Billions and billions of gene expression measurements.

Let's say you are looking for a disease biomarker. Hopefully, one better than prostate specific antigen. Next time you or your student reach for a pipette to see if a gene is expressed in a particular tissue or disease, perhaps you should first check with the public databases of gene expression. As outlined in this article, we now have hit the one million array mark. That is, one million arrays measuring gene expression across thousands of conditions (tissues, diseases, pharmacological or environmental perturbation). And each array has tens of thousands of genes so these corpora have billions of gene expression measurements. That means you'll immediately be able to see if your favorite gene is uniquely expressed in a tissue in a specific disease. Or not.

Another way to think about these corpora is that they constitute one of the largest open access biomedical libraries. A model for clinical research to emulate?

Hat tip: Atul Butte.

Unstandardized standards

An insightful naïf learning about the difficulty of sharing one electronic health record from one hospital to another might reasonably ask "Why don't they just create a standard for data sharing so that I can install or delete health apps at will and view my data on several different electronic health record systems?" An expert will then inform that impertinent naïf that it's much more complicated than she understands and that the standards already exist. When challenged, the expert will cite several august committees which have ratified standards such as the Continuity of Care Document (CCD). At this point, our naive protagonist should refer the expert to this blog entry by Josh Mandel. If by then, the expert is not holding his hands to his ears, he will explain that all standards are evolving entities and that these challenges are just the expected missteps on the path of convergent evolution to interoperable samadhi.

Mad Men and Mad Nerds

Should we enable the following conversation between any website and your web browser (e.g. Safari, Internet Explorer, Firefox, Chrome)?

Your web browser: "Hello website potentiallyInteresting.com."

Website: "Hello web browser."

Your web browser: "Dear Website, please do not track who I am. Do not even try to remember that I came to visit you."

Website: "You mean you don't want me to track you even if though you did not switch on all your privacy controls such as switching off acceptance of 'cookie' files?"

Your web browser: "That's right. You are an upstanding website and when I say to you 'DNT:1" that means that I don't want you to track me. That's what the user who controls me wants."

Website: "I certainly am upstanding and I respect your statement of the user's wishes. Consider this whole visit forgotten."

Your web browser: "Thanks for your understanding."

Website: "Do I know you?"

It turns out that there is a great deal of controversy about these five characters: DNT:1. On the one side are the user advocates who argue that websites should honor the do not track directive. One the other side are the companies who fund large parts of the web infrastructure because of the advertising revenues (~70 billion) that are generated by being able to track the traffic of users across their Internet properties. These companies now wonder where their investments will go if few users allow their websites to track them. Their concerns are not misplaced. After all, how many of us would choose to keep commercial breaks on broadcast television if all we had to do is to flip a switch? Of course, those same companies could choose to have the following alternative ending to the above conversation:

Website: "I certainly am upstanding and I respect your statement of the user's wishes. But we have to pay the bills. If you will not allow tracking, I just cannot show you my contents. Sorry."

Your web browser: "OK then. I'll let my user know that she has to allow tracking if she wants to see your contents."

Website: "I will be waiting. But don't expect me to recognize you."

Ultimately, the debate is going to turn on the valuation that the public places on its autonomy and privacy relative to the broadest access to web content. For those of us in the arts, sciences or businesses of curation of the various forms of knowledge and data, the outcome of this multi-billion dollar debate will affect our work for decades to come.

Hat tip: Ben Adida

Meta-directory of the Countway community

Countway Photo Day from CBMI on Vimeo.

Dearth of Death: A Fatal Wound to Medical Research?

My esteemed colleague L.J. Wei often reminds us that health outcomes which are not as hard-edged as death can be misleading. For example, the early press, decades ago, about the uncovering of early cancer by the Prostate Specific Antigen (PSA) was used to justify the surgical removal of hundreds of thousands of prostates. In hindsight, neither the PSA test nor much of the ensuing expensive and occasionally morbid surgeries made a significant dent in lifespan.

