Sunday, April 26, 2015

Uncertain Health in an Insecure World - 36

"That Other Sex Organ"

Let’s look at that other sex organ… The Brain.

Because only men have the Y-chromosome, and because that Y-chromosome is present in every male brain cell on Earth, it could be fairly stated that the male brain differs from the female brain.

In fact, the 50-60 sex-specific genes that uniquely exist on the Y-chromosome add genetic proof to the concept that men’s brains are different from women’s.

Sex bases for and biases causing health gender disparities are both obvious, and controversial.

Obviously, Y-chromosomal genes don’t make men’s brains better… just different from those of women. The proteins and neurotransmitters coded for by these brain genes may contribute to different neurocognitive genetic traits between females and males, such as recognized gender advantages in languages & memory for women and spatial discrimination for men.

While controversial, many environmentalists, epi-geneticists and neuroscientists believe that in utero toxin exposure and birth prematurity stress accentuates future neurocognitive deficits, also possibly contributing to disease differences between the sexes.

A 2013 PNAS report described the mapping of neural circuit connectivity in the brain scans of nearly one thousand 8-22 year olds. These so-called connectomes have produced insights into brain wiring that may explain gender-based neurocognitive and developmental differences. Boys and girls had similar connectomes up to age 13, with differences appearing between ages 14-17. While right-left hemisphere connections were more developed in young women (above), the right-left connections in the balance center cerebellum were more developed in young men. In general, frontal-occipital connections were also better developed in male brains (below).

Such wiring differences could partially account for gender differences in the biological susceptibility to and age-of-onset of chronic disorders like schizophrenia and depression.

Since 2002, the World Health Organization (WHO) has recognized and actively addressed the obvious health vulnerabilities of women around the globe, with a clear emphasis on socio-economic-cultural disadvantages and the adverse aftermaths of forced migrations & natural disasters.

Highly adverse life circumstances can overwhelm sex-based genetically predisposed brain biology.

Low maternal socio-economic status (SES) and childhood poverty, which affects 47 million children worldwide according to the Organisation for Economic Cooperation & Development (OECD), adversely impacts brain structure & functional organization and early cognitive development.

The culturally-imposed practice of circumcision affecting 125 million women & girls living in 29 African, Middle Eastern and Indonesian countries (and per NHS, 66,000 UK residents!) is called female genital mutilation (FGM). The WHO has considered this as extreme gender discrimination and a violation of the human rights since 2008. Resulting reproductive problems and psychological disorders can be debilitating and long-lasting.

Ironically, the WHO Health 2020 campaign in Europe has decidedly not focused on studying controversial sex-specific health differences.

Why is that?

Perhaps because the daunting realities of developing policies and financing practices to address the root causes of such globally pervasive gender-based health disparities & crises makes securing airplane cockpits from male pilots with suicide on their minds or from male passengers with terrorism in their brains seem simple and cheap by comparison.

One final piece of the sex-brain puzzle remains for our future consideration. 

Scholars at the University of California report REM deep sleep changes in genital blood flow during erotic dreams. Scientists from the Universite de Montreal report that 8% of our dreams are erotic, and that 4% result in spontaneous orgasms. While the biology of a brain-triggered orgasm is interesting, the teleology of reported differences in the experience between men and women is fascinating.

  The newest Diagnostic and Statistical Manual of Mental Disorders (DSM-5, 2013) includes a medical disorder of women who experience repeated hands-free orgasms known as persistent genital arousal disorder (PGAD). Ironically, this uncontrollable female genital arousal can be unpleasurable, and may rarely lead to depression and suicidal behavior. Not to be left out, a male case of PGAD causing 100 orgasms per day was reported in 2014.

Calling this a disorder in women smacks of sexism, either way you might choose to take it.

But the fact is that our sex genes control our brains, and our brains control our behaviors. When our insecure world affects brain wiring, or when abusive cultural beliefs make women's health uncertain, the relationship of gender to sex... of biology to behavior... becomes blurred.

