Alexandru Dan Corlan MD PhD octombrie 2024

TROPOPOP: Population models of high sensitivity cardiac troponins

Introduction to the tropopop project

This is a project to develop a population model of the chronic serum levels cardiac troponin (cTn) in the general population. By `chronic serum levels' we refer to the baseline, unchanging level that is relatively constant, over weeks or months, in apparently healthy subjects, or patients in a stable chronic condition. In this phase, the project does not aim to model acute increases in the troponin level, that occur, for example, during acute coronary syndromes, but to provide a personalised expected range of cTn to which apparent increases may be compared.

The primary anticipated use of this model is to support the differential diagnosis of cTn increases, in particular small increases, less then three times the upper reference limit (URL). Knowing the expected range of the cTn in a particular normal or pathological population with greater accuracy would allow the better identification of unexpectedly high values and lead to the exploration of the cause of the increase.

Methods

In short, we perform a meta-regression of studies and datasets that characterise the general population, from which marginal probability distributions (MPD) of the cTn for some variables, usually specific to each study, in a section of the population that is also specific, are extracted. The meta-regression will result in a joint probability distribution (JPD) of the cTn, defined on a set of variables (gender, age, morphologic parameters of the heart, other investigations, comorbidities, treatment). The project involves five types of activities:
  1. extraction of MPDs from models, aggregate datasets from the literature and also by developing models of microdata where available;
  2. implementation of distinct MPDs as batch and online applications;
  3. development of the JPD based on some of the MPDs and implementation of the main application;
  4. extraction of new MPDs from the JPD for validation with other datasets;
  5. clinical studies of the predictive power of un/expected cTn results in patients.

Results

So far (october 2024) we implemented two MPDs (marginal probability distributions of the cTn), described below.

Tropopop2 model

This is the second version of an online implementation based on the `H' regression model described in McKie et al, 2013. It has an interface that will be used also in the final JPD model: the user provides the variables that are known in a patient and the application computes the probability distribution of the cTn in the subpopulation that has the same values, assuming that the unknown variables have the same distribution as in the general population, conditional on the known ones. The 99th centile of this patient-specific distribution can be used as a personalised URL for diagnostic purposes.

This MPD is limited to a few variables (age, gender, blood pressure, left ventricular mass index and total serum cholesterol) and, moreover, it is based on a population sample of adults aged 40-70. Extrapolations outside this range are possibly unreliable.

General population limits by age and gender

In the table below we propose preliminary upper reference limits, by age and gender, for cardiac troponins T and I. These limits reflect the expected 99th centile in each age and gender group. The line labeled ``Limits:'' represents the 99th centile limits designated by the manufacturer of the testing kit for the whole male or female population. All values in the table are in ng/L.

These limits are computed from an MPD constructed on the dataset reported in McEvoy et al, 2023.

