Robert M. Califf, MD

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The aorta, the largest artery in the body, is almost the diameter of a garden hose.
Nice Shout out from AAMC’s Ann Bonham

Dr. Bonham does a better job than could I, but I will add that its nice to see the support for PCORnet and the citation of Zubin Eapen’s paper. We just finished a Coordinating Center retreat for PCORnet, and the job ahead is daunting, but well worth the exhausting work! Also, Zubin’s paper is the product of the work of many dedicated people who have been working with organizations like CTTI (see www.ctti-clinicaltrials.org) and Practical Clinical Trials, supported by dedicated folks at FDA who want to see better data from well-designed trials relevant to the FDA’s public health mission.

Here is the AAMC Blog from Dr. Bonham:

As I See It

“The upcoming years will be a watershed period for the future of comparative effectiveness research in the US.” This quote from a May 2 Health Affairs blog post on PCORI epitomizes my own opinion on the urgency and importance of this moment for the research community.

One phenomenon in particular is poised to rapidly transform the way research is conducted: the largest coordinated, national-level investment in connecting and mining big data for clinical outcomes research in American history, PCORI’s PCORnet initiative. Nature recently hailed PCORnet – which supports the development of infrastructure to link and query data from Academic Medical Centers, insurers and other key players – as nothing less than “a dream cohort” for researchers.

If You Build It

While PCORnet may seem ambitious or abstract to some, the scope and possibility of the initiative has already entered the public imagination. In their April 15th article “Scientists embark on unprecedented effort to connect millions of patient medical records” for instance, the Washington Post paired exuberant praise of the initiative’s novelty and value with a thoughtful and optimistic examination of the challenges left to overcome: in addition to efforts to successfully engage patients in the process, systems must uphold high standards for privacy, security and reliability.

Meanwhile, research demonstrating the vast potential of integrated, searchable and robust health data is taking off. On his NIH Director’s blog, Francis Collins recently described this big data as “priceless raw material for the next era of biomedical research,” referencing how researchers can develop and test hypotheses without assuming the cost and time resources for new data collection. For instance, in Disease Risk Factors Identified Through Shared Genetic Architecture and Electronic Medical Records (from April’s Science Translational Medicine), a team led by Dr. Atul Butte at Stanford School of Medicine describe a correlation between serum magnesium levels and gastric cancer identified within a large database of genome-wide association studies. The authors describe how this link was further confirmed using deidentified EHRs to compare the occurrence of gastric cancer among tens of thousands of patients whose blood serum had been tested for magnesium, finding a significantly higher rate of the disease in those whose serum levels tested higher than normal. If this work peaks your interest, you can learn more from this TedMed 2012 talk by Atul Butte.

The imperative for progress is clear. It is our collective and proper responsibility to make the most of the information that patients provide to establish an infrastructure and expectation that patient- and population centered care is inherently evidenced-based. Randomized controlled trials (RCTs), are no doubt a gold-standard, yet their costs can be prohibitive and their need for restrictive inclusion and exclusion criteria can mean that the results are hard to generalize to real-world patients and care conditions. RCTs will continue to provide important information for efficacy, safety, and effectiveness studies, but pragmatic trials and observational studies based on networked data will allow researchers to generate hypotheses and answer questions about the risks and benefits for a broad spectrum of patients in a potentially more rapid and less resource-intensive manner. I recommend this Viewpoint on overcoming the barriers to conducting large simple trials from the April 9th JAMA for a deeper treatment of these issues by Eapen, Lauer and Temple.

PCORI’s investments in PCORnet are a critical step in creating the infrastructure and large scale demonstrations to help comparative effectiveness research reach critical mass. This is the kick start we need to accelerate towards our vision of learning health systems that integrate research into care and support evidence-based decision making for both clinicians and patients. It will also pay forward benefits to other important research efforts. Analysts and historians looking back on this window of time may well label PCORnet as PCORI’s most enduring legacy.

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Big Data!

I’m sitting in Palo Alto on the Stanford campus at the “Big Data Meeting”. This joint effort of Stanford and Oxford is highlighting the amazing change afoot in our environment. Everyone is talking about it!

Prof Martin Landry from Oxford is exemplifying what is needed: a surgeon/clinical trialists who has worked at the ground level on so many infrastructure projects, but who is really a leader—driving the system to answer questions that will improve health and healthcare.

I’ll fill in some impressions as we go along, but what’s on my mind right now is the “big discussion” needed to achieve the right balance between people’s need for privacy and the dramatic benefit that can be achieved with analysis applied to big data. The answer is not clear, and there is much at stake for all of us in getting this right!

Todd Park, founder of Athena Health, and now Chief Tech Officer for the US, is an inspiring speaker on this issue.

