Friday, April 30, 2010

At Risk Drinking Common Among Older Primary Care Patients

Journal of General Internal Medicine

Online First
16 April 2010

Prevalence and Correlates of At-Risk Drinking Among Older Adults: The Project SHARE Study
Andrew J. Barnes, Alison A. Moore, Haiyong Xu, Alfonso Ang, Louise Tallen, Michelle Mirkin and Susan L. Ettner


At-risk drinking, excessive or potentially harmful alcohol use in combination with select comorbidities or medication use, affects about 10% of elderly adults and is associated with higher mortality. Yet, our knowledge is incomplete regarding the prevalence of different categories of at-risk drinking and their associations with patient demographics.

To examine the prevalence and correlates of different categories of at-risk drinking among older adults.

Cross-sectional analysis of survey data.

Current drinkers ages 60 and older accessing primary care clinics around Santa Barbara, California (n=3,308).

At-risk drinkers were identified using the Comorbidity Alcohol Risk Evaluation Tool (CARET). At-risk alcohol use was categorized as alcohol use in the setting of 1) high-risk comorbidities or 2) high-risk medication use, and 3) excessive alcohol use alone. Adjusted associations of participant characteristics with at-risk drinking in each of the three at-risk categories and with at-risk drinking of any kind were estimated using logistic regression.

Over one-third of our sample (34.7%) was at risk. Among at-risk individuals, 61.9% had alcohol use in the context of high-risk comorbidities, 61.0% had high-risk medication use, and 64.3% had high-risk alcohol behaviors. The adjusted odds of at-risk drinking of any kind were decreased and significant for women (odds ratio, OR=0.41; 95% confidence interval: 0.35-0.48; p-value<0.001), adults over age 80 (OR=0.55; CI: 0.43-0.72; p<0.001 vs. ages 60-64), Asians (OR=0.40; CI: 0.20-0.80; p=0.01 vs. Caucasians) and individuals with higher education levels. Similar associations were observed in all three categories of at-risk drinking.

High-risk alcohol use was common among older adults in this large sample of primary care patients, and male Caucasians, those ages 60-64, and those with lower levels of education were most likely to have high-risk alcohol use of any type. Our findings could help physicians identify older patients at increased risk for problems from alcohol consumption.

This project was funded by the National Institute of Alcohol Abuse and Alcoholism 1RO1AA013990 (PI: Ettner). Dr. Moore’s time was additionally supported by the National Institute on Alcoholism and Alcohol Abuse 1R01AA15957 (PI: Moore).

Wednesday, April 28, 2010

Moderate drinking linked to lower diabetes risk

Moderate drinking linked to lower diabetes risk
By Amy Norton
2010-04-27 (Reuters Health)

NEW YORK (Reuters Health) - Adults who have a drink or two per day may have a lower diabetes risk than teetotalers -- and the link does not appear to be explained by moderate drinkers' generally healthier lifestyle, a new study finds.
A number of studies have found an association between moderate drinking and a relatively lower risk of developing type 2 diabetes. However, whether that reflects a benefit of alcohol has been unclear. A central issue is the fact that, compared with both non-drinkers and heavy drinkers, moderate drinkers tend to have a generally healthier lifestyle.

In the new study, researchers found that among more than 35,000 Dutch adults followed for a decade, those who averaged a drink or two per day were 45 percent less likely than teetotalers to develop type 2 diabetes.

Moreover, the lower risk was seen among men and women whose diabetes risk was already relatively low because of their weight and lifestyle habits -- namely, not smoking, eating a healthy diet and getting regular exercise.

Even among study participants with at least three of those protective factors, moderate drinkers were 44 percent less likely than non-drinkers to develop type 2 diabetes.

The findings, reported in the American Journal of Clinical Nutrition, do not prove that drinking itself lowers diabetes risk. But they do suggest that the alcohol-diabetes connection is not explained away by other lifestyle factors.