MALESFEMALES
cTnTcTnI cTnTcTnI
RocheAbbottSiemensOrtho RocheAbbottSiemensOrtho
Limits: 22 35 58 12 14 17 39 9
Age
1 11 10 25 17 10 10 24 17
2 10 8 23 12 9 8 23 12
3 10 8 21 9 9 7 21 9
4 9 7 20 7 9 7 20 7
5 9 6 19 6 9 6 19 5
6 9 6 19 5 9 5 18 4
7 9 6 19 4 9 5 18 4
8 9 5 19 4 9 5 17 3
9 9 5 20 3 9 4 17 3
10 10 5 21 3 9 4 16 3
11 10 5 22 3 9 4 16 2
12 11 6 24 4 9 4 16 2
13 11 6 26 4 9 4 16 2
14 12 7 30 5 9 4 16 3
15 13 7 34 6 9 4 17 3
16 14 8 34 5 9 5 15 3
17 14 8 34 5 9 5 15 3
18 14 8 34 5 9 5 15 3
19 14 9 34 5 9 5 15 3
20 14 9 34 5 9 5 15 3
21 14 9 34 5 9 5 16 3
22 14 9 34 5 9 5 16 3
23 14 9 34 5 9 5 16 3
24 14 9 34 5 9 5 16 3
25 14 9 34 5 9 5 16 3
26 14 9 34 5 9 5 16 3
27 14 9 34 5 9 5 16 3
28 14 9 34 5 9 5 17 3
29 14 9 34 6 9 6 17 3
30 14 10 34 6 9 6 17 3
31 15 10 34 6 9 6 17 3
32 15 10 34 6 9 6 17 3
33 15 10 35 6 10 6 17 3
34 15 10 35 6 10 6 18 3
35 15 10 35 6 10 6 18 3
36 15 10 35 6 10 6 18 3
37 16 10 35 6 10 6 18 3
38 16 11 36 7 10 7 19 3
39 16 11 36 7 10 7 19 4
40 16 11 36 7 11 7 19 4
41 17 11 37 7 11 7 20 4
42 17 11 37 7 11 7 20 4
43 17 12 37 7 11 7 20 4
44 18 12 38 8 12 8 21 4
45 18 12 38 8 12 8 21 4
46 18 12 39 8 12 8 22 4
47 19 13 39 8 12 8 22 5
48 19 13 40 9 13 8 22 5
49 20 13 40 9 13 9 23 5
50 20 13 41 9 13 9 23 5
51 21 14 41 9 14 9 24 5
52 21 14 42 10 14 9 25 5
53 22 14 42 10 15 10 25 6
54 22 15 43 10 15 10 26 6
55 23 15 44 11 16 10 26 6
56 24 15 44 11 16 10 27 6
57 25 16 45 12 17 11 28 7
58 25 16 46 12 17 11 28 7
59 26 16 47 13 18 11 29 7
60 27 17 48 13 18 12 30 8
61 28 17 49 14 19 12 31 8
62 29 18 50 14 20 12 32 8
63 30 18 51 15 21 13 33 9
64 31 19 52 16 21 13 34 9
65 32 19 53 16 22 14 35 10
66 34 20 54 17 23 14 36 10
67 35 20 55 18 24 15 37 11
68 36 21 56 19 25 15 38 11
69 38 21 58 20 26 16 39 12
70 40 22 59 21 28 16 41 12
71 41 23 60 22 29 17 42 13
72 43 23 62 23 30 17 43 14
73 45 24 63 24 32 18 45 15
74 47 25 65 26 33 19 46 16
75 49 26 67 27 35 19 48 16
76 52 26 69 29 37 20 50 17
77 54 27 70 30 38 21 52 19
78 57 28 72 32 40 22 53 20
79 60 29 74 34 43 22 56 21
80 63 30 77 36 45 23 58 22
81 66 31 79 38 47 24 60 24
82 70 32 81 40 50 25 62 25
83 73 34 84 43 53 26 65 27
84 77 35 86 46 56 27 67 29
85 82 36 89 49 59 28 70 31

References

[McKie et al, 2013] Clin Chem. 2013 Jul;59(7):1099-107. doi: 10.1373/clinchem.2012.198614. Epub 2013 Apr 16. Defining high-sensitivity cardiac troponin concentrations in the community Paul M McKie, Denise M Heublein, Christopher G Scott, Mary Lou Gantzer, Ramila A Mehta, Richard J Rodeheffer, Margaret M Redfield, John C Burnett Jr, Allan S Jaffe PMID: 23592511 DOI: 10.1373/clinchem.2012.198614

[McEvoy et al, 2023] Eur Heart J. 2023 Jul 21; 44(28): 2595–2605. Jun 2. doi: 10.1093/eurheartj/ehad328 PMCID: PMC10361011 PMID: 37264651 High-sensitivity troponins and mortality in the general population John W McEvoy, Natalie Daya, Olive Tang, Michael Fang, Chiadi E Ndumele, Josef Coresh, Robert H Christenson, and Elizabeth Selvin

Copyright (c) 2002-2024 Alexandru Dan Corlan, ultima modificare 2024/11/09