We in the Square admit that it's sexier to sequence a Y-chromosome in a lab and to dangle the allure of precision medicine than it is to address complex gender-based health disparities in the real world.

Mea culpa... It hurts our brains.

Monday, April 20, 2015

Uncertain Health in an Insecure World – 35

“Y-Chromosome Adam… Meet Mitochondrial Eve”                         

All males have a ZFY locus on their Y-chromosome that is made up of 729 identical base pairs. To scientists, this sameness suggests that all men alive today are descended from a single man… Let’s call him Adam. And because the Y-chromosome is passed directly from fathers to sons, genealogists are able to trace male ancestry back to the evolutionary beginning of humankind.

On the other hand, mitochondrial DNA is passed down from mothers to both daughters and sons. As originally described in a 1987 Nature paper, mitochondria DNA is simpler, comprising some 37 genes as compared to nuclear DNA which contains >70,000 genes. Because mitochondrial DNA is conserved across generations but (almost) never comes from the father, scientists believe that every living person has the same ancestral mother – Let’s call her Eve.

Fascinating stuff!

But what does this mean to developed world buffs seeks their genetic roots using DNA assays?

While our common >200,000 year remote Old Earth ancestors may have lived in east Africa without producing progeny, Adam and Eve were the first to pass their DNA on to children who became Young Earth humanoids. This longer Y-chromosomal DNA lineage may explain why modern male descendants of Adam wait longer for their haplotype DNA roots than do female descendants of Eve.
Unlike geographic mapping, geneography is not this simple.

Over nearly three decades since, the uniformity of the maternal mitochondrial Eve story, as attractive as it was then, has been scientifically assailed and eventually disproven to some persons’ thinking.  Mitochondrial DNA mutations and recombinations are now known to exist, and paternal passage is possible.

In addition, DNA testing introduced by Google-backed 23andMe in 2007 came under extreme regulatory scrutiny in 2013 in the U.K. and the U.S for health risk profiling claims based on genetic traits. But perhaps knowing why you cannot smell asparagus in your urine, whether you will sneeze looking at bright sunlight or whether your earwax is dry aren’t crucial personalized health determinants. For just US$99 and a little of your spit, you are also giving these big data analytic giants the rights to connect your private personal data and genetic details… Whoops!

The perilous journey begun >150,000 years ago by Adam and Eve’s DNA continues today.

For the first time in evolution, in the last decade (that’s 0.00667% of human history), mankind has unlocked the capacity to connect our individual ancestries to our genetically-predicted health futures.

This is both exciting and dangerous. This is also fraught with the potential for global public good, and bad.

We in the Square are agnostic on, but big believers in the capacity of DNA data analytics to our descendants’ DNA to their health futures.    

Sunday, April 12, 2015

Uncertain Health in an Insecure World – 34

“Mark Twain Turns 180”

Epidemiology is old school science. Associations between human characteristics and diseases, even when statistically significant, are not proof of cause and effect. As Mark Twain once put it, “There are lies, damn lies and statistics”. When so-called “weak effects” data make it to the pages of high impact journals, they assume great significance in the minds of readers.

Here are some recent studies from the epidemiology research space.

The United Kingdom Clinical Practice Research Datalink recorded characteristics of 2,000,000 people aged 40+ between 1992 and 2007, with a median age of 55 years, of which 55% were female. As reported in The Lancet, of these individuals, a total of 45,000 developed dementia during the period of observation – 2.4 cases per 1,000 patient years. In this cohort, obese subjects (BMI ≥30) were at lowest risk of future dementia, while underweight subjects (BMI <20) had the greatest risk – 34% greater than those with normal weight. By age 80 years, the incidence of dementia was 9.9% for underweight people versus 4.9% for obese people.

I'm not sure what to make of this so-called “obesity paradox”.

