Metabolic Phenotyping in Personalized and Public Healthcare

UK

Abstract

Despite dramatic strides in health care, there are persistent and far-reaching medical needs that remain unmet. These include challenges in disease management, health care technology, socioeconomics, and health processes. These should be considered in a context of shifting pathology, where global trends in communicable and noncommunicable diseases remain in flux. Personalized Medicine can potentially address many of these persistent needs. We define this as the tailored management and/or prevention of disease according to the specific characteristics of a stratified individual, subpopulation, or population to enhance patient care. These characteristics are derived from the integrated evaluation of phenotype, genotype, and treatment bioresponses realized through a systems biomedicine -omics approach. This employs complex multivariate, network, and hierarchical computation in the context of best evidence-based practice. It offers precision in diagnosis and treatments, in addition to the generation of targeted therapeutics. This approach may offer novel strategies in addressing future unmet medical needs.

Keywords

Personalized medicine; personalized health care; systems biology; omics; biomedicine; public health; epidemiology

Chapter Outline

1.1 A Historical Perspective 1

1.2 Unmet Medical Needs 2

1.3 Addressing the Problems 6

1.4 Personalized Medicine 7

1.5 Personalized Medicine: The Role of Metabolic Phenotyping 12

References 13

1.1 A Historical Perspective

The 21st century has heralded dramatic changes in the global health care ecology. There have been significant fluxes in population dynamics, occupational shifts, environmental changes, drivers of health care economics, political forces, and a technologic explosion that can be considered as dramatic as the advances of both the agricultural and industrial revolutions. Despite an overall increase in the awareness of disease and a more unified approach to its management, health care remains a global problem that challenges society with a voluminous corpus of unmet medical needs.

As early as the 5th century BC, Hippocrates had clarified that disease pathology originated from both inherent patient factors and those of the patient’s environment [1]. In subsequent eras, the increased scrutiny and understanding of disease mechanisms has offered a tentative breakdown of the relative contribution of disease from these two factors. These led to many of the very foundations of medicine as we know it today, including Edward Jenner’s demonstration of controlled immunity, Louis Pasteur’s germ theory of disease [2], and hybridization of Greek anatomy and eastern proto-pharmacotherapy described in Avicenna’s Canon of Medicine [3].

While the work of the luminaries listed above added to a critical mass of health care expertise, the isolated work of John Gaunt in 1662 led to the birth of epidemiology [4]. In this work, for the first time, Gaunt was able to describe quantifiable trends in disease rates in a London population, and his description offered a wider interpretation of modifiable disease mechanism that could lead to a cure.

Three taxonomic questions arose then and continue to confront mankind:

1. What is the nature of diseases, and what are their trends?

2. What are the mechanisms that govern their initiation and progression?

3. How can we best treat them?

Twentieth century medicine, in turn, yielded a number of powerful scientific breakthroughs, including the discovery of the structure of deoxyribonucleic acid (DNA), characterization of the human genome, and the ability to differentiate the protein, transcription ribonucleic acid, and even metabolites of healthy as well as diseased individuals. Such discoveries were also augmented by treatment innovations, including the introduction of population-wide antibiotics following the birth of penicillin, and novel technologies that permit super-precise operations through robotic surgery.

1.2 Unmet Medical Needs

Despite the developments described above, many current treatment strategies remain ineffectual and significant health care needs continue to challenge human society (Fig. 1.1). At a global level, the World Health Organization (WHO) [5] reported ischemic heart disease, stroke, lower respiratory infections, chronic obstructive lung disease, and diarrhea as the top five causes of death in 2011. Both ischemic heart disease and stroke originate from cardiovascular disease and, together, account for 21.8% of all deaths. Adding deaths from diabetes mellitus, an associated condition, to this total results in just fewer than 25% of all deaths from cardiovascular disease (see Fig. 1.1).

Figure 1.1 Causes of global mortality 2011 reported by the World Health Organization (WHO) [5].

