## Sunday, November 30, 2014

### LINEAR REGRESSION

y = mx + c

But what.
It sits at the door waiting
For the chime
But inherently
Remains dormant.
If the C was less
It would change the Y
But only by a little
Have limits of arithmetic.
Quiet and plodding
They rise a step at a time.
Throw in meteoric M
And life changes
The potential grows
Exceeds and infinite
.
The straight linearity
Indefatigable rising
Like Matterhorn
Vertiginous and indomitable
Any X would jump
On this ride
And enjoy the thrust
Of the mind-body
Separation
As the climb would follow.
The thrill of the clouds
The fall to the ground
And nothing in between.
And there the why
Within the Y
Sensitive and promising
Yet truly dependent.

M's slope
Confined to the
Linear in Sine
A dip here
Ignored there
No calamity of thought
No apologies therein.
"Murder" she wrote
"Billions" he said
Confine the Art
Within the science
Not color the landscape
But view the virtue
Deep within.
On the deep sea dive
Of a negative M
And the hard C
Both together
Arm in arm
Cajoling and caroling
Drunkards and driven
Lilting and heaving
Up in the climb
Or down in a draft
Held together
At the fulcrum
Of C
Probabilistic Predictors all
Held together by

The failure to reject
Confined by bounds
Not acceptance,
Exposing the tail!
The turmoil grows
Mandelbrot frowns
Pearson winks
At that Y
When the X
Is but a number
Without a Y
Nothing!

## Sunday, November 23, 2014

### “YOUR DOCTOR IS A COAT HANGER”

“Your doctor is a coat hanger”

What image strikes your mind’s eye? A coat hanger, right?

“Your doctor is a door knob”

What do you see?

Words have meaning. Each one represents a finality to evoke a thought, an idea, a recall a photo or a movie played out in the mind’s eye.

Now let us look at a commonly utilized word to describe a physician; “A provider.” What does the word “provider” conjure up inside your head?

Bland you say. Think again. Let me put a few descriptors so we can all see clearly the intent and purpose of the word. A provider can be someone who provides a service, provides a chair to sit on, provides cleaning services, plumbing services, analytical services, janitorial services, food service, in fact any kind of service available to humanity is delivered through a provider. In fact a robot is a provider too, providing some mechanical redundant service, the robotic assemblers in the auto industry are perfect examples of such descriptors. So now we get it, don’t we? What is in the elusive formlessness of words, but bewilderment! The gift and grace of time locked into the word “doctor” not only replenishes itself in the person- the doctor, but through him or her into the patient seeking help. Extract the essence and deploy the limpid vacuous expression and what is left, but nothingness, no desire, no respect, no toil. The new generation of doctors had better be careful lest what they envision the field of medicine as a 9-5 job with no responsibility actually comes true. Then the profession would have fatally spiraled into a rudderless “provider-ship.”

The doctor as a provider is nothing more than and nothing less than a set of services he or she provides. Angry as some might be and I am one of them, that is the lexical vector of the elites to take down the importance of physicians as doctors in the art of healing and medical care. So what! you say, it is only semantics!

Semantics? Think about it. If we dehumanize the doctor what does he become? Another robot, filled with the guideline software that regurgitates the output we have planned based on a set of course rules. The newly minted graduates from Medical Schools are schooled in the arbitrariness of archaic evidence. In fact some evidence is being “crafted” to denude the essence of the art of healing. The new “art” of medicine is to check the response from an digital monitor and based on the probability factor utilize the best diagnostic and cheapest tool to arrive at to fix a potential malady and then treat that malady with the cheapest medicine or intervention the digital 1 and 0s can output. Unfortunately for the current and future patients most of these guidelines are based on population based data that may have nothing to do with the individual patient. A cough may easily be interpreted as a “cold” given the assemblage of data from other physician electronic medical records that suggest that the “flu is going around!” And yet the diagnosis might be an onset of allergy, adverse drug effect, post nasal drip or even as vicious as cancer. The corruptness within the word is all!

