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InternalMed_Harrison. Also around this time, the WHO began advocating a public health approach to the treatment of people with AIDS in resource-limited settings. This approach, derived from models of care pioneered by the NGO Partners In Health and other groups, proposed standard first-line treatment regimens based on a simple five-drug formulary, with a more complex (and more expensive) set of second-line options in reserve. Clinical protocols were standardized, and intensive training packages for health professionals and community health workers were developed and implemented in many countries. These efforts were supported by new funding from the World Bank, the Global Fund, and PEPFAR. In 2003, lack of access to ART was declared a global public health emergency by the WHO and UNAIDS, and those two agencies launched the “3 by 5 initiative,” setting an ambitious target: to have 3 million people in developing countries on treatment by the end of 2005. Worldwide funding for HIV/AIDS treatment increased


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InternalMed_Harrison. launched the “3 by 5 initiative,” setting an ambitious target: to have 3 million people in developing countries on treatment by the end of 2005. Worldwide funding for HIV/AIDS treatment increased dramatically during this period, rising from $300 million in 1996 to over $15 billion in 2010.


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InternalMed_Harrison. Many countries set corresponding national targets and have worked to integrate ART into their national AIDS programs and health systems and to harness the synergies between HIV/AIDS treatment and prevention activities. Further lessons with implications for policy and action have come from efforts now under way among lower-income countries. Rwanda provides an example: Over the past decade, mortality from HIV disease has fallen by >78% as the country—despite its relatively low gross national income (Fig. 2-3)—has provided almost universal access to ART. The reasons for this success include strong national leadership, evidence-based policy, cross-sector collaboration, community-based care, and a deliberate focus on a health system approach that embeds HIV/AIDS treatment and prevention in the primary health care service delivery platform. As we will discuss later in this chapter, these principles can be applied to other conditions, including NCDs.


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InternalMed_Harrison. Chapter 202 provides a concise overview of the pathophysiology and treatment of TB. In 2011, an estimated 12 million people were living with active TB, and 1.4 million died from it. The disease is closely linked to HIV infection in much of the world: of the 8.7 million estimated new cases of TB in 2011, 1.2 million occurred among people living with HIV. Indeed, a substantial proportion of the TB resurgence FIgURE 2-2 An HIV/TB-co-infected patient in Rwanda before (left ) and after (right ) 6 months of treatment. 100% infection control in hospitals and clinics is associated with explosive and lethal epidemics due to these strains and that patients may be infected with multiple strains.


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InternalMed_Harrison. 100% infection control in hospitals and clinics is associated with explosive and lethal epidemics due to these strains and that patients may be infected with multiple strains. Gross domestic product per capita, 2009 (log) Namibia Swaziland Zambia Gabon South Africa Senegal Benin MaliEthiopia Malawi ChadEritrea Niger Liberia Madagascar Somalia Djibouti Sudan Burundi D.R. Congo Congo Angola Mauritius United Nations 2010 target $100 0% 20% 40% 60% $1,000 $10,000 FIgURE 2-3 Antiretroviral therapy (ART) coverage in sub-Saharan Africa, 2009.


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InternalMed_Harrison. Estimated ART coverage, 2009 registered in southern Africa is attributed to HIV co-infection. Even before the advent of HIV, however, it was estimated that fewer than one-half of all cases of TB in developing countries were ever diagnosed, much less treated. Primarily because of the common failure to diagnose and treat TB, international authorities devised a single strategy to reduce the burden of disease. In the early 1990s, the World Bank, the WHO, and other international bodies promoted the DOTS strategy (directly observed therapy using short-course isoniazidand rifampinbased regimens) as highly cost-effective. Passive case-finding of smear-positive patients was central to the strategy, and an uninterrupted drug supply was, of course, deemed necessary for cure.


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InternalMed_Harrison. DOTS was clearly effective for most uncomplicated cases of drug-susceptible TB, but a number of shortcomings were soon identified. First, the diagnosis of TB based solely on sputum smear microscopy— a method dating from the late nineteenth century—is not sensitive. Many cases of pulmonary TB and all cases of exclusively extrapulmonary TB are missed by smear microscopy, as are most cases of active disease in children. Second, passive case-finding relies on the availability of health care services, which is uneven in the settings where TB is most prevalent. Third, patients with multidrug-resistant TB (MDR-TB) are by definition infected with strains of Mycobacterium tuberculosis resistant to isoniazid and rifampin; thus exclusive reliance on these drugs is unwarranted in settings in which drug resistance is an established problem.


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InternalMed_Harrison. The crisis of antibiotic resistance registered in U.S. hospitals is not confined to the industrialized world or to common bacterial infections. The great majority of patients sick with and dying from TB are afflicted with strains susceptible to all first-line drugs. In some settings, however, a substantial minority of patients with TB are infected with M. tuberculosis strains resistant to at least one first-line anti-TB drug. A 2012 article in a leading journal reported that, in China, 10% of all patients with TB and 26% of all previously treated patients were sick with MDR strains of M. tuberculosis. Most of these cases were the result of primary transmission. To improve DOTS-based responses to MDR-TB, global health authorities adopted DOTS-Plus, which adds the diagnostics and drugs necessary to manage drug-resistant disease. Even as DOTS-Plus was being piloted in resource-constrained settings, however, new strains of extensively drug-resistant (XDR) M. tuberculosis (resistant to


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InternalMed_Harrison. to manage drug-resistant disease. Even as DOTS-Plus was being piloted in resource-constrained settings, however, new strains of extensively drug-resistant (XDR) M. tuberculosis (resistant to isoniazid and rifampin, any fluoroquinolone, and at least one injectable second-line drug) had already threatened the success of TB control programs in beleaguered South Africa, for example, where high rates of HIV infection have led to a doubling of TB incidence over the last decade. Despite the poor capacity for detection of MDRand XDR-TB in most resource-limited settings, an estimated 630,000 cases of MDR-TB were thought to occur in 2011. Approximately 9% of these drug-resistant cases were caused by XDR strains. It is clear that poor


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InternalMed_Harrison. TUBERCULoSIS ANd AIdS AS CHRoNIC dISEASES: LESSoNS LEARNEd


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InternalMed_Harrison. Strategies effective against MDR-TB have implications for the management of drug-resistant HIV infection and even drug-resistant malaria, which, through repeated infections and a lack of effective therapy, has become a chronic disease in parts of Africa (see “Malaria,” below). Equatorial As new therapies, whether for TB or for hepatitis C infec-Guinea tion, become available, many of the problems encountered in the past will recur. Indeed, examining AIDS and TB as chronic diseases—instead of simply communicable diseases—makes it possible to draw a number of conclusions, many of them pertinent to global health in general. First, the chronic infections discussed here are best treated with multidrug regimens to which the infecting strains are susceptible. This is true of chronic infections due to many bacteria, fungi, parasites, or viruses; even acute infections such as those caused by Plasmodium spe cies are not reliably treated with a single drug.


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InternalMed_Harrison. Second, charging fees for AIDS prevention and care poses insurmountable problems for people living in poverty, many of whom are unable to pay even modest amounts for services or medications. Like efforts to battle airborne TB, such services might best be seen as a public good promoting public health. Initially, a subsidy approach will require sustained donor contributions, but many African countries have set targets for increased national investments in health—a pledge that could render ambitious programs sustainable in the long run, as the Rwanda experience suggests. Meanwhile, as local investments increase, the price of AIDS care is decreasing. The development of generic medications means that ART can now cost <$0.25 per day; costs continue to decrease.


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InternalMed_Harrison. Third, the effective scale-up of pilot projects requires strengthening and sometimes rebuilding of health care systems, including those charged with delivering primary care. In the past, the lack of health care infrastructure has been cited as a barrier to providing ART in the world’s poorest regions; however, AIDS resources, which are at last considerable, may be marshaled to rebuild public health systems in sub-Saharan Africa and other HIV-burdened regions—precisely the settings in which TB is resurgent.


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InternalMed_Harrison. Fourth, the lack of trained health care personnel, most notably doctors and nurses, in resource-poor settings must be addressed. This personnel deficiency is invoked as a reason for the failure to treat AIDS in poor countries. In what is termed the brain drain, many physicians and nurses emigrate from their home countries to pursue opportunities abroad, leaving behind health systems that are understaffed and ill equipped to deal with the epidemic diseases that ravage local populations. The WHO recommends a minimum of 20 physicians and 100 nurses per 100,000 persons, but recent reports from that organization and others confirm that many countries, especially in sub-Saharan Africa, fall far short of those target numbers. Specifically, more than one-half of those countries register fewer than 10 physicians per 100,000 population. In contrast, the United States and Cuba register 279 and 596 doctors per 100,000 population, respectively. Similarly, the majority of sub-Saharan African


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InternalMed_Harrison. than 10 physicians per 100,000 population. In contrast, the United States and Cuba register 279 and 596 doctors per 100,000 population, respectively. Similarly, the majority of sub-Saharan African countries do not have even half of the WHO-recommended minimum number of nurses. Further inequalities in health care staffing exist within countries. Rural–urban disparities in health care personnel mirror disparities of both wealth and health. For instance, nearly 90% of Malawi’s population lives in rural areas, but more than 95% of clinical officers work at urban facilities, and 47% of nurses work at tertiary care facilities. Even community health workers trained to provide first-line services to rural populations often transfer to urban districts.