WHO reports that of 36 million annual deaths worldwide from non-communicable diseases, nearly 8 million are from cancer. The American Cancer Society estimates that one in three cancers in the U.S. are linked to excess body weight, where diet and physical inactivity are thought to be contributors. Evidence points to greater prostate cancer risk and poorer post-surgical outcomes in obese men, especially among African-Americans. A large European study (EPIC) showed that greater height and obesity are associated with an increased risk of breast cancer in post-menopausal women – for every 5 kg gained, the risk increased 8%; hormone therapy was partially protective in women with a BMI >30. The Women’s Health Initiative followed 161,809 women from 1998 to 2006, showing that there was an inverse association between lower BMI and higher lung cancer risk in smokers.

Enter the new school science of gene sequencing, or genomics.

A study in The New England Journal of Medicine on the DNA of 65,066 people with coronary artery disease (CAD) compared to 128,383 controls showed that CAD risk increased by 13.5% for each 2.5 inch drop below the average height. ‘Bad’ LDL cholesterol and triglyceride levels were found to statistically account for only 31% this increased short-stature risk. The accepted theory had been that larger people have wider arteries, so that plaques are not as occlusive. Of some 180 DNA sequences in the human genome known to contribute to height, no single genetic variant could explain these CAD risks. The researchers could not explain the other 69% risk for greater CAD risk in shorter people.

In order to explain the statistically unexplained, things get more complicated.

According to the Journal of the American Medical Association, epigenetics is “at the epicenter of modern medicine”. DNA sequences (genes) are generally independent of lifestyle and environmental factors. However, the sub-cellular microenvironment contains heritable chemical factors that can alter genetic controls, thereby influencing disease risk. The overhyping of epigenetic diets and drugs has been criticized, as has the ambiguity of its definition. But epigenetics is a tool – a scientific discipline – that might connect genetic DNA sequences (big data) to the observed risk of disease in populations (statistics).

On Silicon Valley’s Sand Hill Road, the smart money that created eBay, Google, Napster and Facebook is backing the premise that life can be extended by studying big genetic databases, using super-computing analytics at supra-terabyte levels to uncover the causes of death. As public research funding stalls, increasingly, private investors and venture capitalists are driving the biomedical research agenda. If dense data contained within the genome and epi-genome can be sorted, the cause and effect secrets of the human body may be reverse-engineered into deeper understandings of the basis for diseases and longevity.

The same technological wizards who engineered social media, secure online payments and movie streaming are turning their problem solving skills to the ultimate challenge – prolonging life. What would happen to society, to humanity, if the 1% of the world’s population controlling 50% of its wealth could afford the biomedical interventions permitting 150 year lifespans? Along with Bill and Melinda Gates, 130 billionaires have signed the ‘Giving Pledge’ to donate half of their accumulated trillions of dollars to engineer better health through advanced biomedical research tied to big data analytics.

These tech billionaires are ushering in another Gilded Age of philanthropy that could ultimately benefit global health. But to some, these initiatives appear more suited to preventing the ills of the rich – as Bill Gates said, “It seems pretty egocentric while we still have malaria and TB for rich people to fund things so they can live longer”.

Here’s the rub… 
With thousands of genes being sequenced, with untold chemicals in the epigenetic ooze, and with hundreds of thousands of subjects contributing their DNA to big databases, the statistical possibilities are almost endless.

Titans who changed the world by harvesting the power of machines & technology believe that they can also improve the human condition. Whether it’s Rockefellers or the Gates, the belief in what’s possible drives investing more powerfully than any damn statistic.

If Mark Twain had enjoyed great longevity, perhaps he’d opine today that, “There are data, big data and analytics”.

The Square shares such optimism! You gotta believe in something, right?

Thursday, April 9, 2015

Uncertain Health in an Insecure World – 33

“Lollipops of Optimism”

Matthieu Ricard has dubbed placebos the “lollipops of optimism”. Holistic therapists tout the placebo effect of colorful fruit lollipops in children with pain. Heroin addicts can get a high from injecting water into a vein!

It is belief that makes the therapeutic or psychogenic placebo effect happen.

But first, let’s discuss hard science and real drugs.

