FormalPara Key Summary Points

Why carry out this study?

The high costs of confirmatory testing for coronary heart disease (CHD) are a major barrier to providing accessible, high-quality equitable care for all.

PrecisionCHD is a newly developed, highly scalable artificial intelligence guided precision epigenetics tool for diagnosing CHD.

The use of PrecisionCHD in place of conventional testing measures may decrease CHD-related healthcare costs.

What was learned from this study?

Budget impact modeling suggests that the use of PrecisionCHD could lead to large savings for typical insured populations in the USA.

Real-life pilot studies to validate these findings will be necessary because some of the costs of CHD care are not well understood and testing impact may vary as a function of practice style and demography.

Introduction

Coronary heart disease (CHD) is the leading cause of death in both the USA and the world [1]. According to the American Heart Association, by 2035, nearly 45% of the American population will have some form of heart disease [2]. The prevalence of CHD is expected to rise from 16.8 million Americans in 2015 to 24 million Americans by 2035, with the medical costs expected to rise from $89 billion to $215 billion by 2035. Traditionally, attempts to avert mortality from CHD are divided into primary and secondary prevention [3]. The aim of primary prevention is to preclude the development of CHD, while secondary prevention focuses on minimizing the morbidity and mortality in those already diagnosed with CHD. Since both primary and secondary prevention strategies can be costly, governmental and private payors must carefully weigh potential methods for preventing the consequence of CHD such as an acute myocardial infarction in order to minimize financial impact and conserve scarce healthcare resources.

The financial impact of secondary prevention on overall health costs is particularly large. In general, it primarily arises from the cost of initial CHD diagnosis and the cost of preventive interventions [4]. The expenses of the latter are better understood. Thanks to a series of large clinical trials, there has been increasing consensus for the use of optimal medication treatment (OMT) as the initial treatment approach for secondary prevention of stable CHD [5]. This pathway to consensus owes much of its origin to the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE), and International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trials [6, 7]. The COURAGE trial, whose results were initially published in 2009, enrolled 2287 patients with evidence of myocardial ischemia and significant CHD to percutaneous intervention (PCI) with OMT or OMT alone [6]. The trial demonstrated no significant differences for the primary outcome measures, death, stroke, and myocardial infarction (MI), between the two treatment arms. The ISCHEMIA trial, whose first results were published in 2020, built upon these findings by randomizing 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when possible) and OMT or to OMT alone with subsequent angiography if OMT failed [7]. Though there still remains some disagreement in the medical community, the consensus now is that OMT should be the initial management strategy for stable CHD regardless of the degree of obstruction [5]. Because many of the medications used for OMT are generic, this also suggests that the adoption of this OMT may help control the costs of secondary prevention.

Nevertheless, there is still the cost of the process of identifying those with CHD for the initiation of OMT. However, in contrast to the consensus for treatment, the practices for diagnosing CHD vary widely. In Europe and the USA, this practice is guided by a series of guidelines issued by the European Society of Cardiology, the American College of Cardiology and the American Heart Association [8]. In brief, these guidelines recommend that the clinical impression of stable CHD be affirmed with at least one diagnostic testing modality including exercise electrocardiograms, coronary computed tomography  angiography (CCTA), single photon  emission computed tomography (SPECT), or angiography. This testing can be costly. In the USA, the average cost of obtaining a CCTA in 2023 is $806 while the average cost of performing an angiogram was $9438 [9]. However, the upfront costs of the tests are not the only costs associated with these tests. For example, many primary care practitioners are uncomfortable interpreting the results of these tests and request additional clinical input from specialists. Furthermore, many of these tests have medically significant side effects including damage from ionizing radiation and renal damage from contrast dye [10,11,12,13]. Finally, clinicians will often conduct multiple modes of testing on the same patient and add additional testing options, such as the use of third-party software vendors, to analyze already obtained imaging data. The exact combination of testing chosen will vary depending on patient and clinician factors. Therefore, determining the “true” cost for a given testing procedure can be challenging.

Whereas these additional imaging or physiological measures can better inform clinicians as to the nature of the underlying pathophysiology, they also greatly add to the financial costs of secondary prevention. However, since OMT is now recommended as the initial management strategy for stable CHD, this additional information may not be absolutely necessary to achieve optimal treatment outcomes. Furthermore, there remains controversy as to the preferred modality for initial assessment of stable CHD.

