 16.9 49.3 16.0 49.1 14.6
23.3 21.4 34.9 24.3 39.1 25.2 28.7 25.6 35.1 46.2 65.0 50.1 73.4 44.2 57.0 38.8 62.2 40.5
22.9 23.5 31.8 27.9 36.0 22.2 27.6 24.7 34.0 52.6 63.1 62.0 69.6 49.0 59.4 48.6 59.6 45.9
24.7 25.5 39.9 30.3 46.8 21.6 31.4 28.2 43.7 51.8 76.4 59.6 77.5 46.7 65.1 49.9 68.6 49.9
25.7 26.2 34.9 27.6 39.5 22.2 30.1 26.9 36.3 50.6 67.9 58.9 71.9 45.3 60.4 48.2 59.5 49.0
25.4 38.8 75.0 48.7 77.6 42.9 70.4 44.2 81.2 52.1 93.1 57.2 91.6 47.8 86.4 47.7 88.0 46.8
24.3 26.8 43.8 51.6 68.0 77.9 49.7 54.9 75.4 83.9 45.9 45.7 75.1 84.9 50.3 49.0 81.9 88.6 59.9 65.8 96.4 94.3 61.8 62.2 94.2 102.8 50.4 51.2 85.6 87.5 51.0 53.7 84.4 94.4 52.4 53.9
24.3 46.4 74.7 50.8 80.1 51.3 77.8 54.4 85.4 56.0 90.5 63.5 89.9 50.7 87.6 50.5 89.1 47.2
12.7 14.0 10.6 9.6 10.1 20.9 10.2 15.8 13.4 15.6 24.1 14.0 29.5 25.2 16.9 22.2 14.9 14.2
13.5 11.6 7.6 6.1 10.6 18.8 13.7 14.0 10.8 21.3 25.6 20.9 29.3 23.2 18.4 16.3 18.1 13.3
11.8 14.9 26.6 15.1 29.2 11.1 12.4 6.8 14.7 20.8 37.9 23.0 35.8 21.2 26.6 19.4 27.8 15.0
11.5 9.7 14.6 10.7 17.8 13.0 10.0 6.2 11.8 20.8 24.2 18.1 25.9 22.7 18.2 19.2 17.0 11.8
5.3 11.7 30.1 10.7 27.3 22.4 38.1 19.6 31.1 12.2 39.4 11.6 39.1 20.2 33.0 19.3 30.1 14.5
9.2 8.6 30.9 7.1 24.8 19.2 32.7 15.9 34.6 18.8 38.5 17.7 39.5 16.4 35.9 15.3 33.7 8.9
10.9 10.3 41.2 9.0 37.8 11.7 44.1 10.2 40.2 17.6 47.9 18.4 46.7 17.7 41.7 16.9 30.9 11.6
6.8 11.2 34.5 9.1 33.4 11.4 39.9 7.9 35.7 20.3 41.7 18.9 40.5 17.3 39.2 17.1 27.9 10.0
21.8 19.6 26.9 19.3 32.7 23.2 22.9 22.8 25.0 37.1 60.4 45.8 59.8 37.4 50.1 33.6 48.8 36.7
22.6 17.3 27.2 25.4 30.8 20.2 23.8 19.9 25.6 41.2 59.1 49.2 66.8 37.8 52.4 40.5 53.4 42.0
22.1 21.4 40.0 26.5 38.8 17.1 30.9 24.4 30.5 46.5 70.4 49.1 69.1 44.3 56.4 37.8 61.7 42.4
21.7 19.1 32.2 24.3 34.9 21.2 26.9 23.1 32.7 49.4 58.8 51.7 62.7 37.7 49.4 33.5 56.0 40.6
23.8 33.5 65.8 32.0 61.1 37.9 62.7 38.7 68.4 41.7 82.0 43.1 75.0 36.9 73.7 35.0 69.4 42.3
27.9 38.9 65.6 35.1 62.8 38.1 65.6 39.3 64.3 49.9 76.2 47.6 77.7 47.2 77.4 36.7 71.8 39.3
25.9 41.1 73.1 38.6 64.3 37.3 74.1 37.9 72.7 47.4 83.0 48.7 84.6 42.9 87.9 37.8 74.6 44.2
26.1 37.5 63.2 40.3 63.4 37.6 74.6 37.9 65.2 51.8 78.9 46.7 80.3 41.0 71.4 36.4 73.7 40.8
10.6 15.5 7.6 15.9 7.2 28.6 14.0 22.1 7.6 19.9 20.3 16.5 22.9 29.1 17.8 29.9 16.0 20.6
14.2 17.2 8.0 12.2 5.3 25.0 17.5 18.5 10.9 21.1 23.5 19.1 22.2 23.9 20.2 22.4 19.1 12.5
12.9 16.1 16.9 11.5 17.1 16.0 9.2 13.8 9.8 22.3 29.3 19.5 32.7 25.1 22.7 23.4 21.5 12.7
13.4 13.4 11.7 12.3 12.7 16.2 8.5 11.6 6.6 21.8 19.9 17.2 22.3 25.8 18.8 22.8 16.2 13.2
