Category Archives: Publication

What “causes” disease?: Association vs. Causation and the Hill Criteria

Originally published at The Pump Handle

Does cigarette smoking cause cancer? Does eating specific foods or working in certain locations cause diseases? Although we have determined beyond doubt that cigarette smoking causes cancer, questions of disease causality still challenge us because it is never a simple matter to distinguish mere association between two factors from an actual causal relationship between them. In an address to the Royal Society of Medicine in 1965, Sir Austin Bradford Hill attempted to codify the criteria for determining disease causality. An occupational physician, Hill was primarily concerned with the relationships among sickness, injury, and the conditions of work. What hazards do particular occupations pose? How might the conditions of a specific occupation cause specific disease outcomes?

In an engaging and at times humorous address, Hill delineates nine criteria for determining causality. He is quick to add that none of these criteria can be used independently and that even as a whole they do not represent an absolute method of determining causality. Nevertheless, they represent crucial considerations in any deliberation about the causes of disease, considerations that still resonate half a century later.

The criteria, which Hill calls “viewpoints,” are as follows:

1. Strength.  The association between the projected cause and the effect must be strong. Hill uses the example of cigarette-smoking here, noting that “prospective inquiries have shown that the death rate from cancer of the lung in cigarette smokers is nine to ten times the rate in non-smokers.” Even when the effects are objectively small, if the association is strong, causality can be contemplated. For example, during London’s 1854 cholera outbreak, John Snow observed that the death rate of customers supplied with polluted drinking water from the Southwark and Vauxhall Company was low in absolute terms (71 deaths in 10,000 houses). Yet in comparison to the death rate in houses supplied with the pure water of the Lambeth Company (5 in 10,000), the association became significant.  Even though the mechanism by which polluted water causes cholera—transmission of the bacteria vibrio cholera—was then still unknown, the strength of this association was sufficient in Snow’s mind to correctly assign a causal link.

2. Consistency. The effects must be repeatedly observed by different people, in different places, circumstances and times.

3. Specificity. Hill admits this is a weaker criterion, since diseases may have many causes and etiologies. Nevertheless, the specificity of the association, meaning how limited the association is to specific workers and sites and types of disease, must be taken into account in order to determine causality.

4. Temporality. Cause must precede effect.

5. Biological gradient. This criterion is also known as the dose-response curve. A good indicator of causality is whether, for example, death rates from cancer rise linearly with the number of cigarettes smoked. A small amount of exposure should result in a smaller effect. This is indeed the case; the more cigarettes a person smokes over a lifetime, the greater the risk of getting lung cancer.

6. Plausibility. The cause-and-effect relationship should be biologically plausible. It must not violate the known laws of science and biology.

  1. 7.  Coherence. The cause-and-effect hypothesis should be in line with known facts and data about the biology and history of the disease in question.

8. Experiment. This would probably be the most important criterion if Hill had produced these “viewpoints” in 2012. Instead, Hill notes that “Occasionally it is possible to appeal to experimental, or semi-experimental, evidence.” An example of an informative experiment would be to take preventive action as a result of an observed association and see whether the preventive action actually reduces incidence of the disease.

9. Analogy. If one cause results in a specific effect then a similar cause can be said to result in a similar effect. Hill uses the example of thalidomide and rubella, noting that similar evidence with another drug and another viral disease in pregnancy might be accepted on analogy, even if the evidence is slighter.

The impact of Hill’s criteria has been enormous. They are still widely accepted in epidemiological research and have even spread beyond the scientific community. In this short yet captivating address, Hill managed to propose criteria that would constitute a crucial aspect of epidemiological research for decades to come. One wonders how Hill would respond to the plethora of reports published today claiming a cause and effect relationship between two factors based on an odds ratio of 1.2, with a statistically significant probability value of less than 0.05. While such an association may indeed be real, it is far smaller than those Hill discusses in his first criterion (“strength”). Hill does say, “We must not be too ready to dismiss a cause-and-effect hypothesis merely on the grounds that the observed association appears to be slight.” Yet he also wonders if “the pendulum has not swung too far” in substituting statistical probability testing for biological common sense. Claims that environmental exposures, food, chemicals, and types of stress cause a myriad of diseases pervade both scientific and popular literature today. In evaluating these issues, Hill’s sobering ideas, albeit 50 years old, are still useful guidance.