In part, this controversy has continued to be fueled by continuing improvements in diagnostic methods [14]. Some of the most intriguing of these improvements are in the rapidly developing field of cardiac epigenetics [15]. Specifically, our commercial-academic consortium has recently shown in three independent cohorts that a method (trade name, PrecisionCHD™) that uses artificial intelligence to interpret the genetically contextual methylation signals from six methylation-sensitive digital polymerase chain reaction assays (MSdPCR) is capable of determining the presence of CHD with an overall area under the curve of 0.82, and with sensitivities and specificities of 79% and 76%, respectively [16]. Critically for those interested in using precision epigenetics to guide clinical care, each of those six MSdPCR assays maps to pathways known to be critical in the pathogenesis of CHD with changes in their methylation status occurring as a function of therapy [17]. Although much work needs to be conducted, these and similar findings [18] suggest that clinical epigenetic approaches have the potential for becoming a common method for assessing, diagnosing, and monitoring CHD care [19].

As promising as those findings are, perhaps the most interesting aspect of this and other precision epigenetic approaches for assessing diseases of aging is their potential to decrease the cost of CHD-related healthcare. As opposed to CHD tests such as CCTA or angiograms which have high structural and personnel-related infrastructure costs, precision epigenetic approaches rely on polymerase chain reaction (PCR) approaches that are both relatively inexpensive and highly scalable [19]. Furthermore, unlike imaging-based diagnostic approaches, there is no exposure to radiation or contrast dyes whose consequences can further add to the cost of CHD evaluations and downstream side effect management [10,11,12]. Therefore, from a healthcare cost perspective, there may be considerable advantages to the use of PrecisionCHD for the prevention, diagnosis, and management of stable CHD [19].

To demonstrate the healthcare costs saving potential of PrecisionCHD, we conducted a budget impact analysis (BIA) of the effect of using PrecisionCHD in the initial diagnosis of stable CHD in place of current diagnostic tests.

Methods

A cost calculation model was constructed using a 1-year time horizon with no discounting, as recommended by the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) BIA Task Force [20]. The costs include direct medical costs using published estimates, office visits, primary tests, secondary tests, and the treatment of side effects. The results apply to a private insurance plan in the USA with one million individuals that match the distribution of age and sex in the national population for a plan that offers 10% co-insurance, $20 co-pays for office visits, $0 cost for preventive care, and $0 deductible (or the deductible has already been met) to individuals of all ages. The percentage of individuals who receive a CHD test and the type of each test prior to covering PrecisionCHD are based on claims data from this commercial group with a broad mix of ages. The comparison testing procedures in the model are (1) exercise electrocardiogram (exercise ECG), (2) stress echocardiography (stress echo), (3) single-photon emission computed tomography (SPECT), (4) positron emission tomography (PET), (5) cardiac magnetic resonance imaging (CMRI), (6) coronary computed tomography angiography (CCTA), (7) CCTA with third-party imaging processing (e.g., Cleerly™; https://cleerlyhealth.com/) report, and (8) angiogram.

Ethics Approval: Institutional review board approval was not sought because this is a simulation analysis that does not include personal identifying data from human subjects. Similarly, though conducted with high levels of integrity, this investigation does not involve human subject contact or human subject data, and is not covered by the Declaration of Helsinki of 1964 or its amendments.

The total cost (or saving) from covering PrecisionCHD for an insurance organization is equal to the change in costs after covering PrecisionCHD and before covering PrecisionCHD. The costs before and after covering PrecisionCHD are equal to the sum of the number of people receiving each type of test multiplied by the cost per person of that test. Thus, a key factor in determining the costs or savings from covering PrecisionCHD is how covering PrecisionCHD changes which tests patients receive.

The cost per person of each type of test includes the cost of the appointment to order the test; the cost of the test; the cost of the appointment to discuss the results of the test [9]; the cost of the side effects of the test [9]; the cost of statins received [21]; the costs of a CHD event [22]; the cost of a secondary test, which depend on the result of the primary test; and the cost of an appointment to discuss the results of a secondary test [23]. These costs do not include the use of other medications commonly included in OMT such as platelet aggregation inhibitors, beta-blocker, or angiotensin-converting enzyme inhibitors because reliable estimates of these costs are not currently available. Figure 1 is a decision tree illustrating these events that contribute to the cost per person of each type of test.