One might therefore reasonably conclude that the government, the census bureau, Social Security Administration or the Department of Health and Human Services would therefore place the highest premium on the accurate reporting of death, and its causes, for our citizens. Surely, those data are the incontrovertible evidentiary base for our public health monitoring, medical treatment evaluations (whether of drug, device or procedure), and projections of the fundamental demographics of our nation. So, it might be all too easy for most of us to overlook or dismiss the following innocuous-appearing bureaucratese-laden announcement

IMPORTANT NOTICE The National Technical Information Service (NTIS) has been notified by the Social Security Administration (SSA) of an upcoming important change in the Death Master File data. NTIS, a cost-recovery government agency, disseminates the DMF data on behalf of SSA. Please see the attachment, provided by SSA, for an explanation of the change. The implementation date of this change is November 1, 2011. Should you have any questions, please email me at wstrickland@ntis.gov and I will be happy to forward any questions not answered by the attachment to the Social Security Administration for reply.

What does this mean? It means that there is no longer a single, federal authoritative source of death records. Most of the operational details have now devolved to individual states without guarantees of consistency of reporting or a one-stop-shop for researchers looking for the national distribution of the Grim Reaper. Will we have to resort to crowd-sourcing death now in order to perform accurate population research?

Hat tip: Shawn Murphy

Copyright + book = disappearing act?

Many of us worry that the last three decades of scholarship will be lost to posterity because we have yet to provide an institutionalized set of mechanisms for preserving the digital output of academia that are as durable and accessible as our accreted analog/paper-based records. Now here comes word of an equally worrisome trend, the empirical evidence that worries about the effect of copyright on the access to important cultural, literary and scientific works, may be well-founded. A recent article in the Atlantic Monthly describes a yawning gulf in the sale of new books from recent decades such that there are more new books sold by Amazon from 1850, than there are from 1950. In their analyses, the investigators provide intriguing circumstantial evidence suggesting that the copyright laws may be responsible. More detail in this lecture by Paul Heald.

Hat tip: David Osterbur

The passing of clean taxonomies.

Among the most productive constructs of the enlightenment are the modern taxonomies. These have been helpful in bringing order to the chaos of signs and symptoms and other clinical findings and were central tools in achieving our 20th century understanding of pathophysiology. They have also have an influential role to play in reimbursement for medical services. With the dawn of high-throughput molecular diagnostics many of us recognize that we are going to be able to be far more precise in our diagnostic and therefore therapeutic approach to diseases and their prevention.

Nonetheless, as we approach the systematization of medicine, we will be reminded often that nature may not hew to the simplified models that we are developing. This recent study in the New England Journal of Medicine, just does that by demonstrating directly that within a "single" tumor there exists a large multiplicity of tumor types, each with its own genomic characteristics and therefore particular therapeutic responsiveness (or lack of it). It can be argued that this is another instance of the tension between the "neats" and the "scruffies" but perhaps it is a foreshadowing of the decreased effectiveness of taxonomies as a cognitive tool for biomedical discovery and clinical care. If indeed, the underlying substructure of physiology is best represented by a probabilistic network model that can only be best grasped and managed through the use of computational tools, we have to seriously re-evaluate both our approach to disease definition and biomedical education.

City as organism

This video from Geneva, Switzerland is a beautiful instance of the repurposing of data. Shown are the data flows between cell phones across the city over night and day. This glimpse of the interactions over time also suggests new frontiers in real-time epidemiology. What if these (anonymized) data could be tagged with symptoms (e.g. cough, sneeze) could we track the spread of infections? Public health would then start to look a lot more like intensive care medicine, providing real-time monitoring of cities or nations (taking the "pulse" of the population, evaluating the activity and coherence of its "neural" activity). Will there be a new research and medical discipline that fuses the sciences of population ecology and population health? And should populations be empowered to forego such intensive study?

(Hat tip: Joshua Parker).

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Ville Vivante from Interactive Things on Vimeo.

p.s. As a someone who grew up in Geneva, I was quite surprised to see a lot of activity at 2 AM. Is this the consequence of the Swiss work ethic?

Get paid to play

Earlier, I described the SHRINE distributed query system across 6 million patients with 10 billion facts. If you are a member of the Harvard Medical School faculty (with employment at one of the affiliated hospitals) you now have the opportunity to get money and glory (more the latter than the former) to spin clinical data into biomedical gold. Details on the context can be found here: http://catalyst.harvard.edu/services/pilotfunding/shrine.html

If you have questions, use this email contact.

This terminology goes one louder.

There has been considerable controversy about the merit and risk of upgrading the terminology that is used in the USA to bill for most healthcare transactions: ICD9 to ICD10. However, given some of the concerns about the adequacy of ICD10, many are now advocating that we skip ICD10 (with costs of millions of dollars per large hospital and tens of billions of dollars, nationwide) and immediately proceed "one louder" to ICD11. It is argued that the investment will then be far more durable and with a more favorable impact on cost and quality accounting in healthcare. Others argue that we should go for the bird in the hand. No doubt many librarians could opine knowledgeably about the costs and benefits of changing classification systems and Linnaeus would be impressed by how many now labor to classify diseases, drugs and procedures.