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InternalMed_Harrison. One reason doctors and nurses leave sub-Saharan Africa and other resource-poor areas is that they lack the tools to practice their trade there. Funding for “vertical” (disease-specific) programs can be used not only to strengthen health systems but to recruit and train physicians and nurses to underserved regions where they, in turn, can help to train and then work with community health workers in supervising care for patients with AIDS and many other diseases within their communities. Such training should be undertaken even where physicians are abundant, since close community-based supervision represents the highest standard of care for chronic disease, whether in developing or developed countries. The United States has much to learn from Rwanda.


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InternalMed_Harrison. Fifth, the barriers to adequate health care and patient adherence that are raised by extreme poverty can be removed only with the deployment of “wrap-around services”: food supplements for the hungry, help with transportation to clinics, child care, and housing. Extreme poverty makes it difficult for many patients to comply with therapy for chronic diseases, whether communicable or not. Indeed, poverty in its many dimensions is far and away the greatest barrier to the scale-up of treatment and prevention programs. In many rural regions of Africa, hunger is the major coexisting condition in patients with AIDS or TB, and those consumptive diseases cannot be treated effectively without adequate caloric intake.


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InternalMed_Harrison. Finally, there is a need for a renewed basic-science commitment to the discovery and development of vaccines; more reliable, less expensive diagnostic tools; and new classes of therapeutic agents. This need applies not only to the three leading infectious killers—against none of which is there an effective vaccine—but also to most other neglected diseases of poverty.


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InternalMed_Harrison. Chapter 248 reviews the etiology, pathogenesis, and clinical treatment of malaria, the world’s third-ranking infectious killer. Malaria’s human cost is enormous, with the highest toll among children—especially African children—living in poverty. In 2010, there were ~219 million cases of malaria, and the disease is thought to have killed 660,000 people; 86% of these deaths (~568,000) occurred among children <5 years old. The poor disproportionately experience the burden of malaria: more than 80% of estimated malaria deaths occur in just 14 countries, and mortality rates are highest in sub-Saharan Africa. The Democratic Republic of the Congo and Nigeria account for more than 40% of total estimated malaria deaths globally.


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InternalMed_Harrison. Microeconomic analyses focusing on direct and indirect costs estimate that malaria may consume >10% of a household’s annual income. A study in rural Kenya shows that mean direct-cost burdens vary between the wet and dry seasons (7.1% and 5.9% of total household expenditure, respectively) and that this proportion is >10% in the poorest households in both seasons. A Ghanaian study that categorized the population by income group highlighted the regressive nature of this cost: responding to malaria consumed only 1% of a wealthy family’s income but 34% of a poor household’s income.


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InternalMed_Harrison. Macroeconomic analyses estimate that malaria may reduce the per capita gross national product of a disease-endemic country by 50% relative to that of a non-malaria-endemic country. The causes of this drag include impaired cognitive development of children, decreased schooling, decreased savings, decreased foreign investment, and restriction of worker mobility. In light of this enormous cost, it is little wonder that an important review by the economists Sachs and Malaney concludes that “where malaria prospers most, human societies have prospered least.”


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InternalMed_Harrison. Rolling Back Malaria In part because of differences in vector distribution and climate, resource-rich countries offer few blueprints for malaria control and treatment that are applicable in tropical (and resource-poor) settings. In 2001, African heads of state endorsed the WHO Roll Back Malaria (RBM) campaign, which prescribes strategies appropriate for sub-Saharan African countries. In 2008, the RBM partnership launched the Global Malaria Action Plan (GMAP). This strategy integrates prevention and care and calls for an avoidance of single-dose regimens and an awareness of existing drug resistance. The GMAP recommends a number of key tools to reduce malaria-related morbidity and mortality rates: the use of insecticide-treated bed nets (ITNs), indoor residual spraying, and artemisinin-based combination therapy (ACT) as well as intermittent preventive treatment during pregnancy, prompt diagnosis, and other vector control measures such as larviciding and environmental management.


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InternalMed_Harrison. InsectIcIde-treated bed nets ITNs are an efficacious and cost-effective public health intervention. A meta-analysis of controlled trials in seven sub-Saharan African countries indicates that parasitemia prevalence is reduced by 24% among children <5 years of age who sleep under ITNs compared with that among those who do not. Even untreated nets reduce malaria incidence by one-quarter. On an individual level, the utility of ITNs extends beyond protection from malaria. Several studies suggest that ITNs reduce all-cause mortality among children under age 5 to a greater degree than can be attributed to the reduction in malarial disease alone. Morbidity (specifically that due to anemia), which predisposes children to diarrheal and respiratory illnesses and pregnant women to the delivery of low-birth-weight infants, also is reduced in populations using ITNs. In some areas, ITNs offer a supplemental benefit by preventing transmission of lymphatic filariasis, cutaneous leishmaniasis, Chagas’


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InternalMed_Harrison. infants, also is reduced in populations using ITNs. In some areas, ITNs offer a supplemental benefit by preventing transmission of lymphatic filariasis, cutaneous leishmaniasis, Chagas’ disease, and tick-borne relapsing fever. At the community level, investigators suggest that the use of an ITN in just one household may reduce the number of mosquito bites in households up to a hundred meters away by reducing mosquito density. The cost of ITNs per DALY saved—estimated at $29—makes ITNs a good-value public health investment.


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InternalMed_Harrison. The WHO recommends that all individuals living in malaria-endemic areas sleep under protective ITNs. About 140 million long-lasting ITNs were distributed in high-burden African countries in 2006–2008, and rates of household ownership of ITNs in high-burden countries increased to 31%. Although the RBM partnership has seen modest success, the WHO’s 2009 World Malaria Report states that the percentage of children <5 years of age using an ITN (24%) remains well below the World Health Assembly’s target of 80%. Limited success in scaling up ITN coverage reflects the inadequately acknowledged economic barriers that prevent the destitute sick from gaining access to critical preventive technologies and the challenges faced in designing and implementing effective delivery platforms for these products. In other words, this is a delivery failure rather than a lack of knowledge of how best to reduce malaria deaths.


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InternalMed_Harrison. Indoor resIdual sprayIng Indoor residual spraying is one of the most common interventions for preventing the transmission of malaria in endemic areas. Vector control using insecticides approved by the WHO, including DDT, can effectively reduce or even interrupt malaria transmission. However, studies have indicated that spraying is effective in controlling malaria transmission only if most (~80%) of the structures in the targeted community are treated. Moreover, since a successful program depends on well-trained spraying teams as well as on effective monitoring and planning, indoor residual spraying is difficult to employ and is often reliant on health systems with a strong infrastructure. Regardless of the limitations of indoor residual spraying, the WHO recommends its use in combination with ITNs. Neither intervention alone is sufficient to prevent transmission of malaria entirely.


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InternalMed_Harrison. artemIsInIn-based combInatIon therapy The emergence and spread of chloroquine resistance have increased the need for antimalarial combination therapy. To limit the spread of resistance, the WHO now recommends that only ACT (as opposed to artemisinin monotherapy) be used for uncomplicated falciparum malaria. Like that of other antimalarial interventions, the use of ACT has increased in the last few years, but coverage rates remain very low in several countries in sub-Saharan Africa. The RBM partnership has invested significantly in measures to enhance access to ACT by facilitating its delivery through the public health sector and developing innovative funding mechanisms (e.g., the Affordable Medicines Facility—malaria) that reduce its cost significantly so that ineffective monotherapies can be eliminated from the market.


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InternalMed_Harrison. In the last several years, resistance to antimalarial medicines and insecticides has become an even larger problem than in the past. In 2009, confirmation of artemisinin resistance was reported. Although the WHO has called for an end to the use of artemisinin monotherapy, the marketing of such therapies continues in many countries. Ongoing use of artemisinin monotherapy increases the likelihood of drug resistance, a deadly prospect that will make malaria far more difficult to treat. Between 2001 and 2011, global malaria deaths were reduced by an estimated 38%, with reductions of ≥50% in 10 African countries as well as in most endemic countries in other regions. Again the experience in Rwanda is instructive: from 2005 to 2011, malaria deaths dropped by >85% for the same reasons mentioned earlier in recounting that nation’s successes in battling HIV.


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InternalMed_Harrison. Meeting the challenge of malaria control will continue to require careful study of appropriate preventive and therapeutic strategies in the context of an increasingly sophisticated molecular understanding of pathogen, vector, and host. However, an appreciation of the economic and social devastation wrought by malaria—like that inflicted by diarrhea, AIDS, and TB—on the most vulnerable populations should heighten the level of commitment to critical analysis of ways to implement proven strategies for prevention and treatment.


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InternalMed_Harrison. Funding from the Global Fund, the Gates Foundation, the World Bank’s International Development Association, and the U.S. President’s Malaria Initiative, along with leadership from public health authorities, is critical to sustain the benefits of prevention and treatment. Building on the growing momentum of the last decade with adequate financial support, innovative strategies, and effective tools for prevention, diagnosis, and treatment, we may one day achieve the goal of a world free of malaria.


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InternalMed_Harrison. Although the burden of communicable diseases—especially HIV infection, TB, and malaria—still accounts for the majority of deaths in resource-poor regions such as sub-Saharan Africa, 63% of all deaths worldwide in 2008 were held to be due to NCDs. Although we will use this term to describe cardiovascular diseases, cancers, diabetes, and chronic lung diseases, this usage masks important distinctions. For instance, two significant NCDs in low-income countries, rheumatic heart disease (RHD) and cervical cancer, represent the chronic sequelae of infections with group A Streptococcus and human papillomavirus, respectively. It is in these countries that the burden of disease due to NCDs is rising most rapidly. Close to 80% of deaths attributable to NCDs occur in lowand middle-income countries, where 86% of the global population lives. The WHO reports that ~25% of global NCD-related deaths take place before the age of 60—a figure representing ~5.7 million people and exceeding the total number


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InternalMed_Harrison. 86% of the global population lives. The WHO reports that ~25% of global NCD-related deaths take place before the age of 60—a figure representing ~5.7 million people and exceeding the total number of deaths due to AIDS, TB, and malaria combined. In almost all high-income countries, the WHO reported that NCD deaths accounted for ~70% of total deaths in 2008. By 2020, NCDs will account for 80% of the global burden of disease and for 7 of every 10 deaths in developing countries. The recent increase in resources for and attention to communicable diseases is both welcome and long overdue, but developing countries are already carrying a “double burden” of communicable and noncommunicable diseases.