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Distinguished Professors

Academic medicine has its frustrations, but these are offset by substantial benefits. One of the great privileges is the responsibility of nurturing generations of students who become practitioners, faculty, leaders and the mentors to the mentors. Last night I had the chance to attend an event held annually at Duke in which the new distinguished professors are “inducted” in a “black tie” event attended by the current distinguished professor. The President and Provost of the university review the academic exploits of each “inductee,” ranging from English to history, business and medicine. I was particularly proud to be associated with:

Chris O’Connor who arrived at Duke as an intern in a full white pants, white shoes and labcoat outfit! He is a “doer” who at every step of the way has made his workplace better, contributed new knowledge and spent enormous time and energy stimulating and mentoring young people. He is thriving as Director of the Duke Heart Center, which requires enormous skills at multitasking and political maneuvering to satisfy multiple constituencies. Through all the pressure of clinical care, the Heart Center balanced scorecard shows a steady and very successful balance of excellent quality, outstanding academic productivity in basic, translational and clinical research.

Danny Benjamin is fellow “Clemson man”–we both spent considerable time in that special part of South Carolina. Danny has done amazing work in bringing clinical pharmacology and pediatric research into a new era. With an MPH and PhD in epidemiology from UNC, he has an integrated set of skills that have enabled him to lead one of the largest pediatric networks in history–the Pediatric Trials Network (PTN). But, perhaps more important in the long run, Danny has mentored an army of investigators who are now doing well on their own. In his spare time he has done some significant professional gambling–one of the most useful interactions I’ve had with Danny involves his ability to couch decisions in terms of probability of success.

Monica Kraft arrived at Duke a decade ago as an up and coming pulmonary disease translational and clinical investigator. She has steadily increased her span of influence and now is Chief of the Division of Pulmonary and Critical Care Medicine. She just finished a term as President of the prestigious American Thoracic Society, a key professional organization in her field. Most recently she has taken the role of the co-PI of the CTSA grant at Duke. She shows amazing stamina in holding down multiple jobs and keeping many mentees busy with high aspirations. Monica also has the distinction of having lived in Washington Park in Denver, the same neighborhood where my son Sam and his family live.

It is great to be able to celebrate leaders and especially fun to honor people I have had a chance to work with as their careers developed. An interesting aspect of all 3 is that they have supportive spouses and great families–last night was a special treat.

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How do we Configure “Big Data” for small numbers of patients?

Many clinical and translational researchers have dreamed of a day when whole genome sequencing, gene expression, broad proteomics and metabolomics and physiological measurements could be combined to reinvent human physiology. The term “human systems biology” has been used to describe the interaction of multiple systems. For example, we have known that the blood pressure is a complex manifestation of vascular, cardiac, renal and central and peripheral nervous system interaction. The ability to measure, store and perform computations on these parameters is reaching a tipping point. And now we will also be able to measure multiple physiological parameters like blood pressure, heart rate and oxygen saturation using wearable percutaneous devices. I’m now gaining optimism that this revolutionary approach to understanding the human condition will happen during my career. Places like Duke and DTMI/DCRI have an amazing opportunity to put the teams of researchers together with activated research participants to make this a reality, and the benefits for health and disease treatment will be profound.

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The MURDOCK Study–Coming to Fruition

Tomorrow night and Tuesday we have the board meeting for the David H. Murdock Research Institute (DHMRI). Composed of 3 “Dukies,” 3 members from the UNC system and 3 members representing Mr. Murdock, the board will be reviewing plans for the future. Duke’s major contribution has been the MURDOCK Study, now reaching over 10,000 volunteers who have had a baseline assessment, multiple blood and urine samples and followup through a structured interview, and over time, the assessment through electronic health records. While the study has had its complexities, we have basically reached the degree of enrollment and followup needed to “unlock” the deep analysis of the biological basis for health and disease. The combination of the MURDOCK Study, the analytical capacity of DHMRI and the interest of major industry partners who want to understand human systems biology should herald a major advance in our understanding of human biology. I will be reporting on more details soon.

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A Sobering Reminder from Nature

Nature, a prominent bioscience journal, just publishing an editorial warning PCORI about the hazards of developing a national data infrastructure (http://www.nature.com/news/take-care-1.15089). The article is sobering, but also encouraging. The major advance from PCORnet will come from combining the rapidly evolving data and informatics world, the energetic panoply of researchers who are so motivated to answer questions and the patients themsleves. It is the patients and their advocates who stand the best chance of helping us find the balance between protecting privacy and advancing knowledge, between autonomy and the commmon good and between trust in the wisdom of clinical practice and admitting the uncertainty of our current recommendations. The adventure is already a major learning exercise and it is becoming more intense as more people get interested.