The current rates of global mortality, nevertheless, represent a paradigm shift from the main drivers of mortality that afflicted mankind until the end of the 19th century. These included malnourishment, mycobacterial diseases (tuberculosis and leprosy), smallpox (which was eradicated in 1979), diphtheria, typhoid, and dysentery. Consequently, the majority of mankind’s diseases originated from lack of food and exposure to communicable diseases (in the absence of antimicrobials), whereas more recently we have discovered vulnerability to noncommunicable diseases arising from obesity, smoking, aging, environmental change, and the persistence of global infectious diseases due to the expansive worldwide traveling footprint.

Disease trends as a result of industrialization also contribute distinct disease patterns. As an example, trends in mortality in the United States (Fig. 1.2) [6–9] demonstrate that in 1900 infectious diseases accounted for 37% of deaths, cardiovascular diseases (heart disease and stroke) were responsible for 17%, and cancer resulted in only 4.5% of deaths. By 1982, cardiovascular diseases accounted for over half of all deaths (58.3%) and cancer for approximately one quarter of mortality. At the beginning of the 21st century, Alzheimer disease entered the top 10 causes of death as the first example of mortality from neurodegenerative diseases (see Fig. 1.2).

Figure 1.2 Trends in US mortality rates [6–8] in 1900–2010.

These epidemiologic shifts in disease result from the balancing of excess calories, sedentary lifestyle, environmental pollution, and uncontrolled exposure to toxins (such as smoking and alcohol) versus accessibility to advanced health care centers, health care economics, health policy and management, personal economic capital, efficacious pharmaceuticals, and well-trained medical expertise. This simple equilibrium is, in actuality, more complex than one of pathologic factors versus health-promoting elements. Factors such as advanced health systems also lead to longer life span, which, by itself, is associated with pathologic conditions such as frailty, increased cardiovascular risk, and a higher chance of tumorigenesis and neurodegenerative diseases.

At a higher level, based on our biomedical understanding of disease trends, are the roles of human networks and global health care policy. Obesity is a classic example of both a physical disease and a web-based communication network disease [10,11], whereas the global spread of viral diseases such as influenza and bird flu depends directly on global network hubs and travel dynamics. The eradication of smallpox [2] was achieved through successful international lobbying, at a political level, through the WHO, and conversely, increasing global rates of poliomyelitis have been linked to geopolitical rivalry. Also, the management of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) has been less efficient in some nation states due to social nonacceptance of this viral illness as a disease. As a consequence, the 21st century medical community has recognized the need to address disease and health care management through a complete arsenal of (1) disease management, (2) socioeconomics, (3) health process, and (4) technology. Together, these constitute healthcare’s unmet needs (Fig. 1.3).

Figure 1.3 Unmet needs in health care.

The needs of disease management directly reflect the current status of disease trends. These comprise the major diseases that have been present for generations as well as newer diseases that represent current and future pathologies. For example, malaria has plagued mankind for millennia but is associated with our molecular evolution, as sickle cell disease may have come into existence because of a selection trait brought on by protection from this disease. Another example is obesity, which was considered an evolutionary advantage in the Ice Age, but its sudden and dramatic rise to a pandemic level disease has resulted in bariatric surgery rates exceeding those of traditional operations for common disorders such as gallbladder excision (cholecystectomy) in some parts of the Western world [12,13]. Population-based variances in disease trends also exist; for example, in Africa, autoimmunity and asthma are not well recognized, whereas these conditions are common in Western populations. Between 1990 and 2001, deaths due to communicable, maternal, perinatal, and nutritional diseases were reduced by 20% [14], but these have been replaced by new sources of mortality.

Globally, approximately 60–70 million people die each year, 15–20% of which are children. However, 99% of child mortality occurs in low-income and middle-income countries, and over 50% of these deaths result from infectious diseases, including acute respiratory infections, measles, diarrhea, malaria, and HIV/AIDS [14]. Analysis of global data has identified 19 risk factors [14] that account for 45% of deaths and 36% of disease burden worldwide. These include:

 Nutritional: underweight in children, high cholesterol, obesity (and overweight), low fruit and vegetable intake, zinc deficiency, iron deficiency anemia, vitamin A deficiency

 Environmental: unsafe water (as well as poor sanitation and hygiene), indoor air pollution (from solid fuels), urban air pollution

 Behavioral and sociopathologic: unsafe sex, smoking, alcohol use, physical inactivity, illicit drug use, unmet contraception need, sexual abuse of children

 Iatrogenic: contaminated injections

 Physiologic: hypertension.