Hypercholesterolemia is a recognized cardiovascular risk factor. Full disclosure… I have done clinical research on many patients with this medical condition. The available published evidence and expert guidelines have recommended aggressively treating ‘bad’ LDL cholesterol numbers. Drug companies are very interested in treating sub-segments of highly prevalent diseases populations. Pharma was a key driver of many high-impact high cholesterol journal publications.

With changing heart attack risks over the last two decades, the medical benefits of treating high cholesterol to prevent heart attacks have decreased. New evidence from years of retrospectively analyzed data indicates that there is a risk of widespread drug overtreatment of adults without a proportional health benefit.

A 2015 publication in JAMA Pediatrics reported that based on data from 6,300 17-21 year olds studied between 1999-2012, fully 2.5% would qualify for LDL cholesterol lowering statin drug therapy by the numbers. That’s nearly 500,000 young Americans! The authors deftly split the therapeutic baby by advising that doctors & patients “engage in shared decision making around the potential benefits, harms and patient preferences for treatment”. Experts commenting on the research disagreed about the medical wisdom of starting statin drug therapy in this age group, as compared to healthy lifestyle changes like diet and exercise.

In 2012 the New York Times reported on U.S. Institute of Medicine findings that overtreatment, often potentiated by redundant testing called medical waste, costs the U.S. healthcare system US$210 billion per year. Over-prescribing is compounded when the side effects of one or more drugs cause other unintended medical conditions. For example, anti-depression therapy in a stroke victim can produce drug-induced dementia, confusing doctors and patients alike.

There was a time when such over-testing and over-prescribing was conveniently blamed on defensive medicine in highly litigious health care environments. But after we “kill all the lawyers”, there’s still plenty of blame to go around. 

Question: What is a patient or parent to do?

Answer: Consult a magician!

Eric Mead’s 2009 TEDMED talk explored the magical belief system underpinning the medication placebo effect – about one third of patients treated with a sugar pill get a therapeutic benefit. He points out that performing magic is about selling a lie... convincingly.

His placebo story goes on.

Eric recounts that a plain white aspirin-like placebo is less effective than a colored pill, which less effective than a multicolored capsule, which is less effective than an oddly shaped pill with a number and logo pressed into its surface.  The ultimate placebo is a needle with a clear inert liquid… injected not ingested.
Unbelievably believable!! But true…

Honestly, the truth is that some of science is like the placebo effect. We want to believe it, because published research is based on a reality… the data… BIG or small. Medicine is about the facts of the matter, translated into human physiology and pharmacology. Negative clinical trials are not commonly published, and retractions of discredited research are rare.

Why would science that has worked before not work again?

Watching the national news for advertising medical wisdom risks a lifetime of expensive treatment. Drug makers’ digital media commercial warnings and disclaimers abound – “Consult your doctor” if something bad happens to you. That new lump growing in your neck might be worthwhile reporting. And “Oh Yes”, please be aware of the higher risk of suicide when trying to stop smoking with our 35% effective drug.

As I watch the nightly news or the Sunday morning news magazines, heavily populated with direct-to-public Pharma advertising, I wonder what I’m really watching. Is this scientifically infused magic, or worse – a confusing mass media narcosis?

We in the Square are optimistic about good science improving human health. It really exists.

But we must also remain alert to the powerful brain candy placebo effect!

Friday, April 3, 2015

Uncertain Health in an Insecure World – 32

“Size Matters”

Managing healthcare big data with open architecture computing platforms like Hadoop is possible.

 Most major developed world healthcare systems and jurisdictional health insurance plans are still paying for their capital investments in enterprise level electronic medical records (EMR’s). It remains unclear whether these entities produce big enough data to warrant the cost of doing business with Hadoop level processing power.

Certain industry sectors handle truly massive data, and were the raison d’ĂȘtre for Hadoop’s creation a decade ago as a highly efficient data storage and processing ecosystem. Companies like Google and Yahoo! were there at Hadoop’s inception, and LinkedIn and Facebook have enjoyed legacy benefits since.  These social media behemoths leverage 10,000's of nodes in Hadoop clusters in lieu of using typical enterprise software (Microsoft, Oracle) and disk storage.