The simple act of communicating and touching and evaluating through the reams of accumulated mental stores within the physician’s mind would provide a clue based on previous and ongoing human interactions about the potential illness. But, No, the guidelines are what they are and following them is the easiest way to lose the gift of a healer and substitute it with a robotic probability score.

I wrote about the guideline debacle that caused harm to a patient several years ago. Such harm exists in everyday life in medical care. We are so blinded by the seduction of this digital world that our conscious thought and reflexive acts are motivated by the false claim of technology as the wunderkind that will save humanity.

"Medicine is a science of uncertainty and an art of probability." _William Osler

and not

Medicine is an art of certainty and a science of probability.

Individual thought is a wonderful thing. There is purity in it in spite of bias. It follows the letters IMHO (In my humble opinion). For instance arguing against the need for a carotid sonogram in a frail 94 year old or a PET scan in a late stage cancer patient, the use of statin in a confused middle aged or arguing for the need of a biopsy of a neck mass, excision of a changed mole, vigilance as not “watchful waiting,” prescribing hormone therapy past the five year mark before it was fashionable and “study-proven,” are elements of critical thinking! These are the elements of medical care lost in the sea of claims and counterclaims serviced by guidelines and mandates pronounced by the experts who never see the light of day from their ivory towers.

So what is in a name? Everything!

There is meaning in the word doctor, a healer, an educator and a scholar. But a provider is one shifting resource from one place to another. Maybe now we get the gist of this subversive act to deplete the essence of being a doctor. Change the title, load up on guidelines and templates, eliminate individual thought, force the team concept to further suppress unique ideation, force feed the need for technological progress in medicine, interpose intermediaries like the EMRs, Insurers and other dictatorial governance, broadcast and vilify a few bad apples and destroy the nobility of the profession, you suddenly find the lost art and purity of desire diving deep into the sea of oblivion.

## Wednesday, November 19, 2014

### O' PHYSICIAN, MY PHYSICIAN

Where Art thou
O Physician
With comforting smiles
Soft touching hands
And eyes that sympathize

What happened
O Physician
With transforming skills
A frown is affixed
The hands barely touch
And eyes barely size

Like a peach
O Physician
Once with intricate fuzz
And heavenly sweetness
Now the texture all gone
The surface all bland
You seem empty inside

The student
O Physician
With wide opened eyes
Filled with human tenderness
Now dons the cap
Marketing his promotions
All emotions aside

Where once
O Physician
Sleep turned to winks
And concern filled the space
Now emptiness games
The hardened shelled domain
And yawns the great divide

From thought
O Physician
Where purpose once dwelt
And concern crafted desire
Now time is the enemy
And productivity reigns
With anemic emotions implied

It is time
O Physician
For all you hold dear
The change gains permanence
And you lose all pride

You are remembered
O Physician
For the Hands you hold
For the touch to console
For the joy you share
Think hard, the journey
And don't let your pride slide

O Physician
My Physician
Let me see within you
The love you hold
To nurture and care
The desire to heal
Before both our souls are buried in cries

## Wednesday, November 12, 2014

### BRCA gene mutation and Mass SCREENING

In 1990, Mary Claire King discovered the BRCA 1 & 2 gene mutations and their association with breast cancer. The prevalence was found in the Ashkenazi Jewish population predominantly, in Long Island, NY and there were some Peruvian women who tested positive in the original data.

BRCA genes are DNA repair genes. Any mismatch and these segments of the exome are activated in the cell cycle checkpoint control to maintain genomic stability and transcriptional integrity.

The BRCA 1 stands for “Breast Cancer 1 early onset.” The recent estimates of a woman’s lifetime risk of developing breast cancer with the BRCA 1 mutation was 28%-60% by age 70. Additionally women with the BRCA 1 gene mutation also carry a 39% risk of ovarian cancer during their lifetime. BRCA 1 gene is located on Chromosome 17q12-21. Those carrying the BRCA 2 mutation have a 40% risk at age 70. Women who carry the BRCA 2 gene have a 15% lifetime risk of developing ovarian cancer by age 70 also. BRCA 2 gene is located on Chromosome 13. The breast cancer penetrance has increased for those born after 1960 (40%) as compared to those born before 1940 (7.5%). BRCA 1 mutations also have some clinically relevant features that defy the established histo-pathologic paradigm. Breast Cancers with BRCA mutations are mostly basal-type, have no correlation between size and nodal metastasis, they are usually Estrogen Receptor negative, yet respond to SERMs and Tamoxifen also prevents secondary cancers that are ER negative in this subset of individuals.