"Our results indicate that this is very unlikely, because moderate drinkers with the most healthy lifestyle behaviors...had a lower chance of developing diabetes compared with subjects with these healthy lifestyle behaviors who did not drink," lead researcher Dr. Michel M. Joosten, of Wageningen University in the Netherlands, noted in an email to Reuters Health.

The findings are based on 35,625 adults who were between the ages of 20 and 70 and free of diabetes, heart disease and cancer at the outset. Participants had their weight, height and waist and hip circumference measured and completed questionnaires on their health and lifestyle habits.

Over the next 10 years, 796 developed type 2 diabetes.

In general, moderate drinkers -- up to a drink per day for women, and up to two for men -- were less likely to develop the disease than non-drinkers. And that remained true when Joosten and his colleagues examined the effects of other lifestyle-related factors.

For example, when they looked only at normal-weight men and women, moderate drinkers were 65 percent less likely to develop diabetes than teetotalers. Similarly, among regular exercisers, moderate drinkers had a 35 percent lower risk of diabetes.

The "take-home message," Joosten said, is that moderate drinking "can be part of a healthy lifestyle to lower your risk of type 2 diabetes, even if you already comply with multiple other low-risk lifestyle (behaviors)."

That said, he also noted that experts do not recommend that non-drinkers take up moderate drinking simply because it is related to lower risks of certain diseases. Alcohol always carries the potential for abuse, and the known risks of problem drinking have to be balanced against the possible health benefits of moderate drinking.

SOURCE: American Journal of Clinical Nutrition, online April 21, 2010

Thursday, April 15, 2010

Is addiction a disease?

Recently, a reader wrote to me with the following question:

You state that alcoholism can be a chronic progressive disease but is not most of the time. So, do you still believe addiction is a disease or that for the 1% of hard core drug addicts and chronic alcoholics who are literally killing themselves, that at this extreme end of the continuum their brains are no longer able to change without abstinence?”

This is a sophisticated question, which means that the answer is complicated. It's clear I will need to address this question in more detail over a series of blogs, but let me at least take a stab at a relatively straightforward answer. In order to do so, I'm going to break this question into smaller bits and answer them in sequence.

You state that alcoholism can be a chronic progressive disease but is not most of the time.”

Yes, that's true.The NIAAA Epidemiological Study of Alcohol and Related Conditions (NESARC) is a very large (n=43,000) study of a random sample of the US adult population age 18+. So far participants have been interviewed at two different times 3 years apart, and the third wave is underway. One thing that makes this study unique is that it is following the same very large sample over time, something that has never been done before. Deborah Hasin of Columbia University and her colleagues examined the natural history of alcohol dependence (AD), and determined that about three-fourths of people who had an episode of AD in their lifetime had a single episode lasting on average about 3-4 years, and the disorder then went away and did not recur. The remaining quarter had an average of five episodes, each one of decreasing length. So their appears to be two forms of AD, one relatively mild and self-limited and a more chronic or recurrent form.

So, do you still believe addiction is a disease...?”

Yes, I do, not the simplistic disease model that has been part of the Minnesota Model, but a disease in the same way that asthma, diabetes and depression are diseases. Why do I think this? 1) It is a genetically influenced disorder. About 50-60% of the variation in who gets or does not get AD is due to heritable factors, which is very similar to these other disorders. Not everyone with a family history gets the disorder, and not everyone with the disorder has a family history, but the same is true for heart attacks. 2) Both genetic and environmental factors are usually necessary in order for the disease to develop. Some people can drink a lot for a long time and never lose control of their drinking (impaired control over use is the hallmark of addiction,) but vulnerable individuals are more likely to. 3) There is a broad spectrum of severity, ranging from mild to moderate and severe. 4) Need for and response to treatment is predicted by severity and other patient factors. 5) As a clinician, treating addiction feels the same to me as treating any other disease, I use the same basic approach and skills and the response is similar. So, in short, AD resembles other diseases in many ways.

