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

Time to protect lawful sharing of information on the Internet.

This post: http://www.mozilla.org/sopa/ is a timely reminder of the risk to untrammeled sharing of communications (including those that are scholarly) that a blunt and overstepping use of the law is likely to pose. Unless we act now.

Hat tip: Ben Adida.

Genesis of citations

I was just reminded of an excellent review of the various forms of transmission of authoritativeness and outright falsehoods through citations by Steve Greenberg when I saw this all too accurate portrayal of citogenesis.

Conflicts of interest and the need for expertise.

Ben Adida reflects here on Lessig and makes an interesting point about what might be lost if we do not listen to experts (in vaccine efficacy in this instance) even if they are in conflict of interest.

You are not the boss of me!

This assertion, made by millions of children with respect to their siblings, has its echos in many contemporary conversations about scholarship and authoritativeness. Whether it is the dominance of genetic or environmental effects in child development, or the value of a prostate specific antigen test, or the meaning of a genetic mutation, one group's truth is another's discredited hypothesis or outdated approximation. Of course, there some facts whose authoritativeness are beyond doubt, such as the speed of light. Well, maybe. Certainly, until that eschatological moment when we will all know the absolute truth, those of us who are entrusted with the curation and dissemination of knowledge, in its various guises, will have to provide tools to manage the growing multiplicity of perspectives.

In that spirit, I have unearthed a piece I wrote with Russ Altman over a decade ago about authoritativeness in the peer review process and how it could be managed ecumenically. We'll see if our futurology was authoritative.

Faster, cheaper and in control

Let's say you have a problem (e.g aligning the world's literature to defining the phylogenesis of the components of the current world-wide written corpus for scholarly attribution and automatic detection of plagiarism) that requires a computational solution. But it's taking days for the software to run. Buying a faster, bigger computer might provide some speed up, but what if you could get a 1000 fold improvement through a better implementation of the algorithm at the core of your software? Here's your chance to see if it can be done through a contest hosted by the Harvard Catalyst. Will the Overmind answer your most difficult computational questions?

Out in the Open

This impressive compilation from GOOD (the data issue) documents the impressive growth of Application Programming Interfaces that provide third party software developers with access to, and the ability to repurpose, large and very useful data sets. This growth is driven both by altruism and self-interest and represents a dramatic refutation of the skepticism towards the open data movement of merely a decade ago.

Hat tip David Kreda

Take two aspirin and an algorithm and call me in the morning.

This note from the American Medical Association nicely summarizes the recent approval of certification in Clinical Informatics by the American Board of Medical Specialties. It represent the closest encounter between clinical training and librarianship to date. We'll see what it portends for relative compensation.

Augmenting library reality

Much has been written about the importance (or lack of it ) of happenstance in browsing through books on shelves and what we have lost with web-borne search. Thanks to Juliane Schneider, we are exploring how to augment the moment of serendipity using QR codes that students armed with a common "smart phone" can scan and thereby scoop up more information at a glance. Check out our 3rd floor for these codes printed on cards inserted in shelves. Paper chase now has web hints.

Weighty searches

Billions of Google searches may seem to be evanescent, ephemeral, electronic abstractions but this article suggests that they leave a weighty, grimy residue. The company’s electrical consumption (mostly the data centers) is said to create a carbon footprint of one million five hundred thousand tons in a single year. That is possibly much less than the footprint left by the car/bus trips and phone calls that have been made unnecessary by web searches. But it does suggest that search engines that will be better (i.e provide the sought for answer in fewer searches) will also be greener, even without more efficient computational hardware.

Serious secret keeping

This instance of the xkcd comic strip explains much of what is wrong with our current password systems and why, for example, the passwords protecting clinical information systems are hard to remember and easy to crack. Hat tip: Sam Volchenboum

The unbearable effectiveness of data

Researchers in artificial intelligence (AI) of the 1980’s, librarians and aficionados of the Semantic Web have a shared faith: The unique value of human-designed knowledge structures whether they be taxonomies, ontologies or metadata. These knowledge representations are seen as providing important leverage in information retrieval, knowledge discovery, and decision-support. In this context, I was recently reminded by Alal Eran of an article by researchers at Google about the value of BIG data. These researchers (one of whom wrote a wonderful book on Common Lisp—Paradigms of Artificial Intelligence Programming: Case Studies in Common Lisp—widely appreciated by the AI community, which includes applications for expert systems) describe how statistical methods applied to trillion-word corpora can automatically support the aforementioned information tasks without requiring human annotation/categorization. It may be that the combination of human-derived annotations (whether crowd-sourced from the web or carefully curated in the monasteries of the ivory tower) can be used synergistically with the purely statistic-learning methods, but that has yet to be convincingly demonstrated. Until then, those of us working on genomic research will see how far we can get just with data, particularly those obtained in the course of healthcare.

