Genomic and Precision Medicine: Cardiovascular Disease

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Chapter 1

Family Health History and Health Risk Assessment For Cardiovascular Disease in Health Care

Lori A. Orlando and Rebekah R. Wu,    Center for Applied Genomics and Precision Medicine, Duke University, Durham, NC, United States

Abstract

Health risk assessments (HRAs) have the potential to play a key role in health promotion and disease prevention both at an individual and a population level. While the idea has been around since the 1950s and HRAs are commonly performed in the workplace, they have not been as readily adopted by the US health-care system. Several challenges must be addressed before broader uptake of HRAs in clinical care can occur: (1) usability for providers, (2) usability for patients, (3) quality of patient-entered data, and (4) impact on health outcomes. In this chapter, we describe recent developments in HRA design that are aimed at addressing these issues.

Keywords

Family health history; risk assessment; risk prediction; prevention; patient-entered data

Chapter Outline

Introduction 1

In the Beginning 3

Why Family Health History is Central to HRAs 3

An Implementation Crisis 5

Will Providers Use It? 6

Will the Patients Use It? 10

What About Patient-Entered Data? 11

Does It Make a Difference? 12

Conclusion 13

References 13

Introduction

In the continuum from health to disease, there are several key transition periods. The first is from healthy to presymptomatic, where an individual still feels well and is asymptomatic but has developed a disease. An example of this health state is the beginning of cardiovascular disease when an individual is developing plaque but they are unaware of it. The second is from presymptomatic to disease diagnosis and the third is from diagnosis to disease status, which can be either well controlled or uncontrolled. Health risk assessments (HRAs) are an essential component of the healthy period. Their purpose is to estimate an individual’s risk for developing common chronic diseases (see, e.g., Table 1.1) allowing clinicians to tailor preventive care, screening, and testing to each individual’s level of risk—with the goal of keeping healthy people healthy. Personalized care plans developed with the aid of HRAs balance effectiveness and harms with risk, in a way that maximizes benefit and minimizes harm not only for each individual, but when taken as a whole, for the population as well. Unfortunately, HRAs are not widely used in primary care, where they would be most effective, due to a number of constraints. This chapter discusses how HRAs were developed, their key aspects, and what needs to occur in order to integrate them into primary care settings.

Table 1.1

Examples of Conditions for Which Family Health History-Based Health Risk Assessment is Useful

In the Beginning

In 1948, Joseph Mountain, the Assistant Surgeon General, initiated the Framingham Heart Study, an innovative longitudinal study arising from the field of epidemiology. The goal, as devised by the director, Thomas Dawber, was to closely follow a group of individuals living in Framingham, Massachusetts, collecting as much data as possible over the course of many years in order to develop a risk prediction model for heart disease [1]. This was the first time the phrase factor of risk, more commonly termed risk factor today, was introduced [2]. Despite initial skepticism among both the research and medical communities, the trial was successful beyond expectations and the field of HRA was born. In 2009, when Clay Christensen coined the term Precision Medicine, he defined it as precisely predicting a medical outcome by combining a variety of data into rules [3]. By this definition, HRAs are simply the application of precision medicine to those who are healthy.

Today, most HRAs include the following components: data collection (either through a web-based or paper questionnaire), risk calculation, and report of risk results. This last component, the report, may or may not provide guidance about how to manage your risk. Some are exceptionally detailed and even indicate how much your risk can be lowered by initiating one or more recommended preventive actions, while others merely indicate that you are at increased risk for the specified condition. For the first component, data collection, the data collected varies depending upon which conditions are included in the risk assessment, but at a minimum they all include: demographics, lifestyle, personal health history, family health history, and biometrics (such as blood pressure, weight, cholesterol, etc.). Other types of data, such as genetic/genomic and individual preferences, are just now starting to be incorporated into some risk assessment models and have the potential to not only refine the accuracy of risk calculations but to also improve shared decision-making with medical providers [4,5].