... or that for the 1% of hard core drug addicts and chronic alcoholics who are literally killing themselves, that at this extreme end of the continuum their brains are no longer able to change without abstinence?”

NESARC and many other studies have shown that the more severe the dependence, the less likely that anything other than complete abstinence will lead to sustained remission (recovery.) Most of the people who are in treatment programs or AA have the more severe, recurrent, familial form of the illness. Thus, for them, abstinence is by far the best, safest option. For them, any drinking is likely to be very dangerous. However, for the people who have the mild to moderate, self-limiting form, non-abstinent recovery (low-risk drinking without any alcohol related symptoms) eventually occurs in about 40%.

Finally, I'll just briefly comment on the issue of addiction as a “brain disease.” Addiction is a dysregulation of a specific behavior. Where does behavior come from? Is there an organ involved? What organ might that be? Right, behavior is regulated or through the brain. Trying doing, thinking or feeling something without a brain. You won't get very far. So if addiction is characterized by dysregulated behavior, it naturally follows that self-regulatory systems in the brain are out of whack. If you think about it, you'll recognize that we don't need a brain scan to know that. How else could it be? New scientific tools are giving us a more refined view of which systems are involved and in what ways they are dysfunctional. This can be useful in leading us to develop new more powerful tools for aiding recovery, such as medication. With addiction, chronic or frequent exposure to high levels of intoxicants leads the brain to adapt in an attempt to normalize itself (in technical terms homeostasis.) Given enough time these adaptations are not easily reversed, such that if you take away the intoxicant you develop “symptoms” such as acute withdrawal, craving and preoccupation and an exaggerated response to stress. If you take a single dose of the intoxicant, you may lose control and binge even though that was not your intention. This whole topic requires more space than I want to devote here, but I'll just end by noting that this hypothesis does not in any way explain that wide variation in intoxicant use among people. But it is a decent place to start and probably applies pretty well to severe recurrent addiction.

Thursday, April 1, 2010

The Brave New World of Genomics

Here's a fascinating piece published in Nature by Francis Collins, the new NIH Director. Although addictions are not addressed directly (or mental illness), the coming revolution in genomics and individualized medicine has major implications for people who suffer from mental and addictive disorders, as well as their children. Dr. Collins predicts a complete ban on discrimination based upon genetic information, but addiction is one of the most highly stigmatizing diseases, perhaps the single most stigmatizing. At the same time there will be opportunities to identify children at higher risk for these disorders, providing at opportunity for earlier intervention. It's not going to be easy to navigate these waters. Here's Dr. Collin's statement:

Opinion: Has the revolution arrived?

By Francis Collins

March 31, 2010

Looking back over the past decade of human genomics, Francis Collins finds five key lessons for the future of personalized medicine — for technology, policy, partnerships and pharmacogenomics.

On 26 June 2000, Craig Venter and I stood next to the President of the United States, in the same room of the White House where the explorers Meriwether Lewis and William Clark had unfurled their map of the Northwest Territories for Thomas Jefferson. “Today,” Bill Clinton said, “the world is joining us here in the East Room to behold a map of even greater significance. We are here to celebrate the completion of the first survey of the entire human genome ... With this profound new knowledge, humankind is on the verge of gaining immense, new power to heal. Genome science will have a real impact on all our lives — and even more, on the lives of our children. It will revolutionize the diagnosis, prevention, and treatment of most, if not all, human diseases.”

I was honoured to be standing there, but also somewhat embarrassed: the milestone being reported was not yet attached to a publication — there was a lot of analysis still to do, and the paper would not appear in Nature until eight months later. Still, it was a heady moment.