ADVANCE Full Correlated ACCORD BP Standard Therapy ACCORD BP Standard Therapy Correlated ACCORD BP Intensive Therapy ACCORD BP Intensive Therapy Correlated ACCORD BP Full
102.4 106.5 102.9 101.8 53.0 51.5 55.7 55.7 121.6 112.1 123.7 116.1 49.8 50.6 57.6 52.7 112.7 107.5 116.1 112.4 49.4 50.4 58.0 57.0
70.2 44.7 71.4 45.7 68.2 43.0
67.0 54.4 87.3 51.1 82.0 52.6
71.7 81.2 79.0 80.0 78.7 93.7 90.8 94.4 90.8 83.3 80.6 82.0 85.6 51.7 56.5 60.9 62.7 68.0 60.2 58.0 62.1 60.7 46.7 46.6 51.5 52.8 78.4 114.8 107.4 115.2 109.4 101.8 98.5 111.7 103.2 116.6 107.3 117.5 114.4 49.0 57.4 58.7 61.3 56.4 58.5 56.5 62.1 63.5 37.0 39.0 43.8 44.4 74.0 104.4 100.6 104.0 100.2 104.7 100.3 103.7 98.1 96.2 90.7 97.9 94.3 51.3 61.5 64.4 67.3 63.0 60.4 60.6 66.5 63.4 46.2 44.7 48.2 47.1
66.2 47.7 78.1 37.6 64.4 41.8
58.6 43.8 73.9 35.1 62.2 37.4
61.3 46.7 85.3 43.0 70.8 47.8
64.8 70.7 66.9 78.0 68.5 51.1 59.7 60.3 62.6 66.7 77.5 105.0 104.5 112.3 105.2 44.7 51.1 47.8 52.7 54.2 70.1 90.9 91.4 97.4 92.7 46.6 55.3 52.6 58.7 59.5
76.5 57.2 99.3 44.9 76.5 52.0
81.5 59.2 99.4 45.5 69.8 53.2
29.3 25.2 30.3 25.9 28.4 24.8
37.3 28.9 42.8 27.7 41.1 27.9
46.1 32.7 54.1 31.5 52.6 33.4
38.1 27.3 39.6 29.4 38.8 26.6
49.5 19.4 42.7 15.6 38.2 16.2
61.3 27.6 47.8 26.0 46.9 24.9
60.6 33.7 61.8 34.3 60.6 35.8
57.5 30.9 48.1 27.4 47.7 24.2
68.5 35.1 74.9 34.0 66.7 30.1
81.3 41.2 79.3 35.2 79.4 40.9
73.7 48.2 81.0 41.9 81.6 45.7
5.6 32.5 28.9 32.4 28.1 31.9
16.4 32.6 34.2 32.4 33.4 33.6
24.9 38.5 46.6 35.0 46.6 36.5
11.7 34.3 33.7 32.4 33.7 32.5
17.2 28.0 30.3 28.2 21.4 28.0
26.0 29.5 37.4 28.8 33.0 29.5
29.5 35.3 55.4 32.9 43.3 31.3
23.0 30.6 39.7 30.1 35.3 30.8
47.6 19.3 40.7 14.6 30.6 16.9
53.2 26.1 50.0 21.2 43.9 23.3
55.2 34.2 60.8 31.3 55.7 29.4
49.3 30.2 46.0 24.5 42.8 26.1
59.0 36.0 70.6 25.9 62.2 32.4
67.5 39.8 79.1 34.7 66.4 40.1
73.2 46.5 87.0 40.9 71.6 45.6
63.9 45.1 80.9 36.1 70.3 41.7
7.7 35.0 30.1 36.3 30.8 34.5
11.1 35.3 34.1 33.4 32.5 35.2
20.5 36.3 47.0 37.9 45.2 39.1
9.2 33.8 34.8 37.7 35.8 35.0
ACCORD BP Full Correlated KP 20-34 KP 20-34 Correlated KP 35-50 KP 35-50 Correlated KP 50-65 KP 50-65 Correlated KP 65-75 KP 65-75 Correlated KP 75+ KP 75+ Correlated KP Total
114.2 112.2 120.4 116.7 81.4 73.7 78.5 74.7 114.1 9.8 10.4 11.8 11.3 9.5 9.6 10.7 10.3 10.1 13.3 13.9 15.4 14.1 8.6 8.1 9.7 9.7 13.5 20.9 23.5 25.8 24.0 21.4 25.5 27.4 23.4 20.6 30.8 34.0 33.1 33.5 20.0 25.8 25.0 25.2 25.0 40.8 44.5 43.9 41.3 44.3 49.5 51.5 52.1 43.6 60.2 65.7 64.3 63.2 50.9 52.1 57.5 54.2 52.6 70.3 71.3 76.0 83.7 81.7 84.5 86.5 96.2 87.7 97.1 96.7 104.0 106.8 90.1 86.1 94.4 99.1 103.6 134.6 113.2 120.7 150.3 147.5 130.6 136.9 164.1 168.4 152.9 140.3 141.0 164.8 155.6 132.7 144.1 166.2 178.8 55.3 61.4 60.3 66.9 63.8 65.3 66.0 69.5 64.6