Why Family Health History is Central to HRAs

Family health history is an unassuming and often overlooked, but essential data element in HRAs. For many conditions, family health history is the strongest predictor of disease risk and for some, such as hereditary cardiovascular syndromes, it is the only predictor (and thus the only component of the HRA) (see Table 1.1). An example of the impact of family health history on disease risk is type II diabetes, where a first degree relative (parent or child) with the disease increases an individual’s risk from an average of 3.2% to 14.3% [6]. In some cases, excluding a family health history can lead to missing those at highest risk for developing a condition. For example, many risk assessments for chronic obstructive pulmonary disease ask about environmental exposures (such as smoking and asbestos) but do not ask about family history; however, those with alpha-1-antitrypsin deficiency, a hereditary condition that runs in families, are at the highest risk of developing chronic obstructive pulmonary disease even without an environmental exposure [7]. Renal cell carcinoma, a tumor of the kidney, is another example. Almost all risk assessments include smoking, alcohol, and exercise, and some include family members with renal cell carcinoma, but most do not ask about a family history of other cancers even though renal cell carcinoma is part of the constellation of cancers that can occur in two hereditary cancer syndromes, Lynch and Von Hippel–Lindau [8]. While those with hereditary cancer syndromes or alpha-1-antitrypsin deficiency are only a small proportion of those developing these two conditions, they are the ones at the highest risk of developing disease.

As mentioned earlier, the Framingham study and the resultant Framingham risk scores inaugurated the risk assessment field and pushed it steadily forward for the first two decades. However, currently, the three widely used cardiovascular risk scores: Framingham (which has multiple versions and multiple outcomes including atrial fibrillation, atherosclerotic heart disease, and congestive heart failure) (https://www.framinghamheartstudy.org/risk-functions/index.php), Reynold’s risk score (for heart and stroke risk) (http://www.reynoldsriskscore.org/), and the pooled equation for atherosclerotic cardiovascular disease risk recommended in the 2013 ACC/AHA Guidelines [9] (http://tools.acc.org/ascvd-risk-estimator/), do not include family health history of cardiovascular disease though an earlier version of Framingham did. To adjust for this missing information, the Canadian Cholesterol guidelines multiply the Framingham risk score by 2 for an individual who has a first degree relative with a cardiovascular event before age 60 [10]. Similarly, European guidelines recommend multiplying the risk score results by 1.7 in women and 2.0 in men [11].

In addition to being highly predictive, family health history also serves as the basis for a number of evidence-based guidelines that not only indicate the level of disease risk associated with a given combination of affected relatives but also actions to take to manage risk. For example, the National Comprehensive Cancer Network’s guidelines for breast and ovarian cancer recommend BRCA testing if an individuals’ first degree relative (parents or child) developed breast cancer at age 45 or younger [12]. Another example is abdominal aortic aneurysm screening. If an individual has a relative with the condition, then screening is recommended when they are aged 50 or older [13,14].

Despite the fact that the cardiovascular field was early to begin to explore the benefits of risk assessment, there is a complete absence of literature and guidelines addressing the role of family history, even for the many hereditary cardiovascular syndromes, except for Familial Hypercholesterolemia (FH). For FH, there are now four different screening tools (Simon Broom, Dutch Lipid Clinic Network, Med Ped, and the newly published FAMCAT)—all include family history. One important aspect of these hereditary conditions, which include many cardiomyopathies and arrhythmias, as well as FH, is that (for most) there are steps that can be taken to manage risk. For example, there is now a drug class (PCSK-9 inhibitors) approved specifically for use in individuals with FH, echocardiogram screening for cardiomyopathies, and EKG screening for arrhythmias. Another highly important point to consider is the risk to relatives when a family member is found to have a hereditary condition. In these cases, it’s important to inform and screen those individuals at-risk. Processes to facilitate this screening, called cascade screening, are being explored and have been most closely studied in Europe around FH.

Thus, family health history is the only data element in HRAs that is both highly predictive and actionable in combination with other data elements and by itself. Unfortunately, family health history is often hard to obtain. Individuals often do not know much about their relatives’ health and what they do know is often piecemeal or may be inaccurate [15]. This leads to the problem that one of the most informative data elements in HRAs is also one of the more difficult to collect.