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InternalMed_Harrison. diabetes, Cardiovascular disease, and Cancer: A global Perspective In contrast to TB, HIV infection, and malaria—diseases caused by single pathogens that damage multiple organs—cardiovascular diseases reflect injury to a single organ system downstream of a variety of insults, both infectious and noninfectious. Some of these insults result from rapid changes in diet and labor conditions. Other insults are of a less recent vintage. The burden of cardiovascular disease in low-income countries represents one consequence of decades of neglect of health systems. Furthermore, cardiovascular research and investment have long focused on the ischemic conditions that are increasingly common in highand middle-income countries. Meanwhile, despite awareness of its health impact in the early twentieth century, cardiovascular damage in response to infection and malnutrition has fallen out of view until recently.


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InternalMed_Harrison. The misperception of cardiovascular diseases as a problem primarily of elderly populations in middleand high-income countries has contributed to the neglect of these diseases by global health institutions. Even in Eastern Europe and Central Asia, where the collapse of the Soviet Union was followed by a catastrophic surge in cardiovascular disease deaths (mortality rates from ischemic heart disease nearly doubled between 1991 and 1994 in Russia, for example), the modest flow of overseas development assistance to the health sector focused on the communicable causes that accounted for <1 in 20 excess deaths during that period.


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InternalMed_Harrison. dIabetes The International Diabetes Federation reports that the number of diabetic patients in the world is expected to increase from 366 million in 2011 to 552 million by 2030. Already, a significant proportion of diabetic patients live in developing countries where, because those affected are far more frequently between ages 40 and 59, the complications of microand macrovascular disease take a far greater toll. Globally, these complications are a major cause of disability and reduced quality of life. A high fasting plasma glucose level alone ranks seventh among risks for disability and is the sixth leading risk factor for global mortality. The GBD 2010 estimates that diabetes accounted for 1.28 million deaths in 2010, with almost 80% of those deaths occurring in lowand middle-income countries.


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InternalMed_Harrison. Predictions of an imminent rise in the share of deaths and disabilities due to NCDs in developing countries have led to calls for preventive policies to improve diet, increase exercise, and restrict tobacco use, along with the prescription of multidrug regimens for persons at high-level vascular risk. Although this agenda could do much to prevent pandemic NCD, it will do little to help persons with established heart disease stemming from nonatherogenic pathologies.


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InternalMed_Harrison. cardIovascular dIsease Because systemic investigation of the causes of stroke and heart failure in sub-Saharan Africa has begun only recently, little is known about the impact of elevated blood pressure in this portion of the continent. Modestly elevated blood pressure in the absence of tobacco use in populations with low rates of obesity may confer little risk of adverse events in the short run. In contrast, persistently elevated blood pressure above 180/110 goes largely undetected, untreated, and uncontrolled in this part of the world. In the cohort of men assessed in the Framingham Heart Study, the prevalence of blood pressures above 210/120—severe hypertension—declined from 1.8% in the 1950s to 0.1% by the 1960s with the introduction of effective antihypertensive agents. Although debate continues about appropriate screening strategies and treatment thresholds, rural health centers staffed largely by nurses must quickly gain access to essential antihypertensive medications.


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InternalMed_Harrison. The epidemiology of heart failure reflects inequalities in risk factor prevalence and in treatment. The reported burden of this condition has remained unchanged since the 1950s, but the causes of heart failure and the age of the people affected vary across the globe. Heart failure as a consequence of pericardial, myocardial, endocardial, or valvular injury accounts for as many as 5% of all medical admissions to hospitals around the world. In high-income countries, coronary artery disease and hypertension among the elderly account for most cases of heart failure. For example, in the United States, coronary artery disease is present in 60% of patients with heart failure and hypertension in 70%. Among the world’s poorest 1 billion people, however, heart failure reflects poverty-driven exposure of children and young adults to rheumatogenic strains of streptococci and cardiotropic microorganisms (e.g., HIV, Trypanosoma cruzi, enteroviruses, M. tuberculosis), untreated high blood pressure,


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InternalMed_Harrison. of children and young adults to rheumatogenic strains of streptococci and cardiotropic microorganisms (e.g., HIV, Trypanosoma cruzi, enteroviruses, M. tuberculosis), untreated high blood pressure, and nutrient deficiencies. The mechanisms underlying other causes of heart failure common in these populations—such as idiopathic dilated cardiomyopathy, peripartum cardiomyopathy, and endomyocardial fibrosis—remain unclear.


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InternalMed_Harrison. In stark contrast to the extraordinary lengths to which clinicians in wealthy countries will go to treat ischemic cardiomyopathy, little attention has been paid to young patients with nonischemic cardiomyopathies in resource-poor settings. Nonischemic cardiomyopathies, such as those due to hypertension, RHD, and chronic lung disease, account for >90% of cases of cardiac failure in sub-Saharan Africa and include poorly understood entities such as peripartum cardiomyopathy (which has an incidence in rural Haiti of 1 per 300 live births) and HIV-associated cardiomyopathy. Multidrug regimens that include beta blockers, angiotensin-converting enzyme inhibitors, and other agents can dramatically reduce mortality risk and improve quality of life for these patients. Lessons learned in the scale-up of chronic care for HIV infection and TB may be illustrative as progress is made in establishing the means to deliver heart-failure therapies.


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InternalMed_Harrison. Some of the lessons learned from the chronic infections discussed above are, of course, relevant to cardiovascular disease, especially those classified as NCDs but caused by infectious pathogens. Integration of prevention and care remains as important today as in 1960 when Paul Dudley White and his colleagues found little evidence of myocardial infarction in the region near the Albert Schweitzer Hospital in Lambaréné, Gabon, but reported that “the high prevalence of mitral stenosis is astonishing…. We believe strongly that it is a duty to help bring to these sufferers the benefits of better penicillin prophylaxis and of cardiac surgery when indicated. The same responsibility exists for those with correctable congenital cardiovascular defects.”


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InternalMed_Harrison. RHD affects more than 15 million people worldwide, with more than 470,000 new cases each year. Among the 2.4 million annual cases of pediatric RHD, an estimated 42% occur in sub-Saharan Africa. This disease, which may cause endocarditis or stroke, leads to more than 345,000 deaths per year—almost all occurring in developing countries. Researchers in Ethiopia have reported annual death rates as high as 12.5% in rural areas. In part because the prevention of RHD has not advanced since the disease’s disappearance in wealthy countries, no part of sub-Saharan Africa has eradicated RHD despite examples of success in Costa Rica, Cuba, and some Caribbean nations. A survey of acute heart failure among adults in sub-Saharan Africa showed that ~14.3% of these cases were due to RHD.


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InternalMed_Harrison. Strategies to eliminate rheumatic heart disease may depend on active case-finding, with confirmation by echocardiography, among high-risk groups as well as on efforts to expand access to surgical interventions among children with advanced valvular damage. Partnerships between established surgical programs and areas with limited or nonexistent facilities may help expand the capacity to provide life-saving interventions to patients who otherwise would die early and painfully. A long-term goal is the establishment of regional centers of excellence equipped to provide consistent, accessible, high-quality services.


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InternalMed_Harrison. Clinicians from tertiary care centers in sub-Saharan Africa and elsewhere have continued to call for prevention and treatment of the cardiovascular conditions of the poor. The reconstruction of health services in response to pandemic infectious disease offers an opportunity to identify and treat patients with organ damage and to undertake the prevention of cardiovascular and other chronic conditions of poverty.


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InternalMed_Harrison. cancer Cancers account for ~5% of the global burden of disease. Low-and middle-income countries accounted for more than two-thirds of the 12.6 million cases and 7.6 million deaths due to cancer in 2008. By 2030, annual mortality from cancer will increase by 4 million—with developing countries experiencing a sharper increase than developed nations. “Western” lifestyle changes will be responsible for the increased incidence of cancers of the breast, colon, and prostate among populations in lowand middle-income countries, but historic realities, sociocultural and behavioral factors, genetics, and poverty itself also will have a profound impact on cancer-related mortality and morbidity rates. At least 2 million cancer cases per year—18% of the global cancer burden—are attributable to infectious causes, which are responsible for <10% of cancers in developed countries but account for up to 20% of all malignancies in lowand middle-income countries. Infectious causes of cancer such as human


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InternalMed_Harrison. causes, which are responsible for <10% of cancers in developed countries but account for up to 20% of all malignancies in lowand middle-income countries. Infectious causes of cancer such as human papillomavirus, hepatitis B virus, and Helicobacter pylori will continue to have a much larger impact in developing countries. Environmental and dietary factors, such as indoor air pollution and high-salt diets, also contribute to increased rates of certain cancers (e.g., lung and gastric cancers). Tobacco use (both smoking and chewing) is the most important source of increased mortality rates from lung and oral cancers. In contrast to decreasing tobacco use in many developed countries, the number of smokers is growing in developing countries, especially among women and young persons.