30.8 38.0 54.9 39.4 39.8 45.0 58.5 49.1 74.7 81.7 87.4 83.2 5.4 7.4 7.8 5.6 7.9 9.6 9.9 10.3 9.4 13.1 13.3 12.1 6.4 8.2 9.2 8.6 6.6 8.0 10.8 8.5 11.4 13.1 15.8 13.0 6.5 9.6 11.8 9.4 17.3 17.7 22.6 18.9 14.6 19.1 22.2 21.7 10.3 12.7 16.6 12.7 17.5 22.5 25.7 19.7 21.4 23.7 26.0 27.3 15.7 20.9 23.0 21.6 34.3 45.2 45.0 42.2 35.7 45.5 45.6 43.7 21.8 27.7 29.8 27.8 35.5 45.0 48.4 44.8 42.4 52.5 53.3 49.4 33.7 46.4 45.8 47.5 62.3 72.6 75.0 81.0 73.6 85.3 88.5 91.3 40.4 52.3 57.8 55.4 69.1 80.6 81.2 83.4 85.3 93.7 95.8 96.6 87.9 94.8 97.9 116.1 124.5 121.1 132.3 153.4 141.9 149.9 148.3 172.8 97.4 101.1 107.8 120.2 123.6 127.4 138.2 151.9 157.8 159.1 163.7 180.3 28.6 36.9 37.5 42.3 52.4 58.2 54.3 59.3 56.5 60.1 65.7 62.5
27.1 4.5 4.8 6.7 8.2 16.4 16.5 31.5 33.3 85.7 90.3 27.9
33.9 6.6 6.2 11.5 14.1 22.3 25.9 40.8 38.5 89.3 92.9 34.1
44.7 34.4 6.5 6.3 7.2 6.7 12.9 8.8 13.0 10.8 26.0 21.3 30.7 25.8 43.4 45.0 46.2 46.2 92.0 111.9 97.4 107.5 31.7 36.5
26.0 33.9 48.9 37.5 39.3 44.2 56.6 46.7 60.5 72.7 86.3 77.2 4.9 7.3 7.9 7.0 8.3 8.8 9.4 9.5 9.4 10.1 12.0 11.6 6.3 8.4 10.1 7.5 5.9 8.5 8.9 9.1 12.6 10.5 15.3 12.1 7.0 10.0 11.0 9.4 14.0 18.5 21.6 19.3 17.5 20.4 21.1 22.1 10.1 14.9 14.9 14.2 17.6 22.8 23.9 20.3 20.9 26.0 26.7 25.6 12.6 21.1 21.2 18.6 32.2 43.6 42.0 42.2 37.3 46.4 40.7 47.1 18.6 33.8 32.1 27.3 41.7 47.6 51.4 45.1 42.7 50.6 52.3 49.0 37.2 43.5 47.1 51.2 61.7 73.2 75.4 75.9 73.2 84.9 84.8 91.1 43.5 50.5 58.4 55.3 70.4 78.1 83.5 79.9 84.8 89.7 94.3 98.3 89.0 88.9 101.3 116.3 120.7 122.9 136.7 150.2 144.2 148.0 155.0 172.8 96.5 102.4 108.8 122.1 127.0 126.6 144.5 148.9 152.2 161.2 163.1 179.8 28.0 35.5 38.0 39.5 49.3 54.7 58.5 59.9 54.5 61.7 65.4 67.1
29.0 4.6 5.2 6.4 8.9 14.2 16.6 31.3 33.3 86.9 88.2 27.4
32.4 6.6 5.3 9.2 12.5 22.7 26.1 39.0 40.2 90.7 93.6 30.7
45.4 33.2 8.0 5.3 8.0 5.8 10.6 10.4 13.9 11.3 21.6 20.5 27.1 23.2 41.2 44.9 45.3 49.0 93.4 112.3 98.7 110.4 33.4 35.8
KP Total Correlated NDR 20-34 NDR 20-34 Correlated NDR 35-50 NDR 35-50 Correlated NDR 50-65 NDR 50-65 Correlated NDR 65-75 NDR 65-75 Correlated NDR 75+ NDR 75+ Correlated NDR Total
90.0 88.7 91.9 93.5 12.4 12.7 12.1 11.7 13.9 15.8 14.5 13.9 12.1 16.7 12.5 13.8 18.2 23.6 20.5 21.0 32.9 34.7 32.2 30.9 36.1 35.2 33.3 31.3 52.4 50.6 51.7 51.1 79.2 83.3 81.6 83.8 77.1 63.2 69.3 71.1 111.7 106.9 107.9 106.3 43.6 42.3 35.9 42.5
NDR Total Correlated
82.4
75.7
78.0
77.7
70.7 47.3 80.8 39.2 77.5 42.9