Streptococcus pneumoniae is responsible for approximately 11% (8–12%) of deaths in children between 1 and 59 months, whereas Haemophilus influenzae type b (Hib) causes approximately 400,000 deaths in children of the same age group through bacterial meningitis, pneumonia, and other serious infections [15,16].

Other pertinent examples include Epstein–Barr virus, which, for half a century, has been associated with development of cancer in over 200,000, and, to date, the exact mechanism of viral tumorigenesis remains unknown [17]. Other well-known diseases with causes that are better understood, have yet to be addressed by the global society. In the developing world, the maternal mortality ratio is approximately 440 per 100,000 live births; approximately 34 times the rate in the developed world (13 per 100,000 live births) [18]. In terms of a predicted disease mortality, noncommunicable diseases are set to rise from 59% (2002) to 69% (2030). According to both baseline and worst-case scenarios, the three top global causes of death in 2030 have been predicted to be HIV/AIDS, unipolar depressive disorders, and ischemic heart disease [19], with road traffic accidents indicated as the fourth leading cause of death in some simulations.

The WHO currently estimates that HIV/AIDS represents the third most common cause of mortality in the developing world. The prevalence of a significant retroviral load in the populations of the developing world has led to deterioration in the fight against tuberculosis and its drug therapy, which is now heavily complicated by drug resistance [20]. These pathologic factors add to other elements of unmet health care, which include several socio-economic factors that are prominent contributors to early mortality in the developing world.

Although more prevalent in the developing world, chronic noncommunicable diseases are now emerging as a global health problem. Cardiovascular diseases, obesity, diabetes, cancer, chronic respiratory disease, and mental health now account for the majority of global mortality and disability [21]. Furthermore, it has been estimated that over a 10-year period, the financial loss caused by these disorders to low-income and middle-income countries is approximately $84 billion [22]. Despite this, noncommunicable diseases remain a concern of low priority in many health care systems; this situation has led to several calls to action on the global stage of health care, including a recent United Nations high-level meeting [21,23]. Finally, there is a second level of diseases not originating from nascent pathology but, rather, as a result of our unbalanced attempts to treat other diseases. One prominent example is the worsening threat of antimicrobial resistance (agents ineffective against all microbial organisms), specifically antibiotic resistance (agents ineffective against common bacterial infections). In this case, the WHO has identified 450,000 new cases of multidrug-resistant tuberculosis in 2012 and a further 64% higher risk of death from hospital-acquired methicillin-resistant Staphylococcus aureus infections compared with risk of death from nonresistant S. aureus infections [24]. This has resulted from incongruous overconsumption and overapplication of these therapies, which, however, demonstrate the highest efficacy when utilized in a targeted fashion [25].

1.3 Addressing the Problems

Both the developed and developing societies of the world recognize an escalation of health care costs, and there has been a call for targeted therapies that are cost efficient and yet provide care of quality and value. It is expected that the major part of global health care expenditure will come from countries with the fastest-growing markets, termed BRIC (Brazil, Russia, India, and China) and MINT (Mexico, Indonesia, Nigeria, and Turkey). As an example, the expenditure of the health care sector in India in 2012 [26,27] was estimated to be $40 million dollars.

With the changing disease burden, a shortage of qualified health care practitioners is emerging, even in the developed world. The Association of American Medical Colleges has estimated that in the United States, there will be a shortfall of 45,000 primary care physicians and of 46,000 surgeons and medical specialists by 2020 [27,28]. Staffing shortages in both developing and developed countries will likely result in an increased reliance on fast, accurate, and cost-effective diagnostic and treatment methods. Increased access to information with Web 2.0+ technologies, including social media, has empowered patients and increased public awareness of health care so that patient decisions will also contribute significantly to health care practice in the future. This development, coupled with increased global travel, has already resulted in the proliferation of medical tourism [27] (where patients visit countries specifically for the quality and availability of health care available there). This increased global travel has, however, also facilitated the spread of diseases, including pandemics of communicable diseases.