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InternalMed_Harrison. For many reasons, outcomes of malignancies are far worse in developing countries than in developed nations. As currently funded, overstretched health systems in poor countries are not capable of early detection; the majority of patients already have incurable malignancies at diagnosis. Treatment of cancers is available for only a very small number of mostly wealthy citizens in the majority of poor countries, and, even when treatment is available, the range and quality of services are often substandard. Yet this need not be the future. Only a decade ago, MDR-TB and HIV infection were considered untreatable in settings of great poverty. The feasibility of creating innovative programs that reduce technical and financial barriers to the provision of care for treatable malignancies among the world’s poorest populations is now clear (Fig. 2-4). Several middle-income countries, including Mexico, have expanded publicly funded cancer care to reach poorer populations. This commitment of


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InternalMed_Harrison. the world’s poorest populations is now clear (Fig. 2-4). Several middle-income countries, including Mexico, have expanded publicly funded cancer care to reach poorer populations. This commitment of resources has dramatically improved outcomes for cancers, from childhood leukemia to cervical cancer.


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InternalMed_Harrison. Prevention of Noncommunicable diseases False debates, including those pitting prevention against care, continue in global health and reflect, in part, outmoded paradigms or a partial understanding of disease burden and etiology as well as the dramatic variations in risk within a single nation. Moreover, debates are sometimes politicized as a result of vested interests. For example, in 2004, the WHO released its Global Strategy on Diet, Physical Activity, and Health, which focused on the population-wide promotion of healthy diet and regular physical activity in an effort to reduce the growing global problem of obesity. Passing this strategy at the World Health Assembly proved difficult because of strong opposition from the food industry and from a number of WHO member states, including the United States. Although globalization has had many positive effects, one negative effect has been the growth in both developed and developing countries of well-financed lobbies that have aggressively


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InternalMed_Harrison. United States. Although globalization has had many positive effects, one negative effect has been the growth in both developed and developing countries of well-financed lobbies that have aggressively promoted unhealthy dietary changes and increased consumption of alcohol and tobacco. Foreign direct investment in tobacco, beverage, and food products in developing countries reached $90.3 billion in 2010— a figure nearly 490 times greater than the $185 million spent during that year to address NCDs by bilateral funding agencies, the WHO, the World Bank, and all other sources of development assistance for health combined. Investment in curbing NCDs remains disproportionately low despite the WHO’s 2008–2013 Action Plan for the Global Strategy for the Prevention and Control of Noncommunicable Diseases.


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InternalMed_Harrison. FIgURE 2-4 An 11-year-old Rwandan patient with embryonal rhabdomyosarcoma before (left) and after (right) 48 weeks of chemotherapy plus surgery. Five years later, she is healthy with no evidence of disease.


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InternalMed_Harrison. The WHO estimates that 80% of all cases of cardiovascular disease and type 2 diabetes as well as 40% of all cancers can be prevented through healthier diets, increased physical activity, and avoidance of tobacco. These estimates mask large local variations. Although some evidence indicates that population-based measures can have some impact on these behaviors, it is sobering to note that increasing obesity levels have not been reversed in any population. Tobacco avoidance may be the most important and most difficult behavioral modification of all. In the twentieth century, 100 million people worldwide died of tobacco-related diseases; it is projected that more than 1 billion people will die of these diseases in the twenty-first century, with the vast majority of those deaths in developing countries. The WHO’s 2003 Framework Convention on Tobacco Control represented a major advance, committing all of its signatories to a set of policy measures shown to reduce tobacco consumption.


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InternalMed_Harrison. countries. The WHO’s 2003 Framework Convention on Tobacco Control represented a major advance, committing all of its signatories to a set of policy measures shown to reduce tobacco consumption. Today, ~80% of the world’s 1 billion smokers live in lowand middle-income countries. If trends continue, tobacco-related deaths will increase to 8 million per year by 2030, with 80% of those deaths in lowand middle-income countries.


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InternalMed_Harrison. The WHO reports that some 450 million people worldwide are affected by mental, neurologic, or behavioral problems at any given time and that ~877,000 people die by suicide every year. Major depression is the leading cause of years lost to disability in the world today. One in four patients visiting a health service has at least one mental, neurologic, or behavioral disorder, but most of these disorders are neither diagnosed nor treated. Most lowand middle-income countries devote <1% of their health expenditures to mental health.


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InternalMed_Harrison. Increasingly effective therapies exist for many of the major causes of mental disorders. Effective treatments for many neurologic diseases, including seizure disorders, have long been available. One of the greatest barriers to delivery of such therapies is the paucity of skilled personnel. Most sub-Saharan African countries have only a handful of psychiatrists, for example; most of them practice in cities and are unavailable within the public sector or to patients living in poverty.


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InternalMed_Harrison. Among the few patients who are fortunate enough to see a psychiatrist or neurologist, fewer still are able to adhere to treatment regimens: several surveys of already diagnosed patients ostensibly receiving daily therapy have revealed that, among the poor, multiple barriers prevent patients from taking their medications as prescribed. In one study from Kenya, no patients being seen in an epilepsy clinic had therapeutic blood levels of anti-seizure medications, even though all had had these drugs prescribed. Moreover, many patients had no detectable blood levels of these agents. The same barriers that prevent the poor from having reliable access to insulin or ART prevent them from benefiting from antidepressant, antipsychotic, and antiepileptic agents. To alleviate this problem, some authorities are proposing the training of health workers to provide community-based adherence support, counseling services, and referrals for patients in need of mental health services. One such program


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InternalMed_Harrison. are proposing the training of health workers to provide community-based adherence support, counseling services, and referrals for patients in need of mental health services. One such program instituted in Goa, India, used “lay” counselors and resulted in a significant reduction in symptoms of common mental disorders among the target population.


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InternalMed_Harrison. World Mental Health: Problems and Priorities in Low-Income Countries still offers a comprehensive analysis of the burden of mental, behavioral, and social problems in low-income countries and relates the mental health consequences of social forces such as violence, dislocation, poverty, and disenfranchisement of women to current economic, political, and environmental concerns. In the years since this report was published, however, a number of pilot projects designed to deliver community-based care to patients with chronic mental illness have been launched in settings as diverse as Goa, India; Banda Aceh, Indonesia; rural China; post-earthquake Haiti; and Fiji. Some of these programs have been school-based and have sought to link prevention to care. CoNCLUSIoN: ToWARd A SCIENCE oF IMPLEMENTATIoN


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InternalMed_Harrison. Public health strategies draw largely on quantitative methods— epidemiology, biostatistics, and economics. Clinical practice, including the practice of internal medicine, draws on a rapidly expanding knowledge base but remains focused on individual patient care; clinical interventions are rarely population-based. But global health equity depends on avoiding the false debates of the past: neither public health nor clinical approaches alone are adequate to address the problems of global health. There is a long way to go before evidence-based internal medicine is applied effectively among the world’s poor. Complex infectious diseases such as HIV/AIDS and TB have proved difficult but not impossible to manage; drug resistance and lack of effective health systems have complicated such work. Beyond what is usually termed “communicable diseases”—i.e., in the arena of chronic diseases such as cardiovascular disease and mental illness—global health is a nascent endeavor. Efforts to address any


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InternalMed_Harrison. what is usually termed “communicable diseases”—i.e., in the arena of chronic diseases such as cardiovascular disease and mental illness—global health is a nascent endeavor. Efforts to address any one of these problems in settings of great scarcity need to be integrated into broader efforts to strengthen failing health systems and alleviate the growing personnel crisis within these systems.


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InternalMed_Harrison. Such efforts must include the building of “platforms” for care delivery that are robust enough to incorporate new preventive, diagnostic, and therapeutic technologies rapidly in response to changes both in the burden of disease and in the needs not met by dominant paradigms and systems of health delivery. Academic medical centers have tried to address this “know–do” gap as new technologies are introduced and assessed through clinical trials, but the reach of these institutions into settings of poverty is limited in rich and poor countries alike. When such centers link their capacities effectively to the public institutions charged with the delivery of health care to the poor, great progress can be made.


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InternalMed_Harrison. For these reasons, scholarly work and practice in the field once known as “international health” and now often designated “global health equity” are changing rapidly. That work is still informed by the tension between clinical practice and population-based interventions, between analysis and action, and between prevention and care. Once metrics are refined, how might they inform efforts to lessen premature morbidity and mortality rates among the world’s poor? As in the nineteenth century, human rights perspectives have proved helpful in turning attention to the problems of the destitute sick; such perspectives may also inform strategies for delivering care equitably.


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InternalMed_Harrison. A number of university hospitals are developing training programs for physicians with an interest in global health. In medical schools across the United States and in other wealthy countries, interest in global health has exploded. One study has shown that more than 25% of medical students take part in at least one global health experience prior to graduation. Half a century or even a decade ago, such high levels of interest would have been unimaginable. An estimated 12 million people die each year simply because they live in poverty. An absolute majority of these premature deaths occur in Africa, with the poorer regions of Asia not far behind. Most of these deaths occur because the world’s poorest do not have access to the fruits of science. They include deaths from vaccine-preventable illness, deaths during childbirth, deaths from infectious diseases that might be


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InternalMed_Harrison. General Considerations in Clinical Medicine Preventing such a future is the most important goal of global health. decision-Making in Clinical Medicine Daniel B. Mark, John B. Wong INTRodUCTIoN To a medical student who requires hours to collect a patient’s history, 3 cured with access to antibiotics and other essential medicines, deaths from malaria that would have been prevented by bed nets and access to therapy, and deaths from waterborne illnesses. Other excess mortality is attributable to the inadequacy of efforts to develop new preventive, diagnostic, and therapeutic tools. Those funding the discovery and development of new tools typically neglect the concurrent need for strategies to make them available to the poor. Indeed, some would argue that the biggest challenge facing those who seek to address this outcome gap is the lack of practical means of distribution in the most heavily affected regions.