107.9 13.6 13.6 24.4 27.3 50.0 55.6 95.4 108.4 148.5 156.4 63.3
115.3 14.9 14.9 22.9 29.6 49.5 57.7 95.6 107.9 155.7 159.3 69.6
100.5 98.7 96.1 106.6 98.0 109.3 107.5 109.5 110.4 65.6 67.4 75.8 72.8 98.4 91.7 12.2 10.5 11.9 13.0 12.2 11.0 12.5 13.1 11.9 8.5 9.9 11.1 9.5 9.5 9.7 15.9 12.5 14.8 14.8 14.2 12.5 11.8 16.2 14.4 6.1 7.9 8.9 8.7 11.8 14.3 20.5 38.2 41.1 41.2 38.9 21.8 22.3 24.1 24.3 19.0 25.7 25.2 24.5 23.1 25.4 26.8 43.9 49.7 48.8 45.0 28.1 37.1 31.0 34.7 23.4 27.2 29.7 25.3 25.0 29.7 53.7 68.2 77.1 76.3 75.2 40.0 48.8 46.6 48.0 47.0 52.1 52.4 47.5 43.4 51.3 59.0 83.6 85.7 89.0 86.9 59.4 63.0 62.9 63.8 50.7 55.5 54.6 59.5 53.1 58.6 102.0 80.6 87.9 84.1 96.3 73.9 72.9 76.8 83.9 81.0 83.6 83.8 95.7 85.7 90.3 110.2 96.5 92.6 100.9 105.2 102.8 98.4 99.8 110.2 94.1 90.5 89.9 100.3 97.9 101.4 179.9 110.6 90.1 96.2 128.4 136.2 117.9 126.5 155.8 149.5 129.7 139.0 165.1 167.8 150.7 186.5 125.4 100.1 102.8 135.6 151.5 140.5 142.6 163.7 151.4 134.5 136.8 164.3 180.8 156.6 73.9 73.2 71.1 65.7 77.3 61.3 57.6 64.7 68.2 62.1 58.7 61.7 65.8 67.2 67.1
105.9 12.1 15.2 22.4 30.9 48.9 56.9 93.4 107.1 152.9 165.9 68.0
80.4 52.1 97.1 37.9 68.3 43.0
76.1 52.7 92.8 41.9 74.9 45.6
103.1 85.7 80.7 88.9 83.9 12.8 12.0 13.4 14.2 12.0 13.8 12.4 14.5 14.6 14.9 20.2 37.6 40.6 43.1 38.2 27.5 45.8 47.8 50.1 46.8 49.3 66.7 74.0 73.7 76.3 57.5 83.5 84.4 88.8 83.0 108.1 83.1 85.2 89.6 94.0 105.0 97.6 103.2 99.1 103.4 181.1 112.0 94.5 96.3 129.4 184.8 122.5 101.4 104.2 131.2 71.8 73.8 69.7 73.0 79.0
83.9 47.1 87.5 44.8 90.5 48.9
71.3 12.8 14.0 17.0 19.7 39.1 34.1 54.0 65.5 61.5 86.1 44.6
67.2 13.1 15.2 17.0 19.0 37.7 33.3 52.9 55.9 55.0 55.7 42.1
75.7 13.4 14.5 15.5 20.0 38.2 37.8 52.5 61.5 55.1 58.3 43.3
76.2 14.0 13.3 16.0 20.5 39.7 38.2 56.1 62.1 54.9 56.3 43.2
86.2 12.0 14.2 8.0 12.7 28.1 25.1 47.0 62.1 70.1 98.8 35.1
81.5 12.4 14.5 13.6 17.2 25.9 28.9 46.7 61.7 62.7 82.7 37.5
81.0 11.4 12.2 10.5 14.6 26.3 27.9 48.5 59.4 56.8 75.7 33.5
83.6 11.2 12.5 11.7 14.4 28.1 31.8 45.7 60.7 65.1 85.2 40.9
84.3 19.4 20.4 29.4 35.7 56.3 58.2 64.3 70.5 50.5 77.1 44.9
83.1 19.7 21.1 31.6 35.8 54.1 53.7 54.2 72.6 20.2 37.8 45.7
87.0 21.7 21.8 31.8 35.4 57.0 57.3 58.3 76.6 22.5 32.0 48.4
87.5 90.6 86.5 92.1 91.5 21.9 10.5 11.7 13.4 11.1 21.9 15.1 16.4 14.0 13.8 28.9 12.8 13.0 11.3 10.5 37.4 19.1 20.9 21.0 19.3 58.3 30.9 35.8 30.0 35.9 55.2 31.1 33.1 34.4 32.3 57.4 56.2 51.9 54.2 55.4 68.2 79.4 82.2 82.7 85.6 25.3 77.4 68.2 64.5 65.5 42.1 114.9 109.5 105.7 105.4 51.6 44.4 40.7 38.6 41.5
68.0 14.5 14.3 13.7 18.9 35.3 33.5 57.0 62.1 63.3 82.8 40.8
72.3 13.8 14.8 18.3 21.3 36.6 35.6 50.8 60.3 52.5 59.1 42.4