Increased requirements for cost-effectiveness in patient care will likely herald an era in which all stakeholders will join together to generate and deliver the next generation of treatments. This will include collaborations among patients, health care providers, industry, academia, governments, and nongovernmental organizations (NGOs), this, however, will require support from appropriate local and global policies to offer to patients treatments that are selected on the basis of the best evidence.

Obtaining the best evidence in patient care calls for the development of technologic tools that can offer cutting-edge treatments (eg, surgical robots with increased precision, pharmacotherapies with fewer side effects and more efficacy). The increased level of health care precision channeled through evidence-based practice, in turn, requires the interpretation of larger, more complex, and more accurate patient information or big data with the use of more powerful computation tools.

1.4 Personalized Medicine

Questions with regard to unmet medical needs can ultimately be answered through the recently developed concept of Personalized Medicine, which offers targeted health care provision that takes into consideration both inherent patient factors and environmental factors. This concept was developed in response to several advances in health care practice, including:

1. Increased awareness that not all treatments have the same effects on all patients. For example, not all patients respond to similar pharmacotherapies in the same way.

2. Increased precision in the characterization of patients and their diseases, for example, through the Human Genome Project and, more recently, the use of approaches known as Systems Biology (involving so-called omics technologies—genomics, transcriptomics, proteomics, and metabolomics/metabonomics, now often referred to as metabolic phenotyping).

3. Increased ability to evaluate and compute the big data from these sciences to generate treatments.

The term Personalized Medicine has often been used synonymously with precision medicine and stratified medicine. It utilizes biomedical methodology, which can stratify patients within their subpopulations. As a result, it can account for varying susceptibility of patients to different diseases and their fluctuating responses to specific treatments. This powerful methodology can thus maximize patient benefit and minimize patient harm. Numerous definitions of Personalized Medicine have been proposed (Table 1.1), all of which demonstrate common elements [37] (eg, three definitions employ the term tailored or tailoring). Here, we propose a single unifying definition:

Personalized Medicine is the tailored management and/or prevention of disease according to the specific characteristics of a stratified individual, subpopulation, or population to enhance patient care. These characteristics are derived from the integrated evaluation of phenotype, genotype, and treatment bioresponses realized through a systems biomedicine—the -omics approach. This employs complex multivariate, network, and hierarchical computation in the context of best evidence-based practice. It offers precision diagnosis and treatments in addition to the generation of targeted therapeutics.

Table 1.1

Definitions of Personalized Medicine

The birth of Personalized Medicine resulted from the coalescence of several underlying elements (Fig. 1.4). By the late 17th century, Archibald Pitcairne had introduced the concept of applying complex mathematics to medicine [38]. Approximately two and a half centuries later, two fundamental breakthroughs took place, in an unrelated but sequential fashion, in the late 1930s. Alan Turing the renowned British mathematician and cryptographer addressed the Entscheidungsproblem or Decision Problem in 1936 to initiate the era of computation using computers [39]. Shortly after in 1937, Karl Ludwig von Bertalanffy introduced the concept of General Systems Theory or Allgemeine Systemtheorie. This revolutionized our appraisal of biology, overcoming traditional basic models of bio-organization to offer an appreciation or real-life complexity in terms of a hierarchical structure and an interactive, multifaceted communication dialog of metabolic, energetic, and cellular intermediaries [40]. This paved the way for modern systems biology and the birth of the -omics sciences (including genomics, transcriptomics, proteomics, and metabolomics/metabonomics) in addition to contributing to cybernetics, management theory, economics, and a massive range of allied specialties. The final component of the Personalized Medicine coalescence was the renaissance of Avicenna’s concept of treatment evidence discussed in his 11th century Canon of Medicine [3], and subsequently re-adapted in the 1960s by pioneers such as Archibald Leman Cochrane to promote the role of clinical evidence in decisions and was subsequently, in 1990, named evidence-based medicine by Gordon Guyatt.