Fig. 1
figure 1

Decision tree for the budget impact analysis. In this model, two-thirds of all patients with a positive test are directly started on moderate to high dose statins, while one-third are referred for additional testing. Subjects with a negative test are not referred for additional testing. Abbreviations: coronary heart disease (CHD)

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Table 1 includes all cost parameters used in the model that are common across tests and their sources. All costs are measured in 2023 dollars and are adjusted to 2023 dollars using the Consumer Price Index for all Urban Consumers (CPI-U) for medical care [23]. The cost of an appointment to order a test and to review test results from the primary or secondary test is $303, which is the estimated national average for a primary care office visit for an established patient [9]. All tests are ordered through a primary care physician (PCP). PrecisionCHD can also be ordered through a telemedicine visit for $99, which also includes an appointment to discuss the results. Table 1 also includes the cost parameters for statins and CHD events, which depend on the results of the tests.

Table 1 Source of cost parameter estimates for the model
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Table 2 shows the parameters that differ for each test, including the sensitivity, specificity, and cost of each test [16, 27]. The costs that do not depend on the outcome of the test are the cost of the test, the cost of the side effects of the test, and the costs of the appointments to order and discuss the results of the test. The costs of the side effects of contrast dye-induced nephropathy from CCTA are $1811 in 2023 dollars [28]. The costs of side effects of radiation exposure are not considered in this analysis with a 1-year time horizon.

Table 2 Performance and price characteristics of existing diagnostic technologies
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The sensitivity and specificity of each test determine the test outcomes (true positive, false positive, true negative, or false negative). CCTA, CCTA + third party image processing, SPECT, PET, CMRI, and angiogram measure obstructive heart disease only. The model assumes that 67% of heart disease is obstructive, based on the work of Herscovici and colleagues [30]. Since these tests provide no information for unobstructive heart disease [24], their sensitivity and specificity are 0.5 for the 33% of heart disease that is unobstructive.

In the model (see Fig. 1), one-third of patients with a positive test outcome (true positive or false positive) from PrecisionCHD, exercise ECG, CCTA, CCTA + image processing, stress echo, SPECT, PET, or CMRI receive a secondary test. Patients do not receive a secondary test after an angiogram. Half of the patients who receive a PrecisionCHD, exercise ECG, stress echo, SPECT, PET, or CMRI test receive CCTA as a secondary test, while the other half receive an angiogram. The patients who receive CCTA or CCTA + image processing receive an exercise ECG as a secondary test. All patients have an office visit to discuss the results of the secondary test. When a positive test outcome occurs (true positive or false positive) following the secondary test or following the primary test for individuals without a secondary test, patients are prescribed statins. The annual costs of the statins are scaled by the probability that a patient takes the statins (the adherence rate) [25]. Patients with a negative test outcome (true negative or false negative) are not prescribed statins; patients with a false negative test outcome experience a CHD event. Thus, the costs of a false negative test do not include the cost of a secondary test or the cost of statins but do include the cost of a CHD event.

The costs of a CHD event include the direct medical costs only. These costs vary by age (ages 18–44, ages 45–64, and ages 65–79). Statins reduce the likelihood of a CHD event by the risk reduction percentage. The model assumes that the probability of a CHD event if the patient does not take statins is equal to the prevalence of CHD for the age and sex of the patient. This assumption is reasonable if the average person is tested for CHD. Since patients with symptoms or high-risk patients are tested, who have a probability of CHD that is higher than average, the sensitivity of the results to this assumption is discussed in the Results section.

Results

Table 3 shows the cost per person of receiving each potential test, including the cost of the appointment to order the test, the cost of the test, the cost of the appointment to discuss the results, the cost of side effects of the tests, the cost of statins, the costs of a CHD event, and the costs of secondary tests. The cost of PrecisionCHD differs on the basis of whether it is ordered by a primary care physician (PCP) or through telemedicine; the cost of the appointment to discuss the results is included in the cost of the telemedicine appointment. The cost per person for PrecisionCHD is $1724 when ordered through telemedicine and $2231 when ordered through a PCP. The cost of an exercise ECG is $2537. The cost of CCTA is $3721 but is $4457 when CCTA includes image processing. The costs of stress echo, SPECT, PET, CMRI, and an angiogram are $3003, $6667, $6751, $3549, and $10,305, respectively.