71.0 13.0 16.4 17.8 18.2 38.0 35.8 48.2 60.5 48.5 56.2 40.9
74.3 11.5 13.6 16.0 17.9 38.8 35.4 52.2 59.2 50.6 58.6 41.8
84.0 10.9 13.0 9.3 15.5 27.3 29.4 43.9 65.5 72.1 96.0 37.0
77.2 11.1 14.2 14.7 15.7 28.0 30.4 49.6 59.2 59.7 78.4 37.7
84.5 10.2 14.7 11.5 15.7 27.0 26.4 46.1 55.7 60.8 78.1 37.5
82.6 10.7 12.9 10.6 14.1 29.2 27.8 46.9 57.8 58.9 83.6 35.6
86.5 19.0 19.8 28.7 39.4 55.8 55.6 54.1 71.3 52.6 74.9 48.8
88.1 21.5 21.2 30.9 41.0 57.2 54.7 57.9 71.6 25.1 37.4 49.2
88.6 21.3 21.8 30.7 35.4 56.8 57.2 59.3 75.7 22.2 41.0 42.4
87.7 20.9 19.8 30.4 35.9 52.5 57.7 59.6 72.1 30.9 39.5 50.0
40.9 6.8 8.3 2.0 5.0 11.4 10.6 19.0 34.2 8.1 41.5 12.2
50.4 6.5 10.7 8.2 11.2 13.3 12.2 11.4 29.5 9.0 34.9 5.4
56.7 8.0 8.6 6.8 10.8 12.8 13.6 9.4 32.1 5.7 33.4 7.6
49.7 7.1 7.1 4.1 5.9 9.3 7.2 14.7 29.5 14.7 39.4 8.2
55.3 12.3 15.1 15.3 18.7 39.9 33.7 55.9 62.5 50.9 65.4 48.1
62.8 13.3 17.0 16.6 22.8 40.3 35.2 57.8 61.3 53.4 58.7 44.1
67.8 13.2 14.0 18.2 20.6 42.3 34.6 55.7 59.2 51.2 60.7 45.9
64.2 73.2 12.7 14.4 14.9 14.9 16.4 11.5 18.1 14.0 39.7 32.3 33.4 32.3 53.6 55.3 59.3 70.8 55.9 73.8 63.7 100.0 43.9 45.7
80.5 13.9 16.1 13.5 17.5 31.6 34.2 55.0 68.8 75.5 92.9 46.9
82.0 11.8 14.4 13.6 18.0 30.3 33.6 52.6 68.9 73.4 98.9 42.5
75.5 12.2 14.8 11.8 16.0 33.3 32.3 56.6 67.4 78.3 94.4 41.7
35.5 6.9 6.5 1.7 4.1 9.2 10.1 14.6 4.8 37.3 35.4 11.8
37.4 8.7 11.3 7.8 10.0 12.3 11.2 8.6 9.1 36.7 32.3 8.2
43.4 8.2 9.2 7.5 11.4 8.9 10.5 5.7 10.2 40.8 36.3 8.5
39.6 6.3 7.6 4.1 7.2 8.0 8.9 7.1 5.0 40.7 34.6 5.8
45.4 6.6 8.0 1.4 4.5 9.9 11.9 18.1 25.8 5.2 37.0 11.5
49.9 8.6 8.0 9.3 10.5 10.7 13.3 15.2 28.9 10.2 37.3 7.1
52.4 8.6 9.6 5.7 10.5 11.8 10.3 14.5 28.9 8.2 40.5 8.9
50.0 6.9 10.0 4.8 7.2 9.1 8.6 13.3 31.8 18.0 34.7 9.3
59.2 11.0 13.9 15.4 19.1 40.3 37.2 57.1 58.8 52.7 64.7 42.4
64.8 13.6 16.3 19.4 20.9 41.3 41.1 53.6 61.8 50.0 65.0 44.8
65.2 13.6 17.2 17.4 19.0 39.1 38.5 52.9 61.0 55.8 63.0 39.4
63.1 66.8 14.0 12.4 13.9 13.7 16.6 12.6 21.1 15.5 34.9 34.1 37.2 31.3 54.3 56.5 60.3 70.1 56.9 73.0 60.6 100.7 46.2 43.2
76.7 13.9 15.5 15.8 17.7 32.0 34.3 53.8 66.3 72.0 96.7 44.0
82.0 13.4 15.6 14.2 18.0 31.9 31.2 57.3 66.5 73.3 92.2 42.1
80.5 11.8 14.9 13.5 19.3 33.4 32.6 54.9 67.5 73.6 98.6 42.2
34.2 6.4 7.1 2.2 2.8 10.0 8.9 12.0 5.7 37.8 33.5 9.1
36.9 8.6 10.9 9.3 11.3 12.2 10.0 6.6 12.4 36.8 29.0 10.7
42.7 9.0 9.7 7.1 9.5 8.8 10.3 9.5 10.8 38.9 36.1 5.7
37.2 7.0 8.1 4.4 7.7 7.6 6.5 8.4 6.6 40.3 34.1 7.9
52.5
51.7
54.2
55.0
57.7
53.7
50.0
54.4
61.5
68.0
69.5
64.6
75.7
76.6
74.8
79.0
54.7
50.9
54.6
53.6
56.8
53.8