Wisely, the president did not attach timetables to his bold predictions, even though in the early days of the millennium, everyone wanted to hear where this genome revolution was going. I even made my own predictions for 2010. Never having discarded a PowerPoint file, I can reproduce my list verbatim:

Predictive genetic tests will be available for a dozen conditions

Interventions to reduce risk will be available for several of these

Many primary-care providers will begin to practise genetic medicine

Preimplantation genetic diagnosis will be widely available, and its limits will be fiercely debated

A ban on genetic discrimination will be in place in the United States

Access to genetic medicine will remain inequitable, especially in the developing world

It is fair to say that all of these predictions have come true, with some caveats that offer important lessons about the best path forward for genomics and personalized medicine. The promise of a revolution in human health remains quite real. Those who somehow expected dramatic results overnight may be disappointed, but should remember that genomics obeys the First Law of Technology: we invariably overestimate the short-term impacts of new technologies and underestimate their longer-term effects.

Breathtaking acceleration

The decade from 2000 to 2010 was characterized by breathtaking acceleration in genome science. Thanks to advances in DNA sequencing technology that dropped the cost approximately 14,000-fold between 1999 and 2009, finished sequences are now available for 14 mammals, and draft or complete sequences have been done for many other vertebrates, invertebrates, fungi, plants and microorganisms. Comparative genomics has emerged as a powerful approach for understanding evolution and genome function at a level of detail barely imagined a few years ago.

For humans, the HapMap project produced a remarkable catalogue of common variation in the genome in just three years, from 2002 to 2005. As full sequencing has become more practical, researchers have been releasing complete genomes of individuals — a total of 13 at the time of this writing, including my personal hero, Archbishop Desmond Tutu of South Africa. In 2011, an international team is set to complete the data-production phase of the 1000 Genomes Project, designed to produce highly accurate assembled sequences from more than 1,000 individuals whose ancestors came from Europe, Asia and Africa.

The same determination to study the entire genome, not just isolated segments, has now been applied to understanding its function — although this quest is, of course, much more complicated and open-ended. The Encyclopedia of DNA Elements (ENCODE) project (started in pilot form in 2003 and slated to run at least until 2011) and the US National Institutes of Health (NIH) Roadmap Epigenomics Program (started in 2008 and funded until 2013) continue to define the 'parts list' of the human genome. These projects identify the locations of genes (protein coding and non-coding) and the patterns that determine whether genes are switched on or off in a given tissue — patterns of chromatin modification, transcription factors and DNA methylation.

With regard to medical applications, genome-wide association studies (GWAS) have now revealed an astounding number of common DNA variations that play a part in the risk of developing common diseases such as heart disease, diabetes, cancer or autoimmunity. To identify less common variations, methods to target DNA sequencing to subsets of the human genome have been developed. These methods can now sequence 80–90% of the protein-coding regions — the exons or 'exome' — of a human DNA sample for just a few thousand dollars.

Genome research has already had a profound impact on scientific progress. The combination of new technologies and freely accessible databases of high-quality genomic information has enabled the average investigator to make discoveries much more quickly than would otherwise have been possible. For example, the search for the cystic fibrosis gene finally succeeded in 1989 after years of effort by my lab and several others, at an estimated cost of US$50 million. Such a project could now be accomplished in a few days by a good graduate student with access to the Internet, appropriate DNA samples, some inexpensive reagents, a thermal cycler and a DNA sequencer (see graphic).

The consequences for clinical medicine, however, have thus far been modest. Some major advances have indeed been made: powerful new drugs have been developed for some cancers; genetic tests can predict whether people with breast cancer need chemotherapy; the major risk factors for macular degeneration have been identified; and drug response can be predicted accurately for more than a dozen drugs. But it is fair to say that the Human Genome Project has not yet directly affected the health care of most individuals.

GWAS have so far identified only a small fraction of the heritability of common diseases, so the ability to make meaningful predictions is still quite limited, even using chips that test for a million or more common variants. Nonetheless, direct-to-consumer marketing of genetic risk prediction, based on the rapidly growing database of GWAS results, is attracting early adopters. Having gone through that process myself, I can report that I found the opportunity to view my own personal genotype results rather riveting, despite the limited clinical validity and utility of many of these predictions.