Hat tip: Ken Mandl

Research by the numbers

What if you could mine the 10 billion medical facts across 6 million (anonymous) patients in five Harvard affiliated hospitals to ask an important and timely question? What are the other diseases or disorders associated with autism? How has the pharmacological treatment of inflammatory diseases changed over the last five years? Are there gender differences in prevalence of the infections in autoimmune diseases? How is the prevalence of diabetes mellitus changing in young adults?

Now, for the first time, if you are an eligible faculty member (or one of their fellows) in one of the five hospitals, you can now productively seek answers to these questions. The Shared Health Research Information Network (SHRINE) helps researchers overcome one of the greatest problems in population-based research: Compiling large groups of well-characterized patients. Eligible investigators may use the SHRINE web-based query tool to determine the aggregate total number of patients at participating hospitals who meet a given set of inclusion and exclusion criteria. The criteria are currently demographics, diagnoses, medications, and selected laboratory values. Because counts are aggregate, patient privacy is protected.

So, whether you are seeking a study cohort, preliminary studies for a grant proposal, or evaluating an epidemiological hypothesis, take this new tool for a spin and start translating this large mass of hard-won data into useful biomedical knowledge.

Origin of The Theses

For those of you in the throes of defining your doctoral theses, there are some wise words from Enrico Coeira from UNSW which can help you move to the end game. Here is the relevant Twitter stream.

Library Spring?

A wonderfully clear accounting of the growing movement to boycott the publisher Elsevier can be found here.

Let's bring genome-scale sequencing into the clinic—safely and responsibly

Children's Hospital Boston today announced the launch of the CLARITY Challenge, a $25,000 competition intended to advance standards for genomic analysis and interpretation and the reporting of clear, actionable results to clinicians and patients. The competition marks the first time a healthcare institution has sent out a broad call for the development of consistent and clear ways of applying genomic insights to everyday pediatric and adult patient care.

CLARITY (Children’s Leadership Award for the Reliable Interpretation and appropriate Transmission of Your genomic information) competitors will be tasked with discovering the unknown genetic basis of the disorders faced by three pediatric patients and, in the process, create best practices for interpreting and presenting genomic sequence results to patients and their families and physicians in meaningful ways that can help guide healthcare decisions.

Ancestral betrayal

We share many things with our ancestors, including a fraction of their genetic code. This genetic link to the past has further invigorated an already large industry and hobby in the exploration of genealogy and historical provenance. This piece from today's news, shows how these same records can be used to leverage your ancestors to identify you. In this instance, a murder suspect is potentially fingered by his ancestors from the Mayflower.

Hat tip: Ben Reis

Costly questions

Mark Twain once said "Only one thing is impossible for God: To find any sense in any copyright law on the planet."

I was reminded of this upon reading this brief but highly illuminating article describing the delayed but then aggressively pursued commercialization of a widely taught and adopted mental health questionnaire. A newer, perhaps even superior (but free and public domain) questionnaire with a few overlapping questions has been "de-rezzed" after a copyright dispute with the vendor of the earlier questionnaire.

The right questions may help disrupt the progress of disease, but not as effectively as a well-timed exercise of copyright on questions can disrupt progress (with apologies to Mark Twain).

Hat tip: Atul Butte

Crystallizing Methods for Drug Effects

Yet another powerful example of the novel syntheses in which the aggregation of individual knowledge sources becomes a lot more than the sum of its parts: Using only the most well accepted and conventional of compedia of drug characteristics, Cami et al. demonstrate the power of integrative reasoning and systematic applications of "guilt-by-association" to predict accurately, across an interval of 5 years, hundreds of novel adverse events across more than 800 drugs. This performance is likely to improve further as they proceed to integrate healthcare data from electronic health records from consumers. The addition of molecular characterizations are also anticipated to provide further precision and individualization of these predictions.

These developments will be further accelerated if we can liberate data gathered with public funding for the public good.

Alternative Senior Rounds 2011

Let us re-imagine senior rounds for the 21st century.

What I am about to describe does not require any new technologies or biomedical insights; it requires merely a different use of existing resources, different emphases in training and a national focus on the real-time use of clinical data as the evidentiary basis for clinical decision-making.