55.7
52.2
68.2
63.4
64.3
64.6
29.3
32.3
31.6
29.9
52.8
55.3
55.3
55.6
59.9
63.7
65.7
60.9
1.6
5.7
10.8
8.3
31.0
29.1
33.4
32.4
54.7
56.8
56.8
53.7
64.6
59.3
59.7
63.2
1.6
9.7
10.5
8.5
Fitness Score: In Lay terms the fitness score shows the difference between simulation results and end of trial results for 1000 patient s
SORTED
Method_A1c Method_BMI Method_BP Method_Lipids Method_Smoke Method_MI Method_Stroke Method_DeathCHD Method_DeathStroke
1 1 1 1 1 4 1 1 1
0 0 0 0 0 4 1 1 1
1 1 1 1 1 1 1 1 1
1 1 1 1 1 4 2 1 1
0 0 0 0 0 4 2 1 1
0 0 0 0 0 4 4 1 1
1 1 1 1 1 4 4 1 1
0 0 0 0 0 1 1 1 1
1 1 1 1 1 4 3 1 1
0 0 0 0 0 4 3 1 1
1 1 1 1 1 1 2 1 1
0 0 0 0 0 1 2 1 1
1 1 1 1 1 1 4 1 1
1 1 1 1 1 1 3 1 1
0 0 0 0 0 1 4 1 1
0 0 0 0 0 1 3 1 1
1 1 1 1 1 2 1 1 1
0 0 0 0 0 2 1 1 1
1 1 1 1 1 2 2 1 1
0 0 0 0 0 2 2 1 1
1 1 1 1 1 2 4 1 1
0 0 0 0 0 2 4 1 1
1 1 1 1 1 2 3 1 1
0 0 0 0 0 2 3 1 1
1 1 1 1 1 2 2 1 1
0 0 0 0 0 2 2 1 1
1 1 1 1 1 2 3 1 1
1 1 1 1 1 3 1 1 1
1 1 1 1 1 2 1 1 1
1 1 1 1 1 2 4 1 1
0 0 0 0 0 3 1 1 1
0 0 0 0 0 2 3 1 1
0 0 0 0 0 2 1 1 1
1 1 1 1 1 3 2 1 1
1 1 1 1 1 3 2 1 1
1 1 1 1 1 3 3 1 1
0 0 0 0 0 2 4 1 1
1 1 1 1 1 3 3 1 1
1 1 1 1 1 3 1 1 1
0 0 0 0 0 3 2 1 1
0 0 0 0 0 3 2 1 1
1 1 1 1 1 3 4 1 1
1 1 1 1 1 3 4 1 1
0 0 0 0 0 3 3 1 1
1 1 1 1 1 1 2 1 1
1 1 1 1 1 1 3 1 1
1 1 1 1 1 1 1 1 1
0 0 0 0 0 3 3 1 1
0 0 0 0 0 3 4 1 1
0 0 0 0 0 3 1 1 1
0 0 0 0 0 3 4 1 1
0 0 0 0 0 1 2 1 1
1 1 1 1 1 1 4 1 1
1 1 1 1 1 4 2 1 1
0 0 0 0 0 1 3 1 1
0 0 0 0 0 1 1 1 1
1 1 1 1 1 4 3 1 1
0 0 0 0 0 4 2 1 1
0 0 0 0 0 1 4 1 1
1 1 1 1 1 4 4 1 1
1 1 1 1 1 4 1 1 1
0 0 0 0 0 4 3 1 1
0 0 0 0 0 4 4 1 1
0 0 0 0 0 4 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
0
0
0
1
0
0
1
0
0
0
1
0
0
1
0
0
1
0
1
0
0
0
0
1
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Weighted Mean
21.19 21.22 23.84 24.29 24.31 24.79
Best Model
24.8 25.99 26.04 27.05 27.58 28.45 28.78 29.79 29.89 31.14 44.24 45.15 47.91 48.48 48.62 50.17 50.64 51.01 51.24 51.75
52.2 53.49 54.48 54.89 55.04 55.27 56.32 56.47 56.57 56.58 56.77 57.83 58.04
58.4 58.59 58.72 58.75 58.94 59.21 59.62
2. Identify superior models according to weighted average fitness score
60.2 60.38 60.47 60.57 61.58 62.32
62.5 62.63 63.57 63.86 63.88 64.92 65.14
65.2 65.27 67.33 69.01 69.87
Lay Explanation • Clinical trials do not typically publish correlation amongst biomarkers • Therefore it is impossible to distinguish between the following populations:
Better fitness
Population A
Worst fitness
BP HIGH BP Normal LDL Normal LDL High
BP Normal BP HIGH LDL Normal LDL High
Independent: Not Correlated
Dependent: Perfect Correlation
