Wednesday, June 15, 2016

Uncertain Health in an Insecure World – 85

“Auspicious Beginnings“

In Ancient Rome, priests called augurs studied the flight and feeding patterns of birds to prophesize the future. The word auspicious is derived from Latin, auspex, meaning “bird seeker.” The plural, auspices, is often used to refer to “kindly patronage and guidance.”

Precision medicine (PM) enjoyed an auspicious beginning.

In an April 24, 2015 TEDxSantaClara talk, “Collaboration is the New Competition,” David Haussler (University of California Santa Cruz Genomics Institute director, above) describes how he guided Jim Kent (below), then a UCSCgrad student, to write “killer” computer code to sequence of the first human genome. In June 2000, Kent used a cluster of one hundred work stations, each no more powerful than a modern cell phone, to crack The Human Genome.

Their research was prescient – an example of radical collaboration.

Celera, founded by Craig Venter, quickly scaled up commercial genome sequencing. Celera is now a subsidiary of business giant, Quest Diagnostics.


Next generation sequencing (NGS) transformed genomic analyses.

Successful genome alignment and variant calling takes intense computing efforts. Single nucleotide polymorphism (SNP) and insertion and deletion (indel) mutation variant calling methods identify genome positions with polymorphisms relative to a reference file. Variant calling yields insights into nucleoside-level organismal differences between human and microbial genomes. But variant calling is a multistep bioinformatics process with a number of potential sources of error.

Converting millions of gene sequencing reads per sample into meaningful data is hardly trivial.

A conscious human brain can fire 38 thousand trillion synaptic messages per second!

The world’s most powerful supercomputer, IBM’s BlueGene, can manage about 0.002% of that. But human beings have come to rely on supercomputers to make sense of the world. In November 2015, Intel placed its fastest 8-teraflop (8x1012 floating-point operations per second) Knight’s Landing silicon chip into desktop PC’s. Soon, handheld devices will put supercomputer performance into the palms of teenagers.

In 2011, it took supercomputers approximately 10 days to sequence a human genome. Since then, bioinformatics experts have been tackling how to shift from local site computing power to Cloud data sharing. In 2013, many institutional and national data repositories like the U.S. Veterans Administration Million Veteran Program (below, left) contained such numerous genomes that would take one institution months to sequence them. 

The cost per genome being sequenced (above, right) began to dramatically drop in 2008, paradoxically increasing the number of institutional genome data silos. Contemporaneously, the clinical care of children with genetic diseases included more genomic data embedded in electronic health records (EHR). Exomes are now sequenced clinically to determine the metabolic fate of certain drugs, such as expensive Elelyso™ enzyme replacement therapy for children with Gaucher’s Disease.


Bioinformatics is facing down the data sharing bottleneck.

In the research funnel (below), one’s proximity to a bottleneck determines how one approaches the problem. 

In 2015, Stanford bioinformatics researchers began "nitty gritty" work with Google to query the NIH database of Genotypes and Phenotypes (dbGaP) in the Cloud with BigQuery™, dramatically reducing the time required to do a single data query for 30 million annotated variants to mere seconds (below). 

With this advance, by applying Dremel technology (Apache Drill™, below), the era of open source genomic data mining began.

The recent convergence of open source Cloud computing and gene sequencing scalability set the stage for the February 2016 Obama Administration’s Precision Medicine Initiative.


The last bottleneck is personal health information (PHI) privacy.

The press is full of shocking privacy breech stories involving healthcare insurance databases and EHR’s. Data sharing security concerns related to PHI privacy have resulted in increased regulatory hurdles, reducing data access and preventing research collaborations that could lead to real PM progress. 

In the end, the type of privacy required in the PM data sharing milieu boils down to math. At the 2006 Proceedings of the Association of Computing Machinery on Privacy, Stanford’s Philippe Golle showed that with an individual’s birth date and 5-digit zip code, there is a 63.3% probability that a U.S. person’s identity can be determined without any requirement for gender being known.

According to Stanford’s Somalee Datta (below... and yes… it auto-corrects to 'Data'), points-of-view on data privacy differ for patients (“My Health”), companies (“My Business”) and researchers (“My Research”).

Patients want better healthcare for their children, themselves, their extended families and community, and may be willing to accept the unknown risk and longer term implications of genomic data loss.

Businesses seek the value proposition associated with better healthcare for patients, but risk large scale hacking, malicious ransomware, bad press and loss of consumer trust.

Researchers’ end game is effective data use for new discoveries that improve health, and they are willing to tolerate complex data use agreements and/or negotiated service agreements for data access.

In order for bioinformatics to relieve this last bottleneck – timely data sharing with secure privacy protection – patients need transparency regarding the use of their data (informed consent), businesses require secure platforms that allow granular monitoring of data activity (like financial systems currently utilize), and researchers want workflow oriented bioinformatics suites that allow for flexible research plans (open access). 


PM sits squarely at the interface between genomics big data and immense computing power.

 How thinking humans grapple with this complex interface will define the usefulness of genomics data to the future practice of PM.

If PM’s future is to augur well, bioinformaticians must get more patients’ big data into the hands of more genomics researchers who work on more powerful open-source analytic platforms.

The precogs in the Square clearly see how the “kindly patronage and guidance” of patients, businesses and researchers produced PM's auspicious beginning.

But we worry that PM could crash to Earth if regulators fail to properly read the chicken entrails.  