Table 3 Coverage costs with and without the use of PrecisionCHD
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At baseline, prior to expanding insurance coverage to include PrecisionCHD, 4.6% of individuals received any CHD screening test. Of those who received a test, 30.9% received exercise ECG, 7.3% received CCTA, 18.7% received stress echo, 28.7% received SPECT, and 14.4% received angiogram. As shown in Table 3, for this insurance plan with one million members, 14,180 individuals receive exercise ECG at a cost of $36.0 million, 3350 individuals receive CCTA at a cost of $12.4 million, 8600 individuals receive stress echo at a cost of $25.8 million, 13,180 individuals receive SPECT at a cost of $87.9 million, and 6600 individuals receive angiogram at a cost of $68.0 million. The total costs are $447.9 million.

In the model, after covering PrecisionCHD, the same percentage of individuals receive a CHD test, and all patients who receive a CHD test receive PrecisionCHD; 25% of the PrecisionCHD tests are ordered through telemedicine and 75% of the PrecisionCHD tests are ordered by the PCP. For this insurance plan with one million members, 11,478 individuals receive PrecisionCHD ordered through telemedicine at a cost of $19.8 million and 34,432 individuals receive PrecisionCHD ordered through their primary care physician at a cost of $76.8 million. The total costs are $314.3 million.

Expanding insurance coverage to include PrecisionCHD would reduce the costs to an insurance company by $133.6 million, or $133.57 per member per year ($11.13 per member per month), relative to existing testing procedures.

The main result is based on relative costs across different tests. Thus, this result is not sensitive to the cost of CHD, the probability that someone who is tested has CHD, the cost of statins, the adherence rate of taking statins, the risk reduction rate of statins, or the age composition of the insurance pool. Further, this result is not sensitive to the design of the insurance plan; this result is similar for plans that exclude Medicare enrollees, only include Medicare enrollees (Part B or Medicare Advantage), offer higher co-insurance rates, and offer larger co-pays.

The key factors that determine the cost savings are (i) the number of people in the insurance pool who receive each type of test, (ii) the cost of administering the test, (iii) the cost of side effects of the test, (iv) whether PrecisionCHD is ordered by a PCP or through telemedicine, (v) the sensitivity of the test, and (vi) the specificity of the test. These parameters are fixed outside of the model, except for the number of people in the insurance pool who receive each type of test after PrecisionCHD is covered by insurance and the percentage of PrecisionCHD tests ordered through telemedicine. The costs per person of PrecisionCHD are lower than the costs per person of any other test, given the cost of administering the test, no cost from side effects of the test, and the sensitivity and specificity of the test. Thus, the key determinants of the cost savings are percentage of people who receive PrecisionCHD from their PCP and the percentage of people who receive PrecisionCHD through telemedicine. Every 10-percentage-point increase in the percentage of individuals who are tested with PrecisionCHD increases the per-member per-year savings by $13.36, holding fixed the percentage of individuals who receive PrecisionCHD through telemedicine and the relative proportions of individuals receiving other tests. Every 10-percentage-point increase in the percentage of individuals who receive PrecisionCHD through telemedicine increases the per-member per-year savings by $2.33, holding fixed the percentage of individuals who receive a PrecisionCHD test.

Discussion

The complexities of CHD diagnosis and care present a series of challenges to healthcare payors committed to providing high-quality, comprehensive care. These challenges include the rapidly evolving landscape of diagnostic technologies, changes of the prevalence and severity of CHD and CHD spectrum illness, and heterogeneity in governmental regulation service delivery. As a result, risk bearers must frequently update their approach to their coverage of CHD detection and management. In this communication, we model the effect of one innovation in CHD diagnosis, PrecisionCHD, on the cost of covering the initial diagnosis and first year management of stable CHD. In the scenario presented here, we find that the substitution of PrecisionCHD as the initial method of CHD assessment will lead to a savings of over $113 million for a risk bearing entity with one million covered lives.