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Culturally Sensitive Psychiatric Care for Refugees: A Reassessment

Originally published at Health and Human Rights

In recent years, a welcome increase in attention to specific psychological problems among refugees has led to important new insights. Some of this research interest stems from experience with troops and veterans of the Iraqi and Afghani wars. New research has focused not only on the psychiatric effects of torture and human rights abuses, but also on the mental health consequences of victims’ subsequent forced migration. These consequences include the process of seeking asylum, isolation in a new country, and guilt and concern about leaving one’s native land.1, 2, 6

With a renewed focus on the special psychiatric needs of the refugee community, several essential areas of new research have emerged. The epidemiological research on the effects of torture and forced migration on refugee populations has proven helpful in identifying the burden of chronic mental illness on asylum seekers. But are refugees really getting the mental health care they need? Evidence from the Mental Health Commission of Canada suggests that there is a major gap between need and treatment. The report demonstrates that some of the reasons for this inadequacy are related to lack of awareness of available services and socioeconomic barriers. Yet refugees also frequently cite perceived stigma and discrimination as a major barrier to care. This discrimination may not come directly from mental health providers but may be a perceived effect of a system that ignores their special needs. The system inevitably offers poorer treatment options to persons of different cultural backgrounds, including refugees, who may feel cultural barriers particularly prominently as a result of rapid resettlement.

It is quickly becoming apparent that in order to help refugees access treatment and use it successfully, mental health care modules must be adapted to the cultural diversity of the refugee client population.3, 4 Only approaches that incorporate recognition of such diversity have the potential to overcome the low rate of help-seeking behavior among refugees and the often inadequate quality of mental health care they receive.

The language barrier is an urgent problem. Feeling misunderstood by a health care provider is a major barrier to health-seeking behaviors among refugee populations. It may end up unjustly excluding refugees from obtaining treatment. The language barrier between patient and physician causes complex problems. In the case of refugee mental health care, there is the added complication of cultural differences that inform terms for sadness, depression, anxiety, and even psychosis. Semantic equivalency can be achieved in some cases, but it may require extensive consultation with health care workers in the native country who are familiar with the illnesses and words used to describe them.

There is also the question of whether diagnostic questions proposed by the DSM-IV, and its successor, the DSM-V, are phrased in a way that is meaningful in all languages and cultures. For example, in the Somali language, what Western medicine calls PTSD is associated with a form of madness termed waali, basically meaning “madness from trauma.”5 No such sense of “madness” is conveyed by the DSM-IV diagnostic markers for PTSD, which emphasize feelings of anxiety and sadness. The result is that refugees from Somalia may have profound PTSD but may not associate it with the version of the illness presented by the DSM-IV and DSM-V. Quests for semantic equivalency should not only take into account whether a word is translated correctly, but also whether the same concept of the illness exists in the other culture. Translations of diagnostic questions should therefore be culturally, as well as linguistically, informed.

Refugees are needlessly being excluded from the mental health care they desperately need and to which they are entitled. In many cases, this exclusion is the result of unintentional misunderstanding on the part of clinicians. More research should be conducted into how accurately Western notions of PTSD, depression, and other mental illnesses translate across cultures, and how well treatments traditionally used in Western countries for these illnesses work in widespread cultural settings. Most importantly, mental health providers should always remain aware of cultural differences in order to provide the most sensitive, effective, and appropriate care to a population in great need.

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Inequality, stress, and health: The Whitehall Studies

Originally published at The Pump Handle

The current state of public health research is increasingly aware of the effects of various kinds of inequality on health. Especially in the U.S. and other developed countries, the burden of chronic, non-communicable diseases is especially high among low-income individuals. Public health campaigns have thus developed initiatives to bring better health education to low-income communities and to encourage healthier eating, more exercise, and decreased use of tobacco and drugs.

What’s not always recognized is that the rationale behind many of these initiatives stems from the findings of a series of landmark studies among civil servants in England: the Whitehall Studies. Whitehall I began in 1967, at a time when awareness of the relationship between social inequality, work stress, and poor health was not necessarily keen. The Whitehall Studies thus set out to investigate the complex relationships among income, work status, psychosocial support, health behaviors, and resulting morbidity and mortality.

Whitehall I, published in Journal of Epidemiology and Community Health in 1978, followed British civil servants over ten years from 1967-1977 and ultimately showed an inverse association between employment grade and mortality from a variety of illnesses. After ten years of follow-up, those in the highest employment grade had one-third the mortality rate of those in the lowest grade.

The results of Whitehall I demanded some attempt at explanation. Whitehall II, a study of 10,314 British civil servants aged 35-55 published in The Lancet in 1991, represents this attempt. Importantly, while Whitehall I studied only male civil servants, Whitehall II also included women. Particularly important to Whitehall II is the effect of psychosocial factors, such as stress and social support, on disease outcome.

Whitehall II, conducted between 1985 and 1988, collected data primarily via surveys and questionnaires. Questionnaires distributed to the 10,314 British civil servants from 20 civil servanice department included questions about: health status, including questions about past medical history; work characteristics such as job demands and decision-making capacity; social networks and support; health behaviors, including smoking and physical activity; and the Framingham type A score, measuring hostility and stressful life events. In addition to questionnaires, subjects’ blood pressure was measured and screening was provided for angina and ischemia.