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InternalMed_Harrison. The development of tools must be followed quickly by their equitable distribution. When new preventive and therapeutic tools are developed without concurrent attention to delivery or implementation, one encounters what are sometimes termed perverse effects: even as new tools are developed, inequalities of outcome—lower morbidity and mortality rates among those who can afford access, with sustained high morbidity and mortality among those who cannot—will grow in the absence of an equity plan to deliver the tools to those most at risk.


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InternalMed_Harrison. perform a physical examination, and organize that information into a coherent presentation, an experienced clinician’s ability to decide on a diagnosis and management plan in minutes may seem extraordinary. What separates the master clinician from the novice is an elusive quality called “expertise.” The first part of this chapter provides an overview of our current understanding of expertise in clinical reasoning, what it is, and how it can be developed.


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InternalMed_Harrison. The proper use of diagnostic tests and the integration of the results into the patient’s clinical assessment may also be equally bewildering to students. Hoping to hit the unknown diagnostic target, novice medical practitioners typically apply a “shotgun” approach to testing. The expert, in contrast, usually focuses her testing strategy to specific diagnostic hypotheses. The second part of the chapter reviews basic statistical concepts useful for interpreting diagnostic tests and quantitative tools useful for clinical decision-making. Evidence-based medicine (EBM) constitutes the integration of the best available research evidence with clinical judgment as applied to the care of individual patients. The third part of the chapter provides an overview of the tools of EBM.


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InternalMed_Harrison. BRIEF INTRodUCTIoN To CLINICAL REASoNINg Clinical Expertise Defining “clinical expertise” remains surprisingly difficult. Chess has an objective ranking system based on skill and performance criteria. Athletics, similarly, have ranking systems to distinguish novices from Olympians. But in medicine, after physicians complete training and pass the boards, no further tests or benchmarks identify those who have attained the highest levels of clinical performance. Of course, physicians often consult a few “elite” clinicians for their “special problem-solving prowess” when particularly difficult or obscure cases have baffled everyone else. Yet despite their skill, even master clinicians typically cannot explain their exact processes and methods, thereby limiting the acquisition and dissemination of the expertise used to achieve their impressive results. Furthermore, clinical virtuosity appears not to be generalizable, e.g., an expert on hypertrophic cardiomyopathy may be no better (and


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InternalMed_Harrison. of the expertise used to achieve their impressive results. Furthermore, clinical virtuosity appears not to be generalizable, e.g., an expert on hypertrophic cardiomyopathy may be no better (and possibly worse) than a first-year medical resident at diagnosing and managing a patient with neutropenia, fever, and hypotension.


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InternalMed_Harrison. Broadly construed, clinical expertise includes not only cognitive dimensions and the integration of verbal and visual cues or information but also complex fine-motor skills necessary for invasive and noninvasive procedures and tests. In addition, “the complete package” of expertise in medicine includes the ability to communicate effectively with patients and work well with members of the medical team. Research on medical expertise remains relatively sparse overall, with most of the work focused on diagnostic reasoning, and much less work focused on treatment decisions or the technical skills involved in the performance of procedures. Thus, in this chapter, we focus primarily on the cognitive elements of clinical reasoning.


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InternalMed_Harrison. Because clinical reasoning takes place in the heads of doctors, it is therefore not readily observable, making it obviously difficult to study. One method of research on reasoning asks doctors to “think out loud” as they receive increments of clinical information in a manner meant to simulate a clinical encounter. Another research approach has focused on how doctors should reason diagnostically rather than on how they actually do reason. Much of what is known about clinical reasoning comes from empirical studies of nonmedical problem-solving behavior. Because of the diverse perspectives contributing to this area, with important contributions from cognitive psychology, sociology, medical education, economics, informatics, and decision sciences, no single integrated model of clinical reasoning exists, and not infrequently, different terms and models describe similar phenomena.


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InternalMed_Harrison. Intuitive versus Analytic Reasoning A contemporary model of reasoning, dual-process theory distinguishes two general systems of cognitive processes. Intuition (System 1) provides rapid effortless judgments from memorized associations using pattern recognition and other simplifying “rules of thumb” (i.e., heuristics). For example, a very simple pattern that could be useful in certain situations is “African-American women plus hilar adenopathy equals sarcoid.” Because no effort is involved in recalling the pattern, typically, the clinician is unable to say how those judgments were formulated. In contrast, analysis (System 2), the other form of reasoning in the dual-process model, is slow, methodical, deliberative, and effortful. These are, of course, idealized extremes of the cognitive continuum. How these systems interact in different decision problems, how experts use them differently from novices, and when their use can lead to errors in judgment remain the subject of considerable


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InternalMed_Harrison. How these systems interact in different decision problems, how experts use them differently from novices, and when their use can lead to errors in judgment remain the subject of considerable study and debate.


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InternalMed_Harrison. Pattern recognition is a complex cognitive process that appears largely effortless. One can recognize people’s faces, the breed of a dog, or an automobile model without necessarily being able to say what specific features prompted the recognition. Analogously, experienced clinicians often recognize familiar diagnosis patterns quickly. In the absence of an extensive stored repertoire of diagnostic patterns, students (as well as more experienced clinicians operating outside their area of expertise) often use the more laborious System 2 analytic approach along with more intensive and comprehensive data collection to reach the diagnosis. The following three brief scenarios of a patient with hemoptysis demonstrate three distinct patterns:


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InternalMed_Harrison. The following three brief scenarios of a patient with hemoptysis demonstrate three distinct patterns: A 46-year-old man presents to his internist with a chief complaint of hemoptysis. An otherwise healthy nonsmoker, he is recovering from an apparent viral bronchitis. This presentation pattern suggests that the small amount of blood-streaked sputum is due to acute bronchitis, so that a chest x-ray provides sufficient reassurance that a more serious disorder is absent. In the second scenario, a 46-year-old patient who has the same chief complaint but with a 100-pack-year smoking history, a productive morning cough, and episodes of blood-streaked sputum fits the pattern of carcinoma of the lung. Consequently, along with the chest x-ray, the physician obtains a sputum cytology examination and refers this patient for a chest computed tomography (CT) scan.


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InternalMed_Harrison. In the third scenario, a 46-year-old patient with hemoptysis who immigrated from a developing country has an echocardiogram as well, because the physician hears a soft diastolic rumbling murmur at the apex on cardiac auscultation, suggesting rheumatic mitral stenosis and possibly pulmonary hypertension.


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InternalMed_Harrison. Although rapid, pattern recognition used without sufficient reflection can result in premature closure: mistakenly concluding that one already knows the correct diagnosis and therefore failing to complete the data collection that would demonstrate the lack of fit of the initial pattern selected. For example, a 45-year-old man presents with a 3-week history of a “flulike” upper respiratory infection (URI) including symptoms of dyspnea and a productive cough. On the basis of the presenting complaints, the clinician uses a “URI assessment form” to improve the quality and efficiency of care by standardizing the information gathered. After quickly acquiring the requisite structured examination components and noting in particular the absence of fever and a clear chest examination, the physician prescribes medication for acute bronchitis and sends the patient home with the reassurance that his illness was not serious. Following a sleepless night with significant dyspnea, the patient develops


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InternalMed_Harrison. prescribes medication for acute bronchitis and sends the patient home with the reassurance that his illness was not serious. Following a sleepless night with significant dyspnea, the patient develops nausea and vomiting and collapses. He presents to the emergency department in cardiac arrest and is unable to be resuscitated. His autopsy shows a posterior wall myocardial infarction and a fresh thrombus in an atherosclerotic right coronary artery. What went wrong? The clinician had decided, based on the patient’s appearance, even before starting the history, that the patient’s complaints were not serious. Therefore, he felt confident that he could perform an abbreviated and focused examination by using the URI assessment protocol rather than considering the broader range of possibilities and performing appropriate tests to confirm or refute his initial hypotheses. In particular, by concentrating on the URI, the clinician failed to elicit the full dyspnea history, which would have


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InternalMed_Harrison. and performing appropriate tests to confirm or refute his initial hypotheses. In particular, by concentrating on the URI, the clinician failed to elicit the full dyspnea history, which would have suggested a far more serious disorder, and he neglected to search for other symptoms that could have directed him to the correct diagnosis.


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InternalMed_Harrison. Heuristics, also referred to as cognitive shortcuts or rules of thumb, are simplifying decision strategies that ignore part of the data available so as to provide an efficient path to the desired judgment. They are generally part of the intuitive system tools. Two major research programs have come to different conclusions about the value of heuristics in clinical judgment. The “heuristics and biases” program focused on understanding how heuristics in problem solving could be biased by testing the numerical intuition of psychology undergraduates against the rules of statistics. In contrast, the “fast and frugal heuristics” research program explored how and when decision makers’ reliance on simple heuristics can produce good decisions. Although many heuristics have relevance to clinical reasoning, only four will be mentioned here.