Figure 1.4 The components of Personalized Medicine.

The strength of Personalized Medicine can therefore offer a solution to health care’s unmet needs through addressing six core areas [37,41], including:

 Basic research: disease mechanisms, molecular pathways, and drug metabolism

 Drug discovery and development: prediction of drug responders and identifying new roles for drugs already in use for treating other conditions (so-called repurposing)

 Preclinical testing: identifying drug candidates that can progress through the phases of drug testing

 Clinical research: enhanced selection of appropriate trial participants and enhanced analysis of outcomes

 Clinical adoption: better targeted therapies with higher efficacy for public health, medicine, and surgery

 Health care (in general): better diagnostics, better treatments, better patient selection, cost-effectiveness of treatment strategies and enhanced patient outcomes, adoption of novel next-generation technologies such as super-high-precision intraoperative diagnostics.

The ultimate goal of Personalized Medicine is to improve patient outcomes by offering higher-precision treatments of the highest quality and value. It has been projected that reducing the burden of chronic disease by 2% a year over a 10-year period would result in the prevention of 36 million deaths and 500 million life-years saved. The majority of these benefits would result from the improved health of both young and older subjects in low-income and middle-income countries [42]. The potential for Personalized Medicine to offer solutions across all health care areas therefore renders it a powerful tool for current and future health care providers.

In summary, the global shift in the characters and trends of diseases continues to have a significant impact on the health care sector worldwide, which, in turn, is correlated to the scientific, political, and economic landscapes. Traditional medical practice has also expanded to meet the goals of next-generation targeted and precise health care. Personalized Medicine is one paradigm that offers an innovation tipping point, with the potential for achieving high-precision cost-effective treatments to augment medical care at all levels. The scene is now set for the development of this system and for incorporating it into the future of biomedicine, with the ultimate aim of achieving the highest quality treatments and best value-based health care outcomes.

1.5 Personalized Medicine: The Role of Metabolic Phenotyping

Metabolic phenotyping uses a range of modern technologies in analytical chemistry to provide information on the small molecule metabolites present in biofluids such as urine or blood serum/plasma as well as in tissue extracts. Changes in the levels of such metabolites in patients can be used as biomarkers for disease diagnosis, therapy efficacy or side effects and also as prognostic markers of outcome. In population studies, the same approach can lead to epidemiologic biomarkers of disease risk.

The main techniques used are nuclear magnetic resonance (NMR) spectroscopy, and mass spectrometry, the latter detection method usually requiring a chromatographic separation stage first; currently, this is usually ultra-performance liquid chromatography, although other techniques such as capillary electrophoresis and gas chromatography are also used. NMR spectroscopy is also unique in that it can be used to obtain information on metabolites in intact tissue biopsy specimens by using a technique known as magic-angle spinning.

For population screening, there are a number of published examples where novel metabolic biomarkers of disease risk have been discovered. These include markers of cardiovascular disease risk from metabolic profiling of serum [43] and blood pressure from markers in urine [44].

In the context of Personalized Medicine, the concept of the patient’s metabolic trajectory has been suggested [45]. In this approach, biofluid (and stool samples) can be obtained prior to, during, and after a patient undergoes treatment. The metabolic information so obtained can then be used to aid diagnosis, to monitor the effects of any treatment, and to predict outcomes such as the need for Intensive Therapy/Care Unit (ITU) admission. Although the approach can be used for any therapeutic intervention, it has particular benefit for surgical procedures, where fast decision making is necessary and comprehensive biochemical information is usually not available. In surgery, the intelligent knife technology is already beginning to demonstrate its usefulness [46]. These and similar strategies offer a platform on which to build and integrate health care innovations from nanotechnology agents to robotic surgeons, which can, in turn, address pathology at a multitude of scales, ranging from the whole organism to nanoscale molecular targets. In this way, the promise of cutting-edge medical therapies in areas such as genetics, regenerative medicine, surgery, and pharmaceuticals may fulfill their long-term promises.

We believe that this approach holds tremendous potential for helping to fulfill the unmet medical needs of the 21st century.

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