Senior rounds, in which the department chair meets with the senior residents to review the cases and processes of the prior day, are a decades-old tradition in medicine, and a valuable one. But as currently practiced in most residency programs, each senior resident reporting from their written notes or electronic health record system, the rounds fall far short of what they could be. Here, I offer an “alternative reality” for senior rounds, in hopes of catalyzing a discussion about why it is not the standard of care today. As the citations attest, the findings and techniques described here are all already available. So what are the principal obstacles then to the realization of this scenario?

Soma looked around the table, picking out the Seniors whom he would ask to give reports. He glanced at the screen to the side of the conference table listing the admissions and discharges of the prior day, wait times in the emergency department, diagnoses, and laboratory work ups.

He turned to Charles. “I see you admitted a 2-month-old for ‘rule-out’ meningitis but those laboratory results don’t look particularly worrisome.” Charles nodded but directed his tablet to throw up a local map with 5 red “X”s on the room’s screen¹.

“I thought so too,” Charles said, “but the intern pointed out to me the 5 cases of N. meningitis detected in the last week by the State Department of Public Health, including one case in the same day-care center as this infant, so we thought it was prudent. We’re going to wait for culture results.” ²

Soma grunted non-committedly and moved on to Dolores: “I heard you had a little argument with the diabetes service over the discharge of Mr. Smith. Care to share what happened?”

Dolores gave him a quizzical look for this ‘softball.’ “Yes, they were quite emphatic about switching Mr. Smith to a different oral hypoglycemic agent. I argued that its safety profile was far from as well established as the generics in the same structural drug class, and shared several publications with them that made the same point. But it’s only when I showed them that the risk for myocardial infarction, over the last four years, at our hospital was 50% higher for that drug as compared to others that they relented,” ³.

Soma looked at the curve of the myocardial infarction incidence of the drug in question, portrayed in red, and the six green lines showing the myocardial infarction incidence in the same hospital for the other oral hypoglycemic agents. The red curve rose above the green curves, well beyond the reach of their error bars.

He surveyed the seniors and returned to Dolores with a conspiratorial raised eyebrow. “You might want to share with the diabetes service that the FDA just reviewed these data and 20 data sets like it from other academic health centers. They all pointed in the same direction, and when they then reviewed the post-marketing data from the pharmaceutical company manufacturing the drug, the same trend was apparent. Chalk one up for evidence-based medicine. Speaking of which, Harvey, Mrs. Jones’ s headache ended up looking like a glioma on imaging. What are you telling her and her primary care provider about prognosis?”

Harvey directed the screen to replace the map with three graphs. “We’re scheduling the biopsy but it does look like Glioblastoma Multiforme (GBM), less than 2 cm in its largest dimension. The graph on the right shows the outcomes obtained at this hospital over the last 15 years for patients presenting with headaches not attributable to mass effect, like Mrs. Jones. The graph in the middle shows the other patients with GBM at this hospital without this ‘incidental’ presentation. The graph on the right suggests a better outcome but this might be due to the location of these incidental tumors. ⁴Regardless, it’s a tough prognosis but I shared this perspective with Mrs. Jones and her doctor. By the way, for reference you can see the national outcomes on the leftmost graph and you can see that ours are on average about 20% better as measured by survival times.”

Soma shared the slightest of winks and gestured towards Virginia.

“What about the infant you had discharged from the newborn service a week ago? I see that she was readmitted last night.” Virginia, looked up from the muffin that she had been steadily deconstructing, “Yes, that was unfortunate but not completely unexpected. We had not found any cause for the earlier episode of ventricular tachycardia in the first day of life. Because the tachycardia resolved spontaneously within 20 minutes, we decided to observe for another 72 hours. As there was no recurrence and no structural anomalies of the heart on imaging, we discharged the infant with a follow-up appointment with cardiology for a month from now. The ventricular tachycardia event did trigger an automatic rule from our electronic health record system (EHR) ^5,6 which recommended a genetic screen for mutations in the depolarizing sodium and/or calcium channels. We checked the genotyping results on readmission and they are positive for a mutation in a calcium channel—CaCNB2b⁷—that was found in over one hundred children with ventricular tachycardia as per the National Registry and in no control cases. And by the way, as per our EHR data warehouse this is the fifth case in the last decade in our hospital alone. Although we were able to convert the infant back to sinus rhythm within 10 minutes, the cardiology service is considering use of an implantable cardioverter-defibrillator because of the chanelopathy.”