An Implementation Crisis

Despite the acclaim surrounding the publication of the Framingham Heart Study results, there was little movement in the field of HRA until 1980 when the Center for Disease Control (CDC) released a publicly available HRA tool [16]. Incidentally, 1980 was also a time when employers and insurers were being faced with rapidly increasing health-care costs. In their search for a way to manage these costs, they turned to HRAs [17]. To explore the impact of this resource, Prudential funded updates to the CDC’s tool, which ultimately showed that use of a HRA tool in the workplace could lower company health-care expenditures, as well as reduce absenteeism and increase productivity [18,19]. These results and Prudential’s takeover of the program in 1986 led to rapid uptake among US employers and insurance companies; however, uptake continued to be anemic in the health-care setting [16].

Explanations for why implementation in the health-care system failed to take root include the disconnect between public health and health care, increasing demands on primary care providers, and a perverse incentive system that rewarded interventions over maintaining health [16,20]. The combination of these factors encouraged the development of a health-care system, incapable of responding to the needs of the healthy segment of the population, quickly leading to a negative feedback loop dominated by sick patients getting sicker, less time to manage risk among healthy patients, and ultimately healthy patients getting sick [21]. In this environment, it is easy to see how adoption of HRA in clinical practice was slow.

Fortunately, recent studies have highlighted these findings and their unsustainable impact on the US health-care system. In particular, the 5 Mirror, Mirror studies performed by the Commonwealth Fund to assess health-care quality and cost in 11 international health-care systems between 2004 and 2014, not only ranked the US last in quality and highest in expenditures but showed little improvement over the 10-year period [22]. In addition, the Affordable Care Act enacted in 2010 has emphasized the need for improvements in quality of care, maintaining health, and lowering costs. HRAs are neatly aligned with these objectives and are now viewed as a useful tool for redesigning health-care systems. That being said, there are still a number of practical barriers to overcome before implementation in primary care can become widespread: ease of use for providers, ease of use for patients, quality of the data-entered into the HRA (particularly family health history data), and it’s potential to improve quality of care in primary care populations. Each of these is describe in detail below.

Will Providers Use It?

Providers, primary care providers in particular, are frequently overloaded by the number of tasks to achieve within the constraints of the health-care visit, and with face times shrinking to just over 9 minutes for most appointments, many lower priority and/or complex tasks often lose out to higher acuity concerns [21]. Because HRA data collection, risk calculation, and evidence synthesis are complex and time consuming (particularly for family health history data), it often poses a significant challenge for integration into normal workflow [23]. In particular, algorithms are often complex requiring a computer to calculate; however, the calculators are typically scattered across the internet and not integrated into electronic medical record (EMR) systems. In addition, the sheer magnitude of the literature available makes synthesizing an actionable risk-management plan difficult and efforts to initiate provider education around these topics have fallen flat for many of the same reasons that implementing HRAs have [24].

One solution to these complex and interrelated barriers is to leverage the burgeoning field of health IT. Patient-facing web- or computer-based HRA tools can eliminate the data collection component from the physician’s office, moving it to the patient’s home, and provide risk calculations and actionable risk-management plans to the provider at the point of care. Similarly, mobile health technologies (mHealth) are beginning to demonstrate that they can be used to facilitate risk-related data collection (environmental, behavioral, psychological, and biological) and communication between patients and their health-care system. To date, a number of family health history-based HRA tools have been built with just such capabilities [25]. See Table 1.2 for examples of currently available tools and their characteristics. Of note, only one of these tools currently incorporates clinical decision support for cardiovascular diseases. Uptake of these tools has been anecdotally promising. Currently, there is only one published study that reports physician experience with and uptake of a HRA tool. In this study, performed by the authors, primary care providers indicated that the HRA tool was easy to incorporate into workflow (100%), improved their quality of care (85%), made their practice easier (75%), and enhanced their understanding of the importance of family health history (62%) [26] (see Fig. 1.1 for sample provider report). These results suggest that with the right combination of features, electronic HRA tools can gain acceptance by busy primary care clinicians.