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InternalMed_Harrison. When assessing a particular patient, clinicians often weigh the similarity of that patient’s symptoms, signs, and risk factors against those of their mental representations of the diagnostic hypotheses being considered. In other words, among the diagnostic possibilities, clinicians identify the diagnosis for which the patient appears to be a representative example. Analogous to pattern recognition, this cognitive shortcut is called the representativeness heuristic. However, physicians using the representativeness heuristic can reach erroneous conclusions if they fail to consider the underlying prevalence (i.e., the prior, or pretest, probabilities) of the two competing diagnoses that could explain the patient’s symptoms. Consider a patient with hypertension and headache, palpitations, and diaphoresis. Inexperienced clinicians might judge pheochromocytoma to be quite likely based on the representativeness heuristic with this classic symptom triad suggesting pheochromocytoma. Doing so


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InternalMed_Harrison. diaphoresis. Inexperienced clinicians might judge pheochromocytoma to be quite likely based on the representativeness heuristic with this classic symptom triad suggesting pheochromocytoma. Doing so would be incorrect given that other causes of hypertension are much more common than pheochromocytoma, and this triad of symptoms can occur in patients who do not have pheochromocytoma. Less experience with a particular diagnosis and with the breadth of presentations (e.g., diseases that affect multiple organ systems such as sarcoid) may also lead to errors.


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InternalMed_Harrison. A second commonly used cognitive shortcut, the availability heuristic, involves judgments based of how easily prior similar cases or outcomes can be brought to mind. For example, an experienced clinician may recall 20 elderly patients seen over the last few years who presented with painless dyspnea of acute onset and were found to have acute myocardial infarction (MI). A novice clinician may spend valuable time seeking a pulmonary cause for the symptoms before considering and then confirming the cardiac diagnosis. In this situation, the patient’s clinical pattern does not fit the most common pattern of acute MI, but experience with this atypical presentation, along with the ability to recall it, directs the physician to the diagnosis.


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InternalMed_Harrison. Errors with the availability heuristic arise from several sources of recall bias. Rare catastrophes are likely to be remembered with a clarity and force disproportionate to their likelihood for future diagnosis— for example, a patient with a sore throat eventually found to have leukemia or a young athlete with leg pain eventually found to have a sarcoma—and those publicized in the media or that are recent experiences are, of course, easier to recall and therefore more influential on clinical judgments.


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InternalMed_Harrison. The third commonly used cognitive shortcut, the anchoring heuristic (also called conservatism or stickiness), involves estimating a probability of disease (the anchor) and then insufficiently adjusting that probability up or down (compared with Bayes’ rule) when interpreting new data about the patient, i.e., sticking to their initial diagnosis. For example, a clinician may still judge the probability of coronary artery disease (CAD) to be high after a negative exercise thallium test and proceed to cardiac catheterization (see “Measures of Disease Probability and Bayes’ Rule,” below).


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InternalMed_Harrison. The fourth heuristic states that clinicians should use the simplest explanation possible that will account adequately for the patient’s symptoms or findings (Occam’s razor or, alternatively, the simplicity heuristic). Although this is an attractive and often used principle, it is important to remember that no biologic basis for it exists. Errors from the simplicity heuristic include premature closure leading to the neglect of unexplained significant symptoms or findings.


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InternalMed_Harrison. Even experienced physicians use analytic reasoning processes (System 2) when the problem they face is recognized to be complex or to involve important unfamiliar elements or features. In such situations, clinicians proceed much more methodically in what has been referred to as the hypothetico-deductive model of reasoning. From the outset, expert clinicians working analytically generate, refine, and discard diagnostic hypotheses. The hypotheses drive questions asked during history taking and may change based on the working hypotheses of the moment. Even the physical examination is focused by the working hypotheses. Is the spleen enlarged? How big is the liver? Is it tender? Are there any palpable masses or nodules? Each question must be answered (with the exclusion of all other inputs) before the examiner can move on to the next specific question. Each diagnostic hypothesis provides testable predictions and sets a context for the next question or step to follow. For example, if the


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InternalMed_Harrison. before the examiner can move on to the next specific question. Each diagnostic hypothesis provides testable predictions and sets a context for the next question or step to follow. For example, if the enlarged and quite tender liver felt on physical examination is due to acute hepatitis (the hypothesis), certain specific liver function tests should be markedly elevated (the prediction). If the tests come back normal, the hypothesis may have to be discarded or substantially modified.


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InternalMed_Harrison. Negative findings often are neglected but are as important as positive ones because they often reduce the likelihood of the diagnostic hypotheses under consideration. Chest discomfort that is not provoked or worsened by exertion in an active patient reduces the likelihood that chronic ischemic heart disease is the underlying cause. The absence of a resting tachycardia and thyroid gland enlargement reduces the likelihood of hyperthyroidism in a patient with paroxysmal atrial fibrillation.


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InternalMed_Harrison. The acuity of a patient’s illness may override considerations of prevalence and the other issues described above. “Diagnostic imperatives” recognize the significance of relatively rare but potentially catastrophic diagnoses if undiagnosed and untreated. For example, clinicians are taught to consider aortic dissection routinely as a possible cause of acute severe chest discomfort. Even though the typical history of dissection differs from that of MI, dissection is far less prevalent, so diagnosing dissection remains challenging unless it is explicitly and routinely considered as a diagnostic imperative (Chap. 301). If the clinician fails to elicit any of the characteristic features of dissection by history and finds equivalent blood pressures in both arms and no pulse deficits, he may feel comfortable discarding the aortic dissection hypothesis. If, however, the chest x-ray shows a possible widened mediastinum, the hypothesis may be reinstated and an appropriate imaging test ordered


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InternalMed_Harrison. comfortable discarding the aortic dissection hypothesis. If, however, the chest x-ray shows a possible widened mediastinum, the hypothesis may be reinstated and an appropriate imaging test ordered (e.g., thoracic CT scan, transesophageal echocardiogram) to evaluate more fully. In nonacute situations, the prevalence of potential alternative diagnoses should play a much more prominent role in diagnostic hypothesis generation.


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InternalMed_Harrison. Cognitive scientists studying the thought processes of expert clinicians have observed that clinicians group data into packets, or “chunks,” that are stored in short-term or “working memory” and manipulated to generate diagnostic hypotheses. Because short-term memory can typically retain only 5–9 items at a time, the number of packets that can be actively integrated into hypothesis-generating activities is similarly limited. For this reason, the cognitive shortcuts discussed above play a key role in the generation of diagnostic hypotheses, many of which are discarded as rapidly as they are formed (thereby demonstrating that the distinction between analytic and intuitive reasoning is an arbitrary and simplistic, but nonetheless useful, representation of cognition).


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InternalMed_Harrison. Research into the hypothetico-deductive model of reasoning has had surprising difficulty identifying the elements of the reasoning process that distinguish experts from novices. This has led to a shift from examining the problem-solving process of experts to analyzing the organization of their knowledge. For example, diagnosis may be based on the resemblance of a new case to prior individual instances (exemplars). Experts have a much larger store of memorized cases, for example, visual long-term memory in radiology. However, clinicians do not simply rely on literal recall of specific cases but have constructed elaborate conceptual networks of memorized information or models of disease to aid in arriving at their conclusions. That is, expertise involves an increased ability to connect symptoms, signs, and risk factors to one another in meaningful ways; relate those findings to possible diagnoses; and identify the additional information necessary to confirm the diagnosis.


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InternalMed_Harrison. No single theory accounts for all the key features of expertise in medical diagnosis. Experts have more knowledge about more things and a larger repertoire of cognitive tools to employ in problem solving than do novices. One definition of expertise highlights the ability to make powerful distinctions. In this sense, expertise involves a working knowledge of the diagnostic possibilities and what features distinguish one disease from another. Memorization alone is insufficient. Memorizing a medical textbook would not make one an expert. But having access to detailed and specific relevant information is critically important. Clinicians of the past primarily accessed their own remembered experience. Clinicians of the future will be able to access the experience of large numbers of clinicians using electronic tools, but, as with the memorized textbook, the data alone will not create an instant expert. The expert adds these data to an extensive internalized database of knowledge and


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InternalMed_Harrison. using electronic tools, but, as with the memorized textbook, the data alone will not create an instant expert. The expert adds these data to an extensive internalized database of knowledge and experience not available to the novice (and nonexpert).


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InternalMed_Harrison. Despite all the work that has been done to understand expertise, in medicine and other disciplines, it remains uncertain whether there is any didactic program that can accelerate the progression from novice to expert or from experienced clinician to master clinician. Deliberate effortful practice (over an extended period of time, sometimes said to be 10 years or 10,000 practice hours) and personal coaching are two strategies that are often used outside medicine (e.g., music, athletics, chess) to promote expertise. Their use in developing medical expertise and maintaining or enhancing it has not yet been adequately explored.


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InternalMed_Harrison. The modern ideal of medical therapeutic decision making is to “personalize” the recommendation. In the abstract, personalizing treatment involves combining the best available evidence about what works with an individual patient’s unique features (e.g., risk factors) and his or her preferences and health goals to craft an optimal treatment recommendation with the patient. Operationally, there are two different and complementary levels of personalization possible: individualizing the evidence for the specific patient based on relevant clinical and other characteristics, and personalizing the patient interaction by incorporating their values, often referred to as shared decision-making, which is critically important, but falls outside the scope of this chapter.


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InternalMed_Harrison. Individualizing the evidence about therapy does not mean relying on physician impressions of what works based on personal experience. Because of small sample sizes and rare events, the chance of drawing erroneous causal inferences from one’s own clinical experience is very high. For most chronic diseases, therapeutic effectiveness is only demonstrable statistically in patient populations. It would be incorrect to infer with any certainty, for example, that treating a hypertensive patient with angiotensin-converting enzyme (ACE) inhibitors necessarily prevented a stroke from occurring during treatment, or that an untreated patient would definitely have avoided a stroke had he or she been treated. For many chronic diseases, a majority of patients will remain event free regardless of treatment choices; some will have events regardless of which treatment is selected; and those who avoided having an event through treatment cannot be individually identified. Blood pressure lowering, a


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InternalMed_Harrison. choices; some will have events regardless of which treatment is selected; and those who avoided having an event through treatment cannot be individually identified. Blood pressure lowering, a readily observable surrogate endpoint, does not have a tightly coupled relationship with strokes prevented. Consequently, demonstrating therapeutic effectiveness cannot rely simply on observing the outcome of an individual patient but should instead be based on large groups of patients carefully studied and properly analyzed.