Soma interjected “Wasn’t the QRS interval abnormal after the first episode?” Virginia flicked the ECG from the EHR view on her tablet to the conference room screen. “No, as you can see, it was not, and there are several similar reports from the literature.” She followed by displaying several PubMed abstracts describing cases of normal ECG in infants with a chanelopathy.

Soma, turned towards the Chief Resident, “Mary Lee, are we going to have enough beds to keep up with all the activity in the ED?”

This question was asked so often that Mary Lee had already displayed the current bed census, as well as the projected lengths of stay based on several morbidity indices and predictors, on the conference room’s screen. “We’re in good shape. Worst case scenario still gives us 32 free beds by noon today^8,9. Even with seasonal adjustment for influenza ¹⁰ we have at least 8 free beds including 2 in the ICU by the time the evening shift ends. That’s within the 95% confidence interval.”

Charles was glancing repeatedly at the smartphone he kept mostly hidden under the conference table.

“Is there a problem?” Soma asked, girding himself to deliver his well-worn diatribe on the distractions of modern communications.

Charles, stood up, pointing at the smartphone “Actually, there is. The ventilation requirements for one of the preemies is trending higher and the attending pediatrician is suggesting a caffeine infusion but I don’t think it is warranted based on the data. I had better go and check in with the team to see if they are on top of it.” ¹¹

Soma leaned back with a smile. “I should warn you against ‘dismissing long-established clinical opinions without understanding the basis for their existence’¹². But go ahead, rounds are over.”

(Thanks to Carey Goldberg for very constructive comments)

1.         Brownstein JS, Freifeld CC, Madoff LC. Digital disease detection--harnessing the Web for public health surveillance. N Engl J Med 2009;360:2153-5, 7.

2.         Fine AM, Nizet V, Mandl KD. Improved diagnostic accuracy of group a streptococcal pharyngitis with use of real-time biosurveillance. Annals of internal medicine 2011;155:345-52.

3.         Brownstein JS, Murphy SN, Goldfine AB, et al. Rapid identification of myocardial infarction risk associated with diabetes medications using electronic medical records. Diabetes Care 2010;33:526-31.

4.         Potts MB, Smith JS, Molinaro AM, Berger MS. Natural history and surgical management of incidentally discovered low-grade gliomas. J Neurosurg 2011.

5.         Ullman-Cullere MH, Mathew JP. Emerging landscape of genomics in the Electronic Health Record for personalized medicine. Human mutation 2011;32:512-6.

6.         Overby CL, Tarczy-Hornoch P, Hoath JI, Kalet IJ, Veenstra DL. Feasibility of incorporating genomic knowledge into electronic medical records for pharmacogenomic clinical decision support. BMC bioinformatics 2010;11 Suppl 9:S10.

7.         Kanter RJ, Pfeiffer R, Hu D, Barajas-Martinez H, Carboni MP, Antzelevitch C. Brugada-Like Syndrome in Infancy Presenting with Rapid Ventricular Tachycardia and Intraventricular Conduction Delay. In: Circulation; 2011.

8.         Mackay M, Lee M. Choice of models for the analysis and forecasting of hospital beds. Health Care Manag Sci 2005;8:221-30.

9.         Littig SJ, Isken MW. Short term hospital occupancy prediction. Health Care Manag Sci 2007;10:47-66.

10.       Reis BY, Pagano M, Mandl KD. Using temporal context to improve biosurveillance. Proceedings of the National Academy of Sciences of the United States of America 2003;100:1961-5.

11.       Larkin H. mHealth. Hosp Health Netw 2011;85:22-6, 2.

12.       Weiss S, Hatcher RA. Tincture of digitalis and the infusion of therapeutics. JAMA 1921;76:508-13.

Publisher bypass

This piece from the WSJ ("How I Became a Best-Selling Author: Self-publishing is upending the book industry. One woman's unlikely road to a hit novel.") points to a model that academia (except the physics and a few other quantitative science communities) has been slow to embrace. Who will serve the role of Amazon.com to disrupt the current, expensive model? Will it be the open access journals? The current large science publishers? Or a new platform? Or Amazon.com?

Hat tip: Victor Zak

Insignificant significance

An amusing look at correlation. Less amusing when you realize that this kind of analysis is often used to drive public debate. Hat tip: Carey Goldberg