Whitehall II confirmed some of the results of Whitehall I, especially the finding that the lower the job status, the higher the prevalence of ischemic heart disease. New, landmark findings revolved around gender differences and isolation as possible causes of this inverse relationship. In general, women had greater morbidity than men in all grades of employment. The higher the job status of the man, the more likely he was to be married or cohabitating, but the opposite was true for women. Obesity was more prevalent among those in lower status jobs, and the risk factor for increased morbidity and mortality that differed most among job categories was smoking.

Overall, individuals in lower grades of employment were more resigned about their health. Individuals in lower employment grades were more likely to believe that it was not possible to reduce the risk of a heart attack. They were also more likely to rate their health status as poor and to report two or more of eight stressful life events in the previous year. Self-perceived poor health status is known to be a predictor of mortality.

Perhaps most significantly, the Whitehall II study discovered a firm connection among psychosocial factors, perception about work status and environment, and poor health outcomes. People in lower status jobs reported less social support than those in higher status jobs. They also reported less control, less use of skills, and less variety at work, as well as a more demanding workload and more psychological stress at work. All of these factors are associated with risk of cardiovascular disease.

The Whitehall Studies helped public health researchers develop a nuanced perspective on the relationship between socioeconomic position and health. The findings of Whitehall II established that it is not only factors most obviously related to obtainment of healthcare, such as time to attend doctors’ appointments or money to pay for insurance, that seriously affect health outcomes. Rather, psychosocial and socioeconomic factors that may seem unrelated to the provision of healthcare may have a direct impact on risk of developing cardiovascular disease and other chronic illnesses. Whitehall II in particular calls for careful attention to all of the conditions of every socioeconomic category as possible predictors of health outcomes. In many ways, these crucial studies established the interconnectedness of socioeconomic position, psychosocial factors, and health, a concept that is now at the very center of public health.

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Optimism and the HIV/AIDS epidemic

Originally published at The Pump Handle

Recent biomedical advances in AIDS research have allowed political figures such as Secretary of State Hillary Clinton to proclaim that the phenomenon of a generation without HIV/AIDS is within reach. But how well-founded is this optimism? A recent editorial in The New England Journal of Medicine asks this very question and concludes that there is ample reason for scientific optimism but that the global resources needed to achieve the eradication of this illness are simply not being deployed properly.

Yet the science itself does not indicate that the possibility of the eradication of HIV/AIDS is immediately within reach. A vaccine for HIV proved successful in one trial in Thailand, but this is not enough to proclaim victory over the illness. At the same time, research on pre-exposure prophylaxis has proven encouraging and effective in some populations, but there is still a long way to go to establish the safety of these measures as well as their effectiveness in all populations affected by the epidemic. What’s more, certain social and socioeconomic factors still remain a serious barrier to care globally, and we cannot be exceedingly optimistic about the availability of novel treatments until we can ensure that people will actually have access to them.

Much of the scientific optimism about the possibility of eradicating HIV/AIDS derives from the July 16 2012, FDA approval of Truvada (emtricitabine and tenofovir disoproxil fumarate) for daily use as a prophylactic agent against HIV/AIDS. The approval stems from a series of recent studies, some of which demonstrate the efficacy of the drug in preventing HIV/AIDS when used prophylactically. The drug has been shown to be highly effective for prophylactic use in MSM (men who have sex with men) and among heterosexual men. Yet one study conducted in Africa suggests that Truvada for pre-exposure prophylaxis (PrEP) may not be an effective means of preventing HIV/AIDS among women. Researchers found no significant reduction in HIV-acquisition among women taking Truvada compared to the placebo group. The study begs the question of whether more research is needed before women start utilizing Truvada as a reliable prophylactic measure.

Several negative effects of the FDA’s approval are also possible. It remains to be seen whether provision of Truvada for PrEP diminishes use of condoms and other safe sex measures, contributing to a potential increase in STI’s other than HIV/AIDS. The emergence of antiretroviral-resistant strains of HIV/AIDS should be carefully monitored, even though one study of Truvada for PrEP reported low rates of newly resistant strains. Other drugs with lower potential for development of resistant strains, such as maraviroc-based drug regimens, should be tested widely, among heterosexual men and women as well as among men who have sex with men (MSM). Although the FDA’s approval is a step in the right direction, too much optimism can lead to complacency when more research, and more funding for more research, are still desperately needed.