Let us dissect the populace under the BRCA gene mutation stress a bit: Overall independent of BRCA gene mutation, 12% of women will develop Breast Cancer and 1.4% will develop Ovarian Cancer during their lifetime. In the general population based on at least one limited study of 1220 cases the estimates of 0.7% of the population is a carrier for the BRCA 1 and 1.3% for BRCA 2 is of some significance.  Given that estimate and the Breast Cancer penetrance at age 80 of 48% (CI 7-82) for BRCA 1 and 74% (CI 7-14) BRCA 2 and Ovarian Cancer penetrance at a similar age of 22% (CI 6-65) for both BRCA 1 & 2 should give us a moment of pause.

So let us look at this through the lens of Mary Claire King’s recent recommendations in the JAMA article where she advocates that all women at age 40 should be tested for the BRCA genes. In this age of Cost Controls and the Healthcare taking 17.9% of the GDP, some considerations should be made to the costs that all experts tout so vociferously. U.S. currently spends \$6,000,000,000 on Breast Cancer annually.

Based on the population statistics as of Census 2010 there are 156,964,212 (50.6%) women in the United States. The mixed gender population ages 25-44 years is calculated at 82,134,554 and thus 50.6% of that translates to 41,724,353 women. Dr. King recommends that all women by age 40 should be tested for the BRCA gene. The cost of the BRCA test is averaged at \$2000 per test. The expense for such a testing would put the cost to the healthcare industry at \$83,448,708,000.00. With two predicates to keep in mind: One that the incidence of BRCA carriers in the general population is 1.98% that means that \$826,142.00 would yield a positive result and the rest of the expensed monies wasted. But even at that, the second predicate suggests that with the maximum 60% actual breast cancer penetrance in the carriers that would mean only \$495,628.00 spent would actually identify the breast and ovarian cancer cases for prevention.

So it should come as no surprise that logic would dictate that the BRCA gene mutation analysis should be carried out ONLY in high risk families with established evidence of breast, ovarian, colon, prostate and pancreatic malignancies in their members at a young age. And patients who develop breast cancer at a younger age without known family history should also consider being tested for BRCA mutations in hopes of isolating variants of the BRCA genes that may function as disease promoter and consequently may help other family members in making preventative decisions.
Bayesian modeling in various ethnic population shows marked variations of BRCA penetrance. The BRCAPRO and BOADICEA analysis again confirms sensitivity to family analysis data rather than large population based determination. Two large population studies done in the US suggest BRCA 1 mutation in patients younger than 65 years was found in 3.5% of Hispanics, 1.4% in African Americans, 0.5% in Asian American, 2.9% in non-Ashkenazi whites and 10.2% in Ashkenazi Jewish individuals. Additionally 10-15% of the fully sequenced BRCA 1 & 2 population shows Variant of Uncertain Significance (VUS) in the form of SNPs and missense DNA mutations in the intron regions. These VUS however may or may not have any deleterious consequences to the patient. This would also create a dilemma for the genetic counselors and for the patients from such wide-berth screening. Another source of BRCA gene silencing comes from hyper-methylation, which like the hereditary version of the mutation has similar effect of breast cancer promotion. The exact incidence however remains unknown and testing might reveal this anomaly of which little data is available.
Just based on the current data 40% of the BRCA 1 mutated individuals who will never develop breast cancer will be subjected to potential emotional and physical harm and those with BRCA 2 mutated that number will rise to 60%. These percentages would falsely constitute a Type I or False Positive Error in potential Breast Cancer penetrance among patients and create confusion sometime even among physicians and counselors. With the ultimate goal of genetic testing of individuals being to reduce the risk of cancer that they are predisposed to as a consequence of the BRCA mutation, screening the entire population would have far reaching deleterious consequences both emotionally and physically to the individual.