The introduction of a series of precision epigenetic methods over the past several years has presented healthcare insurers new opportunities for saving money. In particular, the use of Cologuard, for assessing the presence of colon cancer, presents the best analogy for the current study. Cologuard is a US Food and Drug Administration-approved screening test for those 45 years of age or older at average risk for colon cancer [31]. It is not indicated for those with a prior history of colon cancer, family history of early onset colon cancer, or other conditions that place them at higher risk for colon cancer. Similarly, the use of PrecisionCHD, which is a diagnostic test to detect CHD, is indicated for those of 35 years of age or older, without a prior history of cardiac surgery or bone marrow transplant [19] who are suspected of having CHD. It is not indicated as the primary method of assessment for more complicated presentations including acute coronary syndrome or unstable CHD. Therefore, even if risk-bearing entities adopt precision epigenetic approaches as the principal modality for initial diagnostic assessment, they will still need to maintain capacity for more complex procedures. Unfortunately, given the rate of change in CHD imaging and percutaneous interventional technologies and the complicated mechanisms through which the infrastructure for these methods is subsidized, the costs of maintaining even a reduced high-complexity diagnostic testing footprint are difficult to calculate.

One unfortunate shortcoming in these types of economic analyses is the inability to model structural barriers such as lack of access to testing resources, transportation, and other hidden barriers to conducting care plans that could lead to missed opportunities to prevent costly CHD events such as a heart attack. A good example of one such barrier was the marked delays or complete arrest of elective high-complexity diagnostic procedures secondary to COVID-19. In many areas of the country, non-emergent angiograms were simply not conducted. However, in the current healthcare market, patients often face delays of weeks to months for the scheduling of routine cardiac testing. As a result of these and similar impediments to the care plans, patients either experience further potentially avoidable complications or fail to follow up. Because PrecisionCHD uses a standard phlebotomy draw, it is not subject to the effects of these difficult to quantitate structural barriers.

For some, the type of information provided by certain diagnostic approaches presents a clinical advantage not accounted for in these deliberations. For example, for many clinicians, the information on the amount and distribution of coronary occlusion provided by angiography or CCTA is desirable information. While these feelings are understandable, randomized studies show that this anatomic information does not impact the initial decision-making process with respect to OMT [32]. Furthermore, in part because of the potential for contrast dye-induced kidney damage, repeat imaging to monitor occlusion in stable CHD is often discouraged [33]. Therefore, for the initial diagnosis and management of stable CHD, this anatomic information is in some manners superfluous.

In contrast, because the six MSdPCR assays contained within PrecisionCHD map to discrete, modifiable risk factors for CHD and we can calculate the relative impact of each of these factors for each patient, this may allow clinicians to personalize OMT therapy for each patient. Therefore, even though it may not be intuitively understood as the anatomical information given by imaging approaches, the epigenetic information provided by PrecisionCHD and other precision epigenetic approaches may provide a personalized, positive economic impact beyond that reported in this study.

One concern that potential customers may have about any test containing genetic information is the potential for population stratification effects such as those seen for polygenic risk scores [34]. However, there is little risk for significant population stratification effects in our testing approach because there is only miniscule loading of the main effects of the 10 SNPs themselves. Instead, the impact of the SNPs in our approach is conveyed through their modification of the methylation set points of the six CpG sites targeted by the methylation assays (i.e., Gene × Methylation or GxMeth effects). Critically, these SNPs and the haploblocks targeted by them are in relative population equilibrium in the major ethnicities as can easily be seen through dbSNP [35]. As a result, our algorithm, which relies on the main effects of methylation and GxMeth interaction effects is robust to population stratification effects. Indeed, in the Iowa cohort from our 2023 Journal of the American Heart Association paper [16], there was no difference in the clustering of the non-White subjects. Still, to be certain, any metric must be broadly tested and we note our academic-commercial consortium is firmly committed to the understanding of the utility of epigenetic predictors in non-European populations [36,37,38].