Table 1.2

Examples of Patient-Facing Electronic Family Health History-Based Health Risk Assessment Tools

ahttp://dukepersonalizedmedicine.org/disease-risk-and-diagnosis/risk-assessments/family-history/metree.

bSchroy PC 3rd, Glick JT, Geller AC, Jackson A, Heeren T, Prout M. A novel educational strategy to enhance internal medicine residents’ familial colorectal cancer knowledge and risk assessment skills. Am J Gastroenterol. 2005;100(3):677–684.

cBraithwaite D, Sutton S, Mackay J, Stein J, Emery J. Development of a risk assessment tool for women with a family history of breast cancer. Cancer Detect Prev. 2005;29(5):433–439.

dYoon PW, Scheuner MT, Jorgensen C, Khoury MJ. Developing Family Healthware, a family history screening tool to prevent common chronic diseases. Prev Chronic Dis. 2009;6(1):A33.

ehttps://familyhealthlink.osumc.edu/Notice.aspx.

fSugg Skinner C, Rawl SM, Moser BK, et al. Impact of the cancer risk intake system on patient–clinician discussions of tamoxifen, genetic counseling, and colonoscopy. J Gen Intern Med. 2005;20(4):360–365. doi:10.1111/j.1525-1497.2005.40115.x.

ghttp://www.hughesriskapps.com/.

hhttp://www.healthheritage.org/.

ihttps://www.invitae.com/en/.

jDoerr M, Edelman E, Gabitzsch E, Eng C, and Teng K. Formative evaluation of clinician experience with integrating family history-based clinical decision support into clinical practice. J Pers Med. 2014 Mar 26;4(2):115–136. doi: 10.3390/jpm4020115.

khttps://fht.myriad.com/app/#.

lhttps://www.powerlineage.com/.

mhttps://familyhistory.hhs.gov/FHH/html/index.html.

Figure 1.1 Sample MeTree provider report.

Will the Patients Use It?

With the expansion of web access, the health systems’ greater emphasis on patient engagement, and the increasing demands on medical providers’ time, there has been a movement towards increased utilization of patient-derived data for HRAs. Some have raised concern that patients do not have the IT know-how to use these tools or the inclination to do so. But current trends would argue that that is not the case. Millions of patients use the internet on a daily basis to better understand their health [27,28] and even among minorities and those with household incomes $25,000–$50,000 per year, internet use is over 66% [29]. In addition, individuals recognize the importance of family health history with over 90% of Americans surveyed reporting that they felt family health history was important to their personal health [30,31]. When HRAs are placed on health systems’ patient portals, significant uptake occurs. For example, when Health Heritage was launched on the Northshore University Health System’s health portal in May, 2014, 500 patients completed the assessment within the first 30 days (unpublished data). This was without any coordinated efforts by the health system to alert patients to the availability of the tool.

There are also concerns that such tools discriminate against those of lower socioeconomic status who may not have the IT literacy or access required to complete such tools. In fact, the reverse is true—HRA tools can reduce health disparities. Algorithms to assess risk and provide recommendations do not hold the inherent biases that providers may subconsciously bring to the patient encounter. Uptake has also not been shown to be limited by education level or ethnicity, two significant risk factors for health-care disparity [26,32]. Patients using one HRA tool, MeTree, reported that the tool was easy to use (94%) and understand (97%) irrespective of education level or ethnicity [26].

When patients do use IT tools for HRA, reactions are overwhelmingly positive. In three studies, participants reported being generally satisfied with their experience (83%–90%), that completing the tool did not cause persistent anxiety (96%), and that they would recommend it to others (93%–99%) [26,32,33]. In addition to having a positive experience using the tool itself, patients incur the additional benefits of raised awareness about their risk for disease and the actions they can take to mitigate their risk, and greater engagement in their health with the potential for an enhanced shared decision-making experience with their providers [4,5] (see Fig. 1.2 for HRA screen shot).

Figure 1.2 MeTree HRA screen shot.

What About Patient-Entered Data?

If we move HRA data collection out of the provider encounter, are the data entered by patients reliable? In particular, there are concerns about patients’ ability to accurately collect and interpret their family’s health history. Questions arise around differentiation of a primary cancer vs metastatic cancer, different types of cardiovascular disease such as coronary artery disease vs arrhythmias, and disease with names that sound similar such as cirrhosis and psoriasis. In a systematic review of family history questionnaires, four studies examined the agreement between patient-entered data and the presumed gold standard of genetic counselor acquired data with evidence of strong agreement between them (70%–100%) [34]. In fact, there is evidence that patient-entered data are significantly superior to what is collected in routine practice within primary care [23,32,34,35]. In our own experience, less than 4% of patients’ medical records contained high-quality family history information documented for even one relative [36]. In comparison, with use of MeTree >99% of pedigrees has at least one relative with high-quality family history information and over 50% of pedigrees had at least 50% of relatives with high-quality information [37].