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InternalMed_Harrison. Therapeutic decision making, therefore, should be based on the best available evidence from clinical trials and well-done outcome studies. Authoritative, well-done clinical practice guidelines that synthesize such evidence offer readily available, reliable, and trustworthy information relevant to many treatment decisions clinicians face. However, all guidelines recognize that their “one size fits all” recommendations may not apply to individual patients. Increased attention is now being paid to understand how best to adjust group-level clinical evidence of treatment harms and benefits to account for the absolute level of risks faced by subgroups and even individual patients, using, for example, validated clinical risk scores.


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InternalMed_Harrison. More than a decade of research on variations in clinician practice patterns has shed much light on the forces that shape clinical decisions. These factors can be grouped conceptually into three overlapping categories: (1) factors related to physicians’ personal characteristics and practice style, (2) factors related to the practice setting, and (3) factors related to economic incentives.


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InternalMed_Harrison. Factors Related to Practice Style To ensure that necessary care is provided at a high level of quality, physicians fulfill a key role in medical care by serving as the patient’s agent. Factors that influence performance in this role include the physician’s knowledge, training, and experience. Clearly, physicians cannot practice EBM (described later in the chapter) if they are unfamiliar with the evidence. As would be expected, specialists generally know the evidence in their field better than do generalists. Beyond published evidence and practice guidelines, a major set of influences on physician practice can be subsumed under the general concept of “practice style.” The practice style serves to define norms of clinical behavior. Beliefs about effectiveness of different therapies and preferred patterns of diagnostic test use are examples of different facets of a practice style. The physician beliefs that drive these different practice styles may be based on personal experience,


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InternalMed_Harrison. preferred patterns of diagnostic test use are examples of different facets of a practice style. The physician beliefs that drive these different practice styles may be based on personal experience, recollection, and interpretation of the available medical evidence. For example, heart failure specialists are much more likely than generalists to achieve target doses of ACE inhibitor therapy in their heart failure patients because they are more familiar with what the targets are (as defined by large clinical trials), have more familiarity with the specific drugs (including adverse effects), and are less likely to overreact to foreseeable problems in therapy such as a rise in creatinine levels or asymptomatic hypotension.


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InternalMed_Harrison. Beyond the patient’s welfare, physician perceptions about the risk of a malpractice suit resulting from either an erroneous decision or a bad outcome may drive clinical decisions and create a practice referred to as defensive medicine. This practice involves using tests and therapies with very small marginal benefit, ostensibly to preclude future criticism should an adverse outcome occur. Without any conscious awareness of a connection to the risk of litigation, however, over time such patterns of care may become accepted as part of the practice norm, thereby perpetuating their overuse, e.g., annual cardiac exercise testing in asymptomatic patients.


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InternalMed_Harrison. Practice Setting Factors Factors in this category relate to the physical resources available to the physician’s practice and the practice environment. Physician-induced demand is a term that refers to the repeated observation that once medical facilities and technologies are made available to physicians, they will use them. Other environmental factors that can influence decision-making include the local availability of specialists for consultations and procedures; “high-tech” advanced imaging or procedure facilities such as MRI machines and proton beam therapy centers; and fragmentation of care.


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InternalMed_Harrison. Economic Incentives Economic incentives are closely related to the other two categories of practice-modifying factors. Financial issues can exert both stimulatory and inhibitory influences on clinical practice. In general, physicians are paid on a fee-for-service, capitation, or salary basis. In fee-for-service, physicians who do more get paid more, thereby encouraging overuse, consciously or unconsciously. When fees are reduced (discounted reimbursement), doctors tend to increase the number of services provided to maintain revenue. Capitation, in contrast, provides a fixed payment per patient per year to encourage physicians to consider a global population budget in managing individual patients and ideally reducing the use of interventions with small marginal benefit. In contrast to inexpensive preventive services, however, this type of incentive is more likely to affect expensive interventions. To discourage volume-based excessive utilization, fixed salary compensation plans pay


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InternalMed_Harrison. preventive services, however, this type of incentive is more likely to affect expensive interventions. To discourage volume-based excessive utilization, fixed salary compensation plans pay physicians the same regardless of the clinical effort expended, but may provide an incentive to see fewer patients.


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InternalMed_Harrison. Despite the great technological advances in medicine over the last century, uncertainty remains a key challenge in all aspects of medical decision-making. Compounding this challenge is the massive information overload that characterizes modern medicine. Today’s clinician needs access to close to 2 million pieces of information to practice medicine. According to one estimate, doctors subscribe to an average of seven journals, representing over 2500 new articles each year. Of course, to be useful, this information must be sifted for applicability to and then integrated with patient-specific data. Although computers appear to offer an obvious solution both for information management and for quantification of medical care uncertainties, many practical problems must be solved before computerized decision support can be routinely incorporated into the clinical reasoning process in a way that demonstrably improves the quality of care. For the present, understanding the nature of diagnostic


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InternalMed_Harrison. decision support can be routinely incorporated into the clinical reasoning process in a way that demonstrably improves the quality of care. For the present, understanding the nature of diagnostic test information can help clinicians become more efficient users of such data. The next section reviews important concepts related to diagnostic testing.


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InternalMed_Harrison. dIAgNoSTIC TESTINg: MEASURES oF TEST ACCURACY The purpose of performing a test on a patient is to reduce uncertainty about the patient’s diagnosis or prognosis in order to facilitate optimal management. Although diagnostic tests commonly are thought of as laboratory tests (e.g., blood count) or procedures (e.g., colonoscopy or bronchoscopy), any technology that changes a physician’s understanding of the patient’s problem qualifies as a diagnostic test. Thus, even the history and physical examination can be considered a form of diagnostic test. In clinical medicine, it is common to reduce the results of a test to a dichotomous outcome, such as positive or negative, normal or abnormal. Although this simplification ignores useful information (such as the degree of abnormality), such simplification does make it easier to demonstrate the fundamental principles of test interpretation discussed below.


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InternalMed_Harrison. The accuracy of diagnostic tests is defined in relation to an accepted “gold standard,” which defines the presumably true state of the patient (Table 3-1). Characterizing the diagnostic performance of a new test requires identifying an appropriate population (ideally, patients in whom the new test would be used) and applying both the new and the gold standard tests to all subjects. Biased estimates of test performance may occur from using an inappropriate population or from incompletely applying the gold standard test. By comparing the two tests, the characteristics of the new test are determined. The sensitivity or true-positive rate of the new test is the proportion of patients with disease (defined by the gold standard) who have a positive (new) test. This measure reflects how well the new test identifies patients with disease. The proportion of patients with disease who have a negative test is the false-negative rate and is calculated as 1 – sensitivity. Among patients without


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InternalMed_Harrison. the new test identifies patients with disease. The proportion of patients with disease who have a negative test is the false-negative rate and is calculated as 1 – sensitivity. Among patients without disease, the proportion who have a negative test is the specificity, or true-negative rate. This measure reflects how well the new test correctly identifies patients without disease. Among patients without disease, the proportion who have a positive test is the false-positive rate, calculated as 1 – specificity. A perfect test would have a sensitivity of 100% and a specificity of 100% and would completely distinguish patients with disease from those without it.


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InternalMed_Harrison. Calculating sensitivity and specificity requires selection of a threshold value or cut point above which the test is considered “positive.” Making the cut point “stricter” (e.g., raising it) lowers sensitivity but improves specificity, whereas making it “laxer” (e.g., lowering it) raises sensitivity but lowers specificity. This dynamic trade-off between more accurate identification of subjects with disease versus those without disease is often displayed graphically as a receiver operating characteristic (ROC) curve (Fig. 3-1) by plotting sensitivity (y axis) versus 1 – specificity (x axis). Each point on the curve represents a potential cut point with an associated sensitivity and specificity value. The area under the ROC curve often is used as a quantitative measure of the information content of a test. Values range from 0.5 (no diagnostic information from testing at all; the test is equivalent to flipping a coin) to 1.0 (perfect test). The choice of cut point should depend on the


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InternalMed_Harrison. content of a test. Values range from 0.5 (no diagnostic information from testing at all; the test is equivalent to flipping a coin) to 1.0 (perfect test). The choice of cut point should depend on the relative harms and benefits of treatment for those without versus those with disease. For example, if treatment was safe with substantial benefit, then choosing a high-sensitivity cut point (upper right of the ROC curve) for a low-risk test may be appropriate (e.g., phenylketonuria in newborns), but if treatment had substantial risk for harm, then choosing a high-specificity cut point (lower left of the ROC curve) may be appropriate (e.g., amniocentesis that may lead to therapeutic abortion of a normal fetus). The choice of cut point may also depend on the likelihood of disease, with low likelihoods placing a greater emphasis on the harms of treating false-positive tests and higher likelihoods placing a greater emphasis on missed benefit by not treating false-negative tests.