As a second step of personalized healthcare, it is also likely that in future years, the information provided by the six MSdPCR assays at the core of PrecisionCHD may provide a mechanism for the monitoring of OMT. Currently, for the initial medical management of stable CHD, in the absence of congestive heart failure (CHF), the three major cardiovascular care organization (American Heart Association, American College of Cardiology, and the European Society of Cardiology) all recommend the use of antiplatelet agents (e.g., aspirin) and cholesterol-reducing agents (e.g., statins) as the mainstay of treatment [5]. As noted above, in part, secondary to the increased risk for contrast dye-induced kidney damage and radiation exposure, repeat imaging is not recommended for determining the effectiveness of treatment. Instead, for those without contraindications, aspirin is dosed empirically while statin dose is guided by serum cholesterol levels. However, there are several limitations to using this approach to guide therapy. For example, prior studies have shown that in the real world, there are structural barriers to the use of lipid testing to monitor statin therapy [39]. Furthermore, the contribution of abnormal lipid levels to any individual CHD presentation is somewhat speculative. However, because the methylation signal captured by the six MSdPCR is dynamic and can change in as little as 90 days after the initiation of treatment [17], it is very possible that precision epigenetic approaches will both inform treatment selection while also serving as a mechanism to determine the effectiveness of treatment.

As a final step in personalized healthcare, fueled by “big data” approaches, it is possible that cardiovascular signals being captured by these precision epigenetics methods could be further incorporated into broader global bioinformatic assessments of health and well-being. In brief, the current landscape of clinical testing for many types of disorders can be fragmented. For example, the information from SPECT, CCTA and PET, though complementary in many respects, is not structured to allow joint analysis of testing outcomes and is not easily integrated into large-scale bioinformatic analyses. However, epigenetic data, in particular that from methylation tests which are serially conducted, could be integrated with other similar quantitative laboratory information, such as hemoglobin A1c values, creatinine levels, and vital sign assessments to provide more holistic, global assessments of personal health and life expectancy [40, 41]. In turn, these assessments could then be used to target at-risk individuals for preventive interventions that could offer further savings to healthcare systems that utilize these forward leaning approaches.

Nevertheless, recognizing the potential of epigenetic technologies such as PrecisionCHD may require additional training of healthcare providers, in particular, those providers who completed their initial education before the advent of epigenetics. However, to date, the introduction of other epigenetic tests such as Cologuard and Galleri has not been hindered by unfamiliarity of clinicians with epigenetics. Furthermore, because topics such as epigenetic aging have captivated many healthcare providers regardless of age, it is likely that the length of training necessary for clinicians to take advantage of these tests will be minimal. Still, additional studies are needed to further elucidate the relationship between MSdPCR values and the rate of epigenetic change to be expected for a given preventive treatment.

Limitations of the Study

Although based on verifiable assumptions and publicly available data from reputable sources, this budget impact analysis may be subject to a number of potential limitations. First, the exact frequency and impact of Ischemia with No Obstructive Coronary Arteries (INOCA) is still being refined. Second, the guideline-driven model presented for the initial evaluation of CHD is simplified for illustration purposes only. It should be acknowledged that guidelines are not recommendations set in stone and that the individual practices for CHD evaluation can vary widely. Third, the costs of clinic visits and statins are gathered from databases that harvest information from general practice sources in the USA. Optimal medication therapy for patients with stable ischemic CHD includes, at a minimum, the addition of antiplatelet therapy, and possibly the addition of beta-blockers and other agents as indicated. Since these costs can fluctuate as a function of patent restrictions or provider practice trends, these values may not be reflective of the costs incurred in other countries or in care administered by governmental providers (e.g., Veteran’s Administration). Fourth, at the current time, although PrecisionCHD is available in all US jurisdictions except New York state and Rhode Island, it has not been approved by the US nor the European Union regulatory agencies. As a result, there may be additional implementation costs. Fifth, PrecisionCHD was developed, tested, and validated in largely White populations. The performance of the test in non-White populations could differ which would affect these results. Sixth, complete care of the patient with CHD will likely necessitate access to a wide variety of testing technologies. How differential use affects the cost and availability of those resources is difficult to predict. Finally, other technologies are not static either. Improvements in physiologic and imaging methods continue to occur and improvements in their performance may alter the cost–benefit analyses.

Conclusion

In summary, we show that the use of PrecisionCHD, a recently introduced epigenetics-based diagnostic tool for CHD, can present significant cost savings in the initial diagnosis and care of stable CHD. As is the case for most budgetary simulations, these findings should be considered as preliminary with the actual real-world results varying depending on the financial, clinical, and demographic features of the healthcare market segment being served. Still, the rapid progress of artificial intelligence and precision epigenetic tools into areas of healthcare such as oncology and cardiovascular care suggests the likelihood that in the future these and other similar twenty-first century technologies will have strong positive impacts on the cost and quality of healthcare globally.