Fitness 5. Fitness DiffDiff due due to tocorrelation: correlation: Avg. 15 ± 17SD 1000 individuals
• • •
4. No model used can explain the phenomenon observed in this cohort 3. Using end of trial biomarkers produces a slightly better model
OVERALL MODEL RANKING RESULTS Model Traits
The Reference Models for disease progression [1-3] uses High Performance Computing (HPC) to simulate a league of published disease models to compete for fitness to known clinical trial results. The resulting color coded fitness score matrix serves the modeler as a reference to improve model design and improve understanding of different models. The Reference Model regenerates baseline population data from publicly published data and does not require access to individual population information. Therefore the base for information is large, combining information from multiple trials, which provides a wider global view of phenomena observed. Using a Multi Scale modeling approach simulations are executed at the individual scale to reproduce information at the population scale and allows drawing conclusions at the multipopulation scale. Never the less, the use of aggregate data instead of individual data brings up questions regarding the sensitivity of the model to assumptions and unpublished information such as biomarker correlations. Fortunately it is possible to address these questions using HPC by running the assumptions and their fitness to observed results. This work demonstrates this by testing two extreme scenarios of biomarker correlation within populations: 1) Independent Bio-Markers with No Correlation, 2) Dependent Bio-Markers with Perfect Correlation. 2 X 34 cohorts of 6 diabetic studies :UKPDS, ASPEN, ADVANCE, ACCORD, KP, NDR, were generated from distributions using those scenarios and tested against 64 model variations composed of cardiovascular risk equations and modeling assumptions [1,2]. The results show the behavior of the model variations within the assumption scope and result rankings help identify superior models. Results consist of 4352=2x34x64 scenario simulations of 1000 virtual individuals and 10 Monte Carlo repetitions each for 10 years ~ 0.4 Billion virtual patient years. The use of HPC allowed running these computations in reasonable time. This simulation took about 36 hours on the cloud by leasing a computer cluster composed of 160 cores using 20 machines with 8 cores each. The Reference Model uses free Python based framework of software tools to run these simulations. MIST (MIcro Simulation Tool) [4-5] is used to run simulations in HPC environment. MIST runs over the cloud with the help of StarCluster [6] and an Anaconda AMI (Amazon Virtual Machine) [7].