For those of us in libraries and those of us who are librarians, there is now an active debate that has yet to achieve resolution on what value there is in human annotations and metadata. If there is value, at what cost? And if it is cost-effective, how do we demonstrate the efficacy? Our Universities' leaders will be interested in the answers and so will our colleagues at Google.

Bibliography of Clinical Genomics

Recently, we held a summit on the topic of clinical grade reporting of full genomic sequence. Given the growth in the number of papers (likely to grow hyperexponentially in the near future) David Osterbur has followed up with a very nice bibliographic guide to this emerging literature. Feel free to contact him if you would like other such articles added to the guide.

Libraries are going to the dogs

Yale Law School has gone for the full monty, so if your medicolegal liability is getting you down, we are pleased to present Cooper as a prescribed cure. Please observe the maximum dose of 30 minutes.

Many happy returns

This twitter feed of returns of items borrowed from the Countway Library provides a glimpse of the vibrant engagement of our community with the scholarship of the present and past. These include The Anatomy of madness : essays in the history of psychiatry, Calories don't count by Herman Taller, Tachycardias--mechanisms, diagnosis, treatment, and Observed brain dynamics by Partha Mitra. One could presume that these were not all borrowed by the same patron, but if they were, what questions were they asking?

Stuffed full of information

That bird rendered by taxidermy in a museum is not only of visual interest. This report by an enterprising undergraduate points to some unexpected public health insights gleaned from the feathers of these museum specimens about the trajectory over centuries of mercury contamination in seabirds. Perhaps needless to say, this could not be done with a purely virtual collection.

Master of your information domain

A nice appreciation for National Librarian Week can be found here.

Hat tip: Daniel Masys

Deadly Medicine

We are hosting a sobering exhibit about what happens when medical science loses its moral compass. More details can be found here.

Write the Future

A very creative approach to impactful scholarship. Worth the try even if if fails.

Hat tip: Christopher Erdmann

Let the games begin!

Do you think that you can create the new software app that will revolutionize healthcare? Do you agree that substitutability will allow us all to innovate healthcare practice? As detailed on the challenge.gov website, there is now a very short term opportunity to "walk the talk" for a modest prize and immodest glory.

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Neat or scruffy?

Is your desk topped by the monumental accreta of your work or does it retain it's pure sheen of Scandinavian simplicity? It turns out that the dichotomy between the "Neats" and the "Scruffies" cuts across several broad swathes of the human condition. Among these are the archane arts of taxonomization and representation so well known to librarians, botanists, and engineers working on electronic health record interoperability. On the latter topic, the President's Council of Advisors on Science and Technology, (PCAST) report has issued a report on how health information technology will or will not be effectively used to improve healthcare. Given the work we are pursuing on substitutability, our own Ben Adida shared a perspective on the report.

Hall or House of Mirrors? The citation perspective.

Kudos to the analysts at SCImago. They have provided an outstanding, entertaining and educational perspective on worldwide academic publishing. I'll focus here on only one aspect: citations. Although the United States is the leader in citations at 87M citations, it is a surprising laggard in self-citation (32% citations are self-citations). The leaders are China (62%), Lithuania (38%), and Iran (37%). However, in the domain of medicine, authors in the United States are considerably less reticent and rack up a self-citation rate of 47%, earning them second place. The map below of the subject areas of the USA publications indicates where the action is.

Hat tip: Peter Park

We, the librarians

As Harvard University reorganizes its extensive library system, it is worth reconsidering where library activity occurs and who drives it. This effort in Finland (hat tip David Osterbur) is a reminder that although professionally trained librarians with a mission and institutional memory are central to the curation, preservation and dissemination of scholarly materials, there is no sharp demarcation as to where expertise, time and effort can be found in our collective efforts. If individual scholars do not curate their own, increasingly electronic, notes, their messages, and other residua of the scholarly process, there will be very little for institutional librarians to work wit and a gaping hole in the scholarly record. But first, academic institutions will have to provide them with a easy to use process that can last their entire careers. This is a first class opportunity for entrepreneurial, techno-librarians who can think at the scale of the Internet. Conversely, libraries must reach out the to network of distributed expertise in all areas of academic endeavors which is populated by experts often well outside the walls of organized academe. Literally tens of thousands of precious modern and ancient scholarly archives remain in the dark, queued up, waiting for an overworked archivist to provide even the most cursory cataloguing. Shotgun mass annotation, leveraging external expertise will have to become the norm and, again, there is a large opportunity for those who are able to provide such capabilities at scale and with the appropriate legal and institutional framework.

Graduation in Five Years

from a doctoral program in the life sciences is a reasonable goal, under most circumstances. For some unfortunates, it is not. Prospective students should make sure that they have the key bits of information required to decide if and where to proceed with a specific graduate program. If you are already in graduate school at Harvard University, you might want to consult with some of the faculty who are knowledgeable mentors.