Yet even in the probable event that our scientific optimism proves justified, the question remains: how should limited resources best be deployed? It is clear that there is still much need for funding for scientific studies in pursuit of an AIDS vaccine and for cheaper and safer drugs for PrEP that work in all populations. Yet it is equally important to evaluate the sub-populations in which the epidemic is growing or most recalcitrant and to provide these populations with better access to prevention and treatment. In the United States, rates of HIV/AIDS are actually rising in some populations, including young racial minorities and African American women. There is a growing HIV/AIDS crisis outside of urban areas and in the American South. One of the greatest challenges to reducing transmission rates is poor access to medical care. Low-income individuals, and especially women, with HIV/AIDS often go without medical care due to transportation challenges and competing needs such as childcare responsibilities. Investment in federal aid programs that provide social support for individuals with HIV/AIDS in the U.S. may go a long way in curbing transmission rates. Funding for similar programming globally must also be implemented.

There is in fact much cause for optimism about the possibility of the eradication of HIV/AIDS in coming generations. But we should be sure not to become too secure and complacent in the progress currently being made and take careful inventory of what remains to be done.

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Why the United States Needs Better Confidentiality Laws for Minors with HIV/AIDS

Originally published at PLoS Speaking of Medicine

At the beginning of the International AIDS Conference held in Washington, D.C. in July, Secretary of State Hillary Clinton renewed the United States’ commitment to an “AIDS-free generation a call to action that would reverberate throughout the rest of the conference.This ambitious goal stems from recent outstanding advancements in biomedical research on treatment and prevention, including the FDA’s approval of the antiretroviral medication tenofovir/embitricitabine (Truvada) for pre-exposure prophylaxis.

But the realization of this goal will take much more work, including evaluating and changing laws that keep people from getting tested and staying in treatment and ramping up supportive services that help low-income people remain in care and access their medicines. This combined effort will require first and foremost identifying the sub-populations in which the epidemic is growing the fastest and in which barriers to testing and treatment are most profound. Young people, and especially adolescents, represent one of these key sub-populations.

Health organizations and city and state governments across the United States have sounded the alarm bell about the rising rate of HIV among adolescents. The U.S. Office of National AIDS Policy estimates that half of all new HIV infections in the U.S. occur in people younger than 25. In 2010, there were 2, 266 new HIV infections diagnosed among individuals in the U.S. between the ages of 13 and 19. In 2008, an estimated 29,056 adolescents and young adults were living with HIV in the U.S. Although the CDC does not distinguish between minors under the age of 18 and young adults for surveillance purposes, high risk sexual behaviors have been shown to be prevalent among adolescents under the age of 18 and rising rates of HIV in this population have been associated with these behaviors.

Adolescents are also less likely than adults to be tested for HIV, indicating that the scope of the problem may be even larger than currently estimated. While it is estimated that between 66% and 80% of adults with HIV in the U.S. are aware of their status, only about 16% of adolescents living with HIV in the United States are cognizant of their illness.

What can be done to curb rates of HIV among adolescents in the U.S.? Moving away from abstinence-only sex education is one part of the solution. But another, and less frequently discussed, part of the solution is to change state laws that restrict the ability of minors to consent to testing and treatment for HIV.

Although Iowa is the only state that requires parental notification when a minor tests positive for HIV, the laws in many other states are confusing. In many states, there is no specific indication that a minor may independently consent to testing for and treatment of HIV. In a state like New York, minors may consent to HIV testing but only if the provider assesses that the minor has the capacity to consent. On what basis the clinician is to make that determination is not clear in the law. At the same time, a minor may not consent to treatment for HIV in New York, even if he or she may receive confidential testing. In effect, if a minor tests positive for HIV and wants to seek treatment in New York, parental notification becomes necessary.

Part of the confusion in many states about whether minors are eligible to consent to HIV testing and treatment has to do with the difficulty of classifying HIV. In some states, HIV is clearly defined as a sexually-transmitted infection (STI), covered under the same confidentiality and consent laws as any other STI. In other states, HIV is not classified as an STI but may have a specific law pertaining to it. State-to-state variability in the classification of HIV as an STI often confuses healthcare providers and adolescent patients, leading to situations in which minors may assume they are not eligible for confidential testing and treatment for HIV. Preliminary evidence demonstrates that minors are deterred by the perception that testing and treatment for HIV will be revealed to their parents or guardians.

A commitment to an AIDS-free generation means a commitment to protecting those most vulnerable to the disease. States should clarify their laws on minors’ right to consent to treatment for HIV and the confidentiality of HIV-related information. HIV should also be explicitly included in laws already in place in many states that allow minors to consent to testing and treatment for STIs. Allowing adolescents to consent to confidential testing and treatment may go a long way in reducing infection rates among youth in the U.S., bringing us one small step closer to realizing the dream of an AIDS-free generation.

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