In the end I am at odds with Mary Claire King’s recommendation of population screening for BRCA 1 and 2 mutations in women aged 40 and younger (even though I laud her for her pioneering work of BRCA discovery)!

References:

D Gareth Evans et al. Penetrance estimates for BRCA1 and BRCA2 based on genetic testing in a Clinical Cancer Genetics service setting: Risks of breast/ovarian cancer quoted should reflect the cancer burden in the family. BMC Cancer 2008, 8:155 ( http://www.biomedcentral.com/1471-2407/8/155 )

Prevalence and penetrance of BRCA1 and BRCA2 mutations in a population-based series of breast cancer cases. Anglian Breast Cancer Study Group. Br J Cancer. 2000 Nov;83(10):1301-8.  ( http://www.ncbi.nlm.nih.gov/pubmed/11044354 )

Narod SA. Modifiers of risk of hereditary breast and ovarian cancer. Nature Review Cancer 2:113-123, 2002.

Chappuis PO, Nethercot V, and Foulkes WD. Clinico-pathological characteristics of BRCA1- and BRCA2-related breast cancer. Seminars in Surgical Oncology 18:287-295, 2000

High-Penetrance Breast and/or Ovarian Cancer Susceptibility Genes http://www.cancer.gov/cancertopics/pdq/genetics

Frank TS, Deffenbaugh AM, Reid JE, et al.: Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10,000 individuals. J Clin Oncol 20 (6): 1480-90, 2002

Malone KE, Daling JR, Doody DR, et al.: Prevalence and predictors of BRCA1 and BRCA2 mutations in a population-based study of breast cancer in white and black American women ages 35 to 64 years. Cancer Res 66 (16): 8297-308, 2006.

John EM, Miron A, Gong G, et al.: Prevalence of pathogenic BRCA1 mutation carriers in 5 US racial/ethnic groups. JAMA 298 (24): 2869-76, 2007.

Narod SA, Dube MP, Klijn J, Lubinski J, Lynch HT, Ghadirian P, Provencher D, Heimdal K, Moller P, Robson M, et al. Oral contraceptives and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. Journal of the National Cancer Institute 94:1773-1779, 2002.

## Thursday, November 6, 2014

### INCUBATE THIS!

Nietzsche: There are no facts, only Interpretations.

Frankly I never cared to comprehend the undisputed policies handed down from above. They are after all “manna” from the scientific heaven. Everything arriving from the “House of the gods” must be relevant and filled with indisputable truths. But now I am set to question the very complexion of that argument; its color and texture, its declaration and gravitas.

Incubation Periods of various illnesses are based on potential event of exposure and the duration that exposure will eventually lead to an illness in a living being (humans in this case). There are several diseases with varying incubation periods. For instance Influenza virus can have a short Incubation of less than 24 hours and wham it is in the body like a wrecking ball. Hepatitis B on the other hand has a range goes from a few days all the way to six months. A few of the virally mediated illness with their prodrome onset are listed below…

Which leads me to the Ebola thingy, its suggested Incubation is 2-21 days and there are fires all over the landscape with fire-hoses positioned on either side to win the fight. The quarantine group assails everything that moves and wants them secluded for at least 21 days after all that is the right tail of that incubation period duration. The argument is sound given the declaration of the potential for infection between a carrier/exposure and the time it takes for the virus to burrow into the various organs of the body and initiate the calamity. The longest incubation period being the Human Immunodeficiency Virus (HIV) is something to reckon with and consider along the spectrum of these illnesses based on the model and behavior of each virus.