Certainly, the context within which family health history is collected will affect its validity. When patients are offered education and the opportunity to discuss their family health history with relatives, significant improvements in accuracy can be seen. When patients are informed of the key components of a quality family history and use that information to guide discussions with family members, almost half will provide new or updated information and 16% will have a change in recommendations for disease risk management following conversations with family members [38].

Does It Make a Difference?

Knowing that providers and patients will use a HRA and that patient reported data are reliable, does use of such tools make a difference in outcomes? The value of HRAs is that there are now a considerable number of guidelines that tailor recommended risk-management strategies to an individual’s risk for disease. These higher risk strategies often not only have a greater sensitivity than strategies recommended for population-based screening but are also typically associated with higher costs or adverse events rates that warrant limiting them to those that are most likely to benefit. This tailoring of risk strategies to risk level helps to balance benefits and harms at the individual level and when assessed at the population level is better than using one-size-fits-all recommendations. To show that HRAs are in fact able to increase uptake of these guidelines and improve individual/population health, they need to be able to improve identification of individuals at increased disease risk, increase the match between risk level and risk-management strategy, and improve patient acceptance of management recommendations above what is currently occurring in routine care.

Surveys of providers have shown that physicians frequently over- or underestimate risk and do not feel confident in their ability to assess risk [39–42]. Fortunately, several studies have shown that family health history-based HRAs can accurately estimate risk and identify a significant number of patients who were not identified during routine visits with their providers [35,43]. For example, The Family Healthware Trial found that 82% of participants were at strong or moderate risk for at least one of six conditions [44]; the Health Heritage trial found 42% to be at increased risk [32]; and the Genomedical Connection study found 44% to be at increased risk [45].

While evidence is clear that using HRAs increases identification of at-risk individuals, less has been done to evaluate the impact on provider and patient behavior as a result of this risk information. In the authors’ experience with MeTree, use of the tool decreased overutilization of high-risk services among average risk individuals by 81% while increasing use among appropriate high-risk individuals [46]. In another study, the implementation of a breast cancer risk assessment tool, HughesRiskApps, resulted in significant increases in referrals to genetic counseling and genetic testing [47]. Other studies have also confirmed that understanding of family history increases appropriate utilization of cancer screening services [48,49]. As of yet, there have not been similar trials around cardiovascular risk assessment. Trials are ongoing to better understand how to engage patients and providers in shared decision-making surrounding patients’ behavioral and psychosocial risks [5]. One example is the National Human Genome Research Institute (NHGRI)-funded Implementing Genomics in Practice (IGNITE) network which consists of six genomic implementation demonstration projects (http://www.genome.gov/27554264). Three of these projects address HRA: two are pilots exploring new HRA markers and one is a large scale implementation of MeTree into primary care practices across five diverse national health-care systems [50]. The MeTree study is also leveraging just-emerging health-related data transmission standards (SMART on FHIR) to evaluate the impact of bidirectional data flow between a patient-facing web-based HRA application and EMR systems on patient care. Further work needs to be done in this area to better understand the impact of HRAs on patient and provider behavior as it relates to screening [51].

Conclusion

HRAs, a precision medicine tool intended to be used by well patients, hold promise for improving both individual health and population health by accurately estimating risk for disease and improving the match between risk level and risk-management strategy above what is currently occurring in clinical care. These tools may also enhance patient experiences by increasing patient activation and shared decision-making, thereby incorporating patient values into the patient–provider encounter and improving adherence to recommendations. Their accuracy and effectiveness may be further enhanced by combining genetic and genomic data about disease risk into risk algorithms. While uptake in the US health-care system has been slow to start, it is beginning to gain traction as the evidence builds around their benefit and innovations in health IT permit more seamless integration into clinical workflow. It is one of the few genomic and personalized medicine tools that is ready for immediate translation into clinical care (especially primary care) and as such can lead the way for translation of other genomic and personalized medicine in these fields by increasing clinicians’ familiarity with these types of tools and their