Process CHD
Population 1
1. The best 24 model variations include the temporal correction for model outdating/ treatment
Population B
This work tested both these extreme scenarios for each population The fitness results show: Implies Need • Correlation matters since a range in results is visible for HPC • Correlation does not change the big picture much Conclusions: • Modeling at the individual level is important and makes a difference • Correlation is not the main hurdle in understanding disease progression Better models needed
References: [1] J. Barhak, The Reference Model Scores Fitness of Models and Populations. Poster Presentation. ISPOR 18th Annual International Meeting, May 18-22, 2013, Sheraton New Orleans, New Orleans, LA, USA. Poster: http://sites.google.com/site/jacobbarhak/home/PosterTheReferenceModel_ISPOR_Submit_2013_05_14.pdf [2] J. Barhak, The Reference Model: Improvement in Treatment Through Time in Diabetic Populations, The Fourth International Conference in Computational Surgery and Dual Training. The Joseph B. Martin Conference Center at Harvard Medical School. Boston, MA, USA. December 9-10-11, 2012. Video: http://web.cs.uh.edu/~cosine/?q=node/140 , Presentation: http://www2.cs.uh.edu/~cosine/talks_cosine4/monday/MultidisciplinaryTalks/2_JacobBarhak.pptx [3] J. Barhak, The Reference Model for Chronic Disease Progression. 2012 Multiscale Modeling (MSM) Consortium Meeting, October 22-23, 2012, Abstract: http://www.imagwiki.nibib.nih.gov/mediawiki/images/7/77/Reference_Model_for_Chronic_Disease_Progression_Barhak.pdf Poster: http://www.imagwiki.nibib.nih.gov/mediawiki/images/c/c4/PosterTheReferenceModel_IMAGE_MSM_Submit_2012_10_17.pdf [4] J. Barhak, MIST: Micro-Simulation Tool to Support Disease Modeling. SciPy, 2013, Bioinformatics track, Abstract: https://github.com/scipy/scipy2013_talks/tree/master/talks/jacob_barhak Video: http://www.youtube.com/watch?v=AD896WakR94 [5] MIST - MIcro Simulation Tool software in the GitHub repository. Online (Accessed 12-Aug-2013): https://github.com/Jacob-Barhak/MIST [6] StarCluster home page. Online (Accessed 12-Aug-2013): http://star.mit.edu/cluster/ [7] B. Zaitlen, StarCluster Anaconda. Online (Accessed 12-Aug-2013): http://continuum.io/blog/starcluster-anaconda
Acknowledgments: The GPL 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. The Reference Model was developed independently without financial support.