But what if it wasn't true? What if the virus incubation period was longer? Huh? Can that be true? Ok here are a few “not so feel-good thoughts.” One, for instance to declare a country Ebola Free it has to have a mandatory period of 42 days of no new infection. Now why would that be? The simple answer would be we want to be “doubly” sure before that declaration. “That’s good, really thoughtful and good,” one would be inclined to say. But then there are the nagging data that come flurrying across the digital landscape, which confound the rational argument from the gods that the virus has expressed itself as illness in humans all the way up to 56 days. “56 days?” you scream in your mind. “What the heck?” It is all a lie? It is all a lie! Is the differing drumbeat of politics emanates from the proponents and the dissidents. Meanwhile the curvilinear sweep of the viral profile as it enters the human habitat is finding a happy medium of coexistence.

We now add another twist to this monstrous discussion that none of us find entirely palatable. What are the potential reasons for the long range of this incubation period? Watson would say, “Elementary, my dear.” The virus, as it enters the body via the mucus membranes and “bodily fluids” or as some have conjectured even through the skin surface, it meets with some issues.

Those issues include; A) the “viral load.” By viral load, science means the amount of virus that enters another human’s body via “exposure.” So a low viral load will mean that the virus has to multiply within the body for a longer period of time to get to the Gladwell’s “Tipping Point” to create illness. A larger load on the other hand has only to multiply a few times to create the same illness. B) The human recipient’s Immune system. There is an immunological pressure imposed upon the virus as it tries to multiply and expose itself to the human body’s immune defenses. A strong immune defense and a weak viral load may make the virus impotent in causing the illness. These individuals would be considered “immune” to the virus. On the other hand a large viral load and a weak immune system would render the body defenseless and exposed to “a thousand natural shocks that the flesh is heir to.” C) The selection pressures impressed upon the virus through the immune systems of humans will force it to mutate and acquire some RNA changes that will help both the deaths of the hosts (humans) and allow for its own survival through a mechanism of co-existence. These mutational forces are well known in the field of virology. Hepatitis B and C viruses have their DNA mutated and now exist in multiple forms and exert damage to humans differently. Some create the acute prodrome and then “are heard from, no more.” Others coexist surreptitiously and raise their ire when the immune system weakens, while others still cause chronic disease in the liver; from cirrhosis to cancer. Similarly the Ebola virus has mutated across its RNA landscape over the four or so outbreaks it has unleashed on the humans and even to some extent from one geographical location to another. This recent onset is the one that got away due to the promiscuity of travel and weaker epidemiological controls at the index (source) site (methinks).

So getting back to the 21 days, there is the very probing and provocative graph that I presented in the beginning. The purpose is to show the linkage between costs and the imposed incubation period. The idea of the hard-and-fast rule of science has been softened and made pliable by the eagerness of cost-effective strategies. We cannot quarantine for more than 21 days since the cost to do such is exorbitant both for the Health Agencies and the financial well-being of the individuals. Exploring the concept that the virus is not infective unless symptoms arise has never been tested to my knowledge and based on the ancillary data from the quoted study I have placed in the reference box there is cause for contemplation. As costs are the over-riding features in all aspects of medical endeavor, this one might as well be too.

The Ebola virus is not considered a “shedding virus” in the incubation period. However the biology of its replication rate seems to suggest other possibilities, yet not completely resolved. If it is not then a series of actions taken by the health agencies appear draconian in visible light.

So the questions remain: 1. Are the incubation period days arbitrary and capricious? 2. Are they based on hard science or soft peddling of the cost structure? 3. Will selection pressures due to immunotherapy ultimately evolve the virus into a more/less comfortable coexistence with its human hosts? 4. Will it change the mode of spread? 5. Will it, like other hardy viruses exist on sufaces longer than we want to think? Ah questions, questions!

This is merely a thought experiment for those interested in a “Borg”-type-mind-meld to extract reality from fiction.