This dynamic is likely to change in the next five years. Much of the missing heritability (the 'dark matter' of the genome) will probably turn up as the technology advances. Whole-genome sequencing, coming into its own as the cost per genome falls below $1,000 in the next three to five years, will identify rare variants of larger effect and the copy number variants that GWAS may have missed. With an increasing inventory of these discoveries, prediction of disease risk and drug response will continue to improve.

This profusion of therapeutic opportunites is a challenge to prioritize.

As the cost falls and evidence grows, there will be increasing merit in obtaining complete-genome sequences for each of us, and storing that information, with appropriate privacy protections, in our medical records, where it will be quickly available to guide prevention strategies or medication choice.

Perhaps the most profound consequence of the genome revolution in the long run will be the development of targeted therapeutics based on a detailed molecular understanding of pathogenesis. However, this is also the goal most challenged by long timelines, high failure rates and exorbitant costs. Despite those obstacles, inspiring examples of success are in hand, many of them (trastuzumab, imatinib, gefitinib and erlotinib) for the treatment of cancer. Furthermore, the identification of new cancer drug targets is accelerating rapidly as a consequence of the ability to do deep genome sequencing of many tumours to identify recurrent mutations. Projects such as the Cancer Genome Atlas, which is carrying out the equivalent of 20,000 genome projects on matched tumour and blood DNA samples from 20 common types of cancer, have begun to reveal numerous opportunities for therapeutic development. And GWAS have pointed to hundreds of previously unrecognized drug targets for dozens of other diseases.

This profusion of therapeutic opportunities is a challenge to prioritize. Efforts are now under way to forge innovative partnerships between the traditional strengths of the private sector and academic labs. The NIH has provided new resources to catalyse such partnerships, including access by academic investigators to high-throughput screening through the Molecular Libraries Roadmap project, and to preclinical testing of promising lead compounds through the Therapeutics for Rare and Neglected Disease initiative.

Enabling the future

I propose five major lessons that could be gleaned from this first decade of the genome era. First, free and open access to genome data has had a profoundly positive effect on progress. The radical ethic of immediate data deposit, adopted by the Human Genome Project in 1996 and now the norm for other community resource projects, empowers the best brains on the planet to begin work immediately in analysing the massive amounts of genomic data now being produced. It is a very good thing that the 'race for the genome' in 1998–2000 resulted in the human genome sequence being immediately and freely available to all, rather than becoming a commercial commodity.

Second, technology development for sequencing and functional genomics — key to the success achieved thus far — must continue to be a major focus of investment by both the public and private sectors. Although huge leaps have been made in increasing the speed and reducing the costs of DNA sequencing, expression analysis and methods to assess the epigenome, the limits are still nowhere near being reached.

Third, the success of personalized medicine will depend on continued accurate identification of genetic and environmental risk factors, and the ability to utilize this information in the real world to influence health behaviours and achieve better outcomes. This will require well designed, large-scale research projects, for discovering risk factors and for testing the implementation of prevention and pharmacogenomic programmes.

Fourth, achieving the enormous promise of the myriad new drug targets emerging from genomic analysis of common and rare diseases requires new paradigms of public–private partnership. Academic investigators will have a much more important role in the early stages, effectively 'de-risking' projects for downstream commercial investment. Closer relationships between the US Food and Drug Administration and the NIH, announced this February, will assist this process.

Finally, good policy decisions will be crucial to reaping the benefits that should flow from the coming revelations about the genome. These will include protection of individual privacy, effective education of health-care providers and the public about genomic medicine, and appropriate health-care system reimbursement for the cost of validated preventive measures.

In The Wisdom of the Sands, author Antoine de Saint-ExupĂ©ry wrote: “As for the future, your task is not to foresee, but to enable it.” Genomics has had an exceptionally powerful enabling role in biomedical advances over the past decade. Only time will tell how deep and how far that power will take us. I am willing to bet that the best is yet to come.

Francis Collins is director of the National Institutes of Health, Bethesda, Maryland 20892, USA. Between 1993 and 2008 he was director of the National Human Genome Research Institute.