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The Status of the US in Health and Health Care

The rhetoric has heated up again about the health status of the US population and the role of the organized delivery system in fixing the problem. On Fareed Zacharia’s GPS (http://cnnpressroom.blogs.cnn.com/2014/04/20/michael-porter-on-gps-is-the-u-s-1/) on CNN, Michael Porter’s latest ranking showed the US at 60th among countries for health and wellness. This doesn’t square with the view most Americans have of our country, yet the population statistics are compelling that we have work to do as a society.

Much of the our poor standing derives from cultural issues that lead people to do self-destructive behaviors with diet, exercise, substance abuse and violence. And the increasing focus on income inequality with its basis in educational disparities provides ample room for arguing that this is not a healthcare delivery issue. On the other hand, our integrated healthcare delivery systems (otherwise known as academic health and science systems-AHASs), particularly those with a large university base, have become the largest economic engines in many parts of America.

Is there a way to harness the power of informatics, the reach of our healthcare systems into neighborhoods and the integration with the knowledge engine of univerisities in order to change this equation?

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The PCORnet Challenge

The development of PCORnet has been every bit as fascinating and challenging as expected. The concept of 29 networks involving between 11 and 100 million Americans is breathtaking. The socialization is still ongoing, as the many involved participants are just beginning to get to know each other.

One of the many fascinating issues is the fragmentation of the clinical research communities. Each fragment has its own view of the world, including special nomenclature and often, different meanings for the same terms. One of the most important of these divisions is the world view of informaticians and clinical investigators–this was symbolized by the fact that the AMIA meeting was held in San Francisco at the same time the Association for Clinical and Translational Science and the Clinical Research Forum were held in Washington.

Despite these issues and much fatigue from long days, the spirits of the group remain great, and it’s inspiring to see the different sectors working to overcome schisms for the common purpose. Part of the fun for me will be to see if we can shape an institution to help by providing a model and a pipeline of talent for this national purpose of creating a learning health system.

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Research Permissions–Angels on the Head of a Pin, or the Key Issue to Decipher?

NEJM today has a pair of sentinel papers on the issue of research permissions for comparing therapies already in routine use in practice. Ruth Faden, Nancy Kass and colleagues from Hopkins, building on the ir Learning Health System work featured in the Hastings Center Reports, argue that in a proper context specific informed consent is not needed. Scott Kim and Franklin Miller from NIH argue that consent is needed, but that current circumstances call for a very different approach that integrates information needs in clinical care with knowledge acquisition through randomization. In their approach the consent would be very short and consistent with a fabric of information already given to people about what is known about the care they are receiving and the choices being made by the patient and provider.

The exciting element of the pair of articles is that the agreement is much greater than disagreement. Both groups of ethicists agree that the current approach is not optimal. In discussions about this issue, many colleagues have pointed out to me how seldom we really inform people about the uncertainties of current clinical recommendations. Over 85% of decisions in cardiovascular disease are not based on high quality evidence and other specialties have even a lower rate.

I hope these articles will move people to a better place that might include:

1. much better information in practice about what we really know (evidence based medicine) vs our opinions (opinion based medicine) and a better characterization of the uncertainty
2. notification and consent that doesn’t treat randomization as a major event, but rather as a tool to help inform us all about what we should do to optimize health

A colleague recently said: “When you get offered the next procedure where the evidence is unclear, maybe you should be asked: “Would you rather that I guess whether this procedure is good for you, not tell you that the doctor next door would do something different and do the procedure with a promise that we will learn nothing that will give the next patient a better chance? Or would you rather enter a study in which we let you know about our uncertainty and learn about the procedure so that all future patients can benefit?”.

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A Tipping Point?

In the past 48 hours I have been involved in many meetings and discussions about learning, health decisions and healthcare. Ray Gibbons, a former Duke fellow who went on to greatness at Mayo Clinic and was President of the American Heart Association, pointed out that we could save a million lives if we just implemented systems that made sure effective therapies were given. On many conference calls and discussions, patient advocates and researchers were realizing that the evolving texture of health system data would give us the ability to intelligently provide useful information about choices to patients in the near future. Liberating us from the ignorance that comes from the isolation of practitioners as they try to learn from their own limited experience will be a major advance in medical history. Even as we struggle trying to put data into cumbersome systems like EPIC we are beginning the see the fruits of our labor as patterns emerge in data that guide better decision making. The invigoration of administrators and clinicians, now armed with information, is leading to fascinating discussions about the boundaries (or lack thereof) between quality improvement and research involving human “subjects” (also known as participants!).

The outcome seems inevitable– much better decisions made by patients and clinicians armed with better and better data. The question is: when will we reach the tipping point and what can we do to reach that point more quickly?

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