So ponder away…

References:

1b. T.J. Piercy, S.J. Smither, J.A. Steward, L. Eastaugh and M.S. Lever. The survival of filoviruses in liquids, on solid substrates and in a dynamic aerosol. Journal of Applied Microbiology 2010 ⁄ 0516

## Sunday, November 2, 2014

### LIFE IS NON-LINEAR

Internalizing is a slow ponderous process. I mean you cannot go to an advanced class on genetics and come out with an understanding how the human body works. May be upon reflection think to yourself, “life is complicated!” Indeed most disciplines are. Some are, as Taoists would point out, dried sponges for minds that soak material at a phenomenal scale, while most, like myself, plod through the process one solitary step at a time. But even among the upper echelons of thinkers internalization requires ridding the past paradigm, before the new one takes its rightful place.

Nonlinear systems do not satisfy the properties of superposition or homogeneity. They have multiple equilibrium points and stability dynamics cannot be precisely programmed.

It would be easy to apply the old linearity argument to all matters in life and come up at the end with “sum of parts is equal to the whole,” but that is reducing everything to a set of numbers and then adding them up to the grand total. That is not how life operates. One cannot predict when the rotor blade of the helicopter will fail. One cannot easily surmise when the engine of a car will cease or for that matter when you or I will die. Even those living at the edge of survival, riddled with infections, bad heart, failing kidneys and confused brains have been brought back to live with their loved ones for few more years. Applying the IFTTT Boolean mechanisms as arbiters of future is fraught with failure.

Life is non-linear!

There are unknown multi-variables that confound the polynomials of real life. There is always a Lorentz attractor waiting to jump and bite the fortune-tellers hand. Let me take you into the confined space of the heart (with respect and some latitude from my cardiology friends). Let us ignore the embryology and dive straight into the mechanics of a beating heart. If one were to simply take into consideration the basics; there is the S-A node that sends electrical impulses to the atria and to the A-V node that triggers the electrical impulse, which spreads through the ventricular musculature and makes the heart muscle cells contract in unison.

Each atrial contraction sends blood into the ventricle and each ventricular contraction then forces blood out into blood vessels: from the right heart into the lungs where the blood is refreshed with oxygen and then from the left heart into the brain and rest of the body for distributing that new-found oxygen for replenishment. One could apply numerical values as have been for something called ejection fraction and using that information be in a position to diagnose a sluggish or a failing heart.

The simplicity of that concept would be easily graphed into a software algorithm and voila the automatons within the CPUs would give us probabilities of survival. And that is precisely how the physician turned technology wizard foresees the world; in linear terms. But the breakdown is more complex than that.

There is much more to this I am sure you will agree. For instance a limited blood supply to the A-V Node from atherosclerosis might create a dysfunctional node and cause the secondary fibers to take on the function and create a chaotic rhythm, as in atrial fibrillation, or spread down into the ventricles and create mischief there whereby the pump mechanism would fail to pump the blood out due to the erratic and chaotic individual heart muscle contractions and thus to an untimely demise. I am not taking us into the sub-membrane space and the Calcium channels that might also unbeknownst to technologist create their own version of chaos. How would one sum up those parts into the whole. And even if one were to assign coefficients and betas to the proposed mechanisms of failure we would be far off the field in terms of reality. Case in point for arrhythmia occurring in young athletes: there are no predictors available to circumvent those tragic events.

The unknown independent forces exerted on dependent variables

Medicine is being considered as a simplistic linear model by some and it is to the detriment of the health of the people. The Art in medicine supersedes the Science of probability when non-linearity is at play. There is an intuition-labored thought process that is absent in the IBM Watson-like thinking. Yet even with all the known information poured into Watson’s funnels, the heavily air-conditioned, blazing Blue still comes back with percentage probabilities just like the Differential Diagnosis text book from yesteryear. Solving the real puzzle in life as in all non-linear processes, intuit must play a part, that intuit, arrives from critical thinking and reason. And reason is absent within the hot data circuits of the CPUs.

My twitter friend extraordinaire @DrHubaevaluator has this mind map (I borrowed for the sake of explanation) that is telling in its complexity.

Giving the computer a reasoning power through Artificial Intelligence? Well that is a double edged sword, but I digress…

Next time reflect on what your doctor says and not entirely on what Siri or Cortana can drum up in seconds. The discrepancy might well be worth more investigation.