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InternalMed_Harrison. Unfortunately, there are no perfect tests. After every test is completed, the true disease state of the patient remains uncertain. Quantifying this residual uncertainty can be done with Bayes’ rule, which provides a simple way to calculate the likelihood of disease after a test result or posttest probability from three parameters: the pretest probability of disease, the test sensitivity, and the test specificity. The pretest probability is a quantitative estimate of the likelihood of the diagnosis before the test is performed and is usually the prevalence of the disease in the underlying population although occasionally it can be the disease 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 illustrates a trade-off that occurs between improved test sensitivity (accurate detection of patients with disease) and improved test specificity (accurate detection of patients without disease), because the test value defining when the test turns from “negative” to


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InternalMed_Harrison. (accurate detection of patients with disease) and improved test specificity (accurate detection of patients without disease), because the test value defining when the test turns from “negative” to “positive” is varied. A 45° line would indicate a test with no predictive value (sensitivity = specificity at every test value). The area under each ROC curve is a measure of the information content of the test. Thus, a larger ROC area signifies increased diagnostic accuracy.


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InternalMed_Harrison. incidence. For some common conditions, such as CAD, nomograms and statistical models generate estimates of pretest probability that account for history, physical examination, and test findings. The posttest probability (also called the predictive value of the test) is a revised statement of the likelihood of the diagnosis, accounting for both pretest probability and test results. For the likelihood of disease following a positive test (i.e., positive predictive value), Bayes’ rule is calculated as: For example, with a pretest probability of 0.50 and a “positive” diagnostic test result (test sensitivity = 0.90 and specificity = 0.90): 0.50× 0.90 Posttest probability = 0.50× 0.90+ (1− 0.50)0.10 × = 0.90


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InternalMed_Harrison. Posttest probability = 0.50× 0.90+ (1− 0.50)0.10 × = 0.90 The term predictive value often is used as a synonym for the posttest probability. Unfortunately, clinicians commonly misinterpret reported predictive values as intrinsic measures of test accuracy. Studies of diagnostic tests compound the confusion by calculating predictive values on the same sample used to measure sensitivity and specificity. Since all posttest probabilities are a function of the prevalence of disease in the tested population, such calculations may be misleading unless the test is applied subsequently to populations with the same disease prevalence. For these reasons, the term predictive value is best avoided in favor of the more informative posttest probability following a positive or a negative test result.


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InternalMed_Harrison. The nomogram version of Bayes’ rule (Fig. 3-2) helps us to conceptually understand how it estimates the posttest probability of disease. In this nomogram, the impact of the diagnostic test result is summarized by the likelihood ratio, which is defined as the ratio of the probability of a given test result (e.g., “positive” or “negative”) in a patient with disease to the probability of that result in a patient without disease, thereby providing a measure of how well the test distinguishes those with from those without disease.


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InternalMed_Harrison. For a positive test, the likelihood ratio positive is calculated as the ratio of the true-positive rate to the false-positive rate (or sensitivity/ [1 – specificity]). For example, a test with a sensitivity of 0.90 and a specificity of 0.90 has a likelihood ratio of 0.90/(1 – 0.90), or 9. Thus, for this hypothetical test, a “positive” result is nine times more likely in a patient with the disease than in a patient without it. Most tests in medicine have likelihood ratios for a positive result between 1.5 and 20. Higher values are associated with tests that more substantially increase the posttest likelihood of disease. A very high likelihood ratio positive (exceeding 10) usually implies high specificity, so a positive high-specificity test helps “rule in” disease. If sensitivity is excellent but specificity is less so, the likelihood ratio will be reduced substantially (e.g., with a 90% sensitivity but a 55% specificity, the likelihood ratio is 2.0).


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InternalMed_Harrison. For a negative test, the corresponding likelihood ratio negative is the ratio of the false-negative rate to the true-negative rate (or [1 – sensitivity]/ specificity). Lower likelihood ratio values more substantially lower the posttest likelihood of disease. A very low likelihood ratio negative (falling below 0.10) usually implies high sensitivity, so a negative high-sensitivity test helps “rule out” disease. The hypothetical test considered above with a sensitivity of 0.9 and a specificity of 0.9 would have a likelihood ratio for a negative test result of (1 – 0.9)/0.9, or 0.11, meaning that a negative result is about one-tenth as likely in patients with disease than in those without disease (or 10 times more likely in those without disease than in those with disease).


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InternalMed_Harrison. Consider two tests commonly used in the diagnosis of CAD: an exercise treadmill test and an exercise single-photon emission CT (SPECT) myocardial perfusion imaging test (Chap. 270e). Meta-analysis has shown that a positive treadmill ST-segment response has an average sensitivity of 66% and an average specificity of 84%, yielding a likelihood ratio of 4.1 (0.66/[1 – 0.84]) (consistent with small discriminatory ability because it falls between 2 and 5). For a patient with a 10% pretest probability of CAD, the posttest probability of disease after a positive result rises to only about 30%. If a patient with a pretest probability of CAD of 80% has a positive test result, the posttest probability of disease is about 95%.


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InternalMed_Harrison. In contrast, exercise SPECT myocardial perfusion test is more accurate for CAD. For simplicity, assume that the finding of a reversible exercise-induced perfusion defect has both a sensitivity and a specificity of 90%, yielding a likelihood ratio for a positive test of 9.0 (0.90/ [1 – 0.90]) (consistent with moderate discriminatory ability because it falls between 5 and 10). For the same 10% pretest probability patient, a positive test raises the probability of CAD to 50% (Fig. 3-2). However, despite the differences in posttest probabilities between these two tests (30% versus 50%), the more accurate test may not improve diagnostic likelihood enough to change patient management (e.g., decision to refer to cardiac catheterization) because the more accurate test has only moved the physician from being fairly certain that the patient did not have CAD to a 50:50 chance of disease. In a patient with a pretest probability of 80%, exercise SPECT test raises the posttest probability to 97%


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InternalMed_Harrison. from being fairly certain that the patient did not have CAD to a 50:50 chance of disease. In a patient with a pretest probability of 80%, exercise SPECT test raises the posttest probability to 97% (compared with 95% for the exercise treadmill). Again, the more accurate test does not provide enough improvement in posttest confidence to alter management, and neither test has improved much on what was known from clinical data alone.


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InternalMed_Harrison. In general, positive results with an accurate test (e.g., likelihood ratio positive 10) when the pretest probability is low (e.g., 20%) do not move the posttest probability to a range high enough to rule in disease (e.g., 80%). In screening situations, pretest probabilities are often particularly low because patients are asymptomatic. In such cases, specificity becomes particularly important. For example, in screening first-time female blood donors without risk factors for HIV, a positive test raised the likelihood of HIV to only 67% despite a specificity of 99.995% because the prevalence was 0.01%. Conversely, with a high pretest 0.1 99 0.1 0.5 98 0.2 0.5 95 0.5 0.5 0.5 40 0.2 0.2 0.1 0.05 0.1 0.05 5 0.02 0.02 70 0.01 0.01 0.5 95 0.5 0.2 98 0.2 0.1 99 0.1 Pretest Likelihood Posttest Pretest Likelihood Posttest Probability, % Ratio Probability, % Probability, % Ratio Probability, %


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InternalMed_Harrison. FIgURE 3-2 Nomogram version of Bayes’ rule used to predict the posttest probability of disease (right-hand scale) using the pretest probability of disease (left-hand scale) and the likelihood ratio for a positive test (middle scale). See text for information on calculation of likelihood ratios. To use, place a straight edge connecting the pretest probability and the likelihood ratio and read off the posttest probability. The right-hand part of the figure illustrates the value of a positive exercise treadmill test (likelihood ratio 4, green line) and a positive exercise thallium single-photon emission computed tomography perfusion study (likelihood ratio 9, broken yellow line) in a patient with a pretest probability of coronary artery disease of 50%. (Adapted from Centre for Evidence-Based Medicine: Likelihood ratios. Available at http://www.cebm.net/ index.aspx?o=1043.) probability, a negative test may not rule out disease adequately if it is not sufficiently sensitive. Thus, the


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InternalMed_Harrison. Medicine: Likelihood ratios. Available at http://www.cebm.net/ index.aspx?o=1043.) probability, a negative test may not rule out disease adequately if it is not sufficiently sensitive. Thus, the largest change in diagnostic likelihood following a test result occurs when the clinician is most uncertain (i.e., pretest probability between 30% and 70%). For example, if a patient has a pretest probability for CAD of 50%, a positive exercise treadmill test will move the posttest probability to 80% and a positive exercise SPECT perfusion test will move it to 90% (Fig. 3-2).


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InternalMed_Harrison. As presented above, Bayes’ rule employs a number of important simplifications that should be considered. First, few tests have only positive or negative results, and many tests provide multiple outcomes (e.g., ST-segment depression and exercise duration with exercise testing). Although Bayes’ rule can be adapted to this more detailed test result format, it is computationally more complex to do so. Similarly, when multiple tests are performed, the posttest probability may be used as the pretest probability to interpret the second test. However, this simplification assumes conditional independence—that is, that the results of the first test do not affect the likelihood of the second test result—and this is often not true.


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InternalMed_Harrison. Finally, it has long been asserted that sensitivity and specificity are prevalence-independent parameters of test accuracy, and many texts still make this statement. This statistically useful assumption, however, is clinically simplistic. A treadmill exercise test, for example, has a sensitivity in a population of patients with one-vessel CAD of around 30%, whereas its sensitivity in patients with severe three-vessel CAD approaches 80%. Thus, the best estimate of sensitivity to use in a particular decision may vary, depending on the severity of disease in the local population. A hospitalized, symptomatic, or referral population typically has a higher prevalence of disease and, in particular, a higher prevalence of more advanced disease than does an outpatient population. Consequently, test sensitivity will likely be higher in hospitalized patients, and test specificity higher in outpatients.