Discovery scientists can effectively employ this platform to manage very large gene sequencing data sets. Public health investigators can correlate the U.S. National Oceanic & Atmospheric (NOAA) Administration weather data with children’s asthma admissions. And environmental toxicologists can compare U.S. Environmental Protection Agency (EPA) chemical levels in effluent waste water to long-term cancer rates. But a typical patient generating only 100MB of data per year in a modern healthcare system which must store 200 terabytes of data over 20 years does not demand Hadoop computing power.

By comparison, Facebook adds 500 terabytes of data capacity every day to handle its big data demands: 4.8 billion content changes, 4.5 billion ‘likes’, 10 billion messages and 350 million uploaded photos!

A mid-sized domestic U.S. airline’s fleet of 600+ Boeing 737’s generates >250,000 terabytes every day of unstructured data, most of which is neither stored nor actively used. Yet, in the wake of the Flight 9525 tragedy, these streaming data may eventually become part of a system that can take over the operations of a rogue airplane from the ground.

If healthcare systems used Hadoop’s power, what would doctors and providers actually do with the data to improve the quality or quality of healthcare? 

Hadoop advocates propose using MapR for case-by-case personalized treatment planning, diagnostic predictive modeling, prescription fraud detection, remote vital sign monitoring, legacy medical records searches, and patient self-directed care and prevention management. Some of these Hadoop ecosystem functionalities might even allow for smart programs to learn from trending of streaming data (i.e., machine learning). University of California at Irving Medical Center initiated an small 8-node Hadoop platform in 2012, with some early economies of scale. However, such big data applications are generally beyond the affordability threshold of most healthcare systems or jurisdictions, and most lack the highly qualified personnel to support it.

The Cloud also offers potentially secure healthcare information sharing and data storage capacity, but it is non-analytical. The only way for healthcare systems to predict failures and/or solve problems before they occur is through smart programming or machine learning, whereby the power of analytics can be brought to bear on massive data sets in real time, during the actual patient care moment

People, especially untrained people, are the problem with this promising construct.

The slow adopters for EMR will be the same foot-draggers on big data analytics. Not even severe financial penalties for poor healthcare informatics performance have moved the needle much; in many developed counties, such penalties do not exist. Progressives like the Cleveland Clinic spun off Explorys which offers the allure of combining clinical and claims data to establish population-based health profiles to either measure or mitigate future risk. Wherever you sit in the purchaser-provider split, such information would be powerful as a means to determine insurability and project future costs of care, for individual patients, bundled cohorts and entire countries.

Take a small country, like Denmark – population 6.2 million.

A colleague of mine has recently published research in Nature Communications from the entire Danish population, where standard non-Hadoop computer crunching of medical histories in a 14.9 year medical claims registry led investigators to predict disease progression from previously unseen patterns of health data.  These so-called disease “trajectories” could potentially be a key tool in predicting or even preventing future diseases for selected patients within these risk profiles.
Take a big country, like India – population 1.3 billion.

Big data and analytics has exploded in this, the world’s most dense population center, where the current $1 billion market could more than double to $2.3 billion in 2018. Whether personalizing patient services at scale or trending unstructured data from devices & monitors, India's healthcare sector is now in play.  

For example, Metaome company produced DistilBio, a web-based search or enterprise level computing platform that generates health risk patterns from private & public laboratory data management systems. In a country where 29.5% of the billion plus people are below the poverty line, and where 46% of children are malnourished, there is hope that big data analytics can also improve the country’s rural under-served health system, achieving Svasth Bharath (Healthy India). 

Hewlett Packard and other big data and analytics firms with a firm India footprint in mining, oil & gas, business & retail, video security, social media, engineering, etc. now have a healthcare market presence. And India's software engineers and analysts are relatively abundant, spawned by a growing number of digital health innovator start-ups and accelerators.

Countries and companies considering the use of open architecture computing to analyze their healthcare big data should look critically at the size of their platforms before taking this leap.

The Square is small, but the risks and related rewards should not be underestimated.