Wednesday, June 1, 2016

Uncertain Health in an Insecure World – 84

“Science and Faithlessness”

In the Showtime series Penny Dreadful, madness finds the heroine Vanessa Ives (played by Eva Green) in a padded cell awaiting a lobotomy. In the episode titled A Blade of Grass, Miss Ives is seduced by Dracula in the guise of an orderly. When Dracula’s twin, Lucifer, also enters the cell, they both vie for her eternal soul.

Dracula, the lesser of two evils, baits Lucifer… “If they cease to believe in you, do you even exist? They won’t believe forever, brother. We live in a mighty age of science and faithlessness. You’re fading into insignificance, even as I look at you.

We are incessantly courted by changelings in the guise of policy, science and technology. Do we need to pause and reflect upon the rapid pace of progress, before humanity fades into insignificance... Or even fails to exist?

CHANGE is so seductive...

Loss of faith in The System by the global masses has prompted the rise of movements, upending party lines and loyalties. As the U.S. careens towards another “hope presidency”, many Hillary Clinton liberals find themselves uncomfortably to the right of Bernie Sanders progressives. His Feel the Bern movement has exerted a gravitational pull on her coolly calculated campaign, shifting the Democratic Party away from the comfortable center that manufactured the first Clinton presidency. And on the Republican right, billionaire Donald Trump’s brilliant decision to tap into the root of economically disaffected voters, while boasting the return of American greatness, has forced socially conservative demagogues to look the other way – just as they did for Ronald Reagan in The Eighties.

What are the societal consequences of such neo-political movements?

As noted by Thomas Frank (above) in his new book, Listen Liberal, if the U.S. body politic (The Establishment) does not view this as the right time to take its own racing pulse, then American democracy will surely suffer a fatal arrhythmia.

We have addressed the promise and practical challenges of precision medicine (PM). Recognizing that F.D.A. approved treatment regimens (largely based on randomized clinical trials) subsequently fail in a high percentage of individual patients, and that one’s personal genetic predisposition to disease and treatment response is highly varied within the herd, science has recently made great strides towards the creation of individually gene mutation-tailored treatments for disease subsets within an illness (i.e. oncogenes for blood cancers). As a result, precise immuno-therapies are quickly replacing toxic chemotherapies.

But even global PM mavens like Dr. Thomas Wilckens realize that the new
U.S. Precision Medicine Initiative is not a panacea for complex multi-gene mutation chronic illnesses.

Upon reflection, not only has the last 40 years seen medical practice move from generalists (i.e., internists) to sub-specialists (often with procedural/surgical skills), but the care of certain diseases can now only be guided by a team of precisionists. These physician-scientists can tease out the unique genetic characteristics that lead singular patients to a remission or cure.

We have discussed the disintermediation of physicians in patient care by healthcare insurance bureaucracies and electronic medical record burdens. But perhaps the greater threat to modern medicine is the loss of personalized care by generalists – care quarterbacks who can knowledgeably direct a comprehensive medical home model in a longitudinal fashion, with a fundamental understanding of the interplay between the concurrent chronic diseases and potent drug interactions.

One technology that is quick-stepping into the mix is genome editing.

We have reviewed how Clustered Regularly Interspaced Short Palindromic Repeats associated protein-9 nuclease (CRISPR Cas9) has effectively replaced gene recombination techniques, zinc-finger nucleases (ZNF’s) and RNA interference (RNAi) for gene editing. CRISPR is less costly and far more scale-able. The silencing of a solo gene using the type II CRISPR system approach can create targeted gene alterations in both somatic and gene cells. This technique may prove useful in sickle cell disease, where the mutated red blood cell hemoglobin gene could be selectively edited back to a healthy state, without the controversial effects on patients’ germ cell DNA.

The Possible – CRISPR genetic engineering of germ cells – should be deliberately ethically scrutinized for its potential future adverse impact on society.

Do you ever stop to wonder how much of your own personal data is housed in the world’s exploding acreage of server farms (The Cloud)?

Data mining companies have been proliferating. Reddit and Lifehacker (among others) publish lists of the top companies that mine and sell our personal data. movements offer pathways to opt-out links that block data brokers like Acxiom, Intelius, Dex Media, Arcadia, xG (Geisinger Health), Watson Health (IBM), Aetna, OptumLabs, etc.

The need for us to thoughtfully consider ownership of our little data was emphasized in a recent court ruling against Myriad Genetics, a Salt Lake City gene testing company that was sued by the American Civil Liberties Union (ACLU) on behalf of four people in the growing movement of those who want all of their genetic information. Typically, Myriad only shares pathogenic gene variants such as BRCA-1 & -2 with patient-clients. On behalf of the complainants, the ACLU’s argued that we are legally entitled [per January 2016 HHS Office for Civil Rights (OCR) regulations and by U.S. federal HIPAA laws] to both our known cancer-predisposing genes and (currently) benign polymorphisms. The Global Alliance for Genomics and Health filed an amicus brief in the case because, unlike other gene testing companies, Myriad has declined to contribute its voluminous big data to an international gene science-sharing network called ClinVar, or to the Harvard-based BRCA Challenge.

Under such careful scrutiny, the regs and the law appear to support the movement’s contention that, “It’s my body, my blood, my data, my choice how I wish to share my information.”

CHANGE is so seductive...

"We live in a mighty age of science and faithlessness"

Like Dracula and Lucifer, science and politics place threatening expectations on innocents.

Perhaps dialing change back just a little today would make for a better future.

We in the Square still believe... and retain a guarded faith in The System.

And like Miss Ives, we have not been lobotomized… YET.