Sunday, December 21, 2014

GAMIFICATION OF MEDICAL EDUCATION

Sometime things take you by surprise. And like embers glowing steadily the logic and thought ignite the spark into a fire. That is exactly what happened when I read this article from the British Medical Journal about Gamification of Graduate Medical Education (1).

I thought well, this seems like a nice idea to enhance education. I read the article and came away with a different impression than was sought by the Authors. “We named our software Kaizen-Internal Medicine (Kaizen-IM). Kaizen, a Japanese word from the quality improvement literature, signifies the need for continuous daily advancement, a concept analogous to the principle of lifelong learning we seek to inculcate in our residents.” Whereas they sought to prove that a Kaizen-IM modelling technique helped ensure educational learning, reading through the article I came away with the tortured use of statistics to prove what they set out to prove. “Analyses focused on acceptance, use, determination of factors associated with loss of players (attrition) and retention of knowledge. Because traditional tests of normality such as the Kolmogorov–Smirnov test, the Anderson–Darling test and the Shapiro–Wilk test are subject to low power, particularly when the sample size is small, continuous outcome measures were graphically assessed for normality by investigating the distributional form of the outcomes using histograms. When normality assumptions were not met, the appropriate rank-based Wilcoxon test was used.”

But here is where it struck a chord and the tumbled notes all fell in a crash of dissonance. “We used the conceptual frameworks of user-centered design and situational relevance to achieve meaningful gamification, including connecting with users in multiple ways and aligning our ‘game’ with our residents’ backgrounds and interests in furthering their education.”

Now why would that bother my internals? Learning by rote in medicine is akin to getting ready for a Multiple Choice Q and A. Now hold on, you power-jockeys of the esteemed elite schools! Think about Medicine as a holistic mechanism for caring for the patient, not as a yes and no binary form of interaction. I need a new paragraph to start that thought, so hold on…



The sheet of paper in front of you has many inked marks on it as the proctor tells you “Start!” And away you go answering all the questions within the bounds of the allotted time. Some, you skip and some you hesitantly answer “C” as a hedge against the limited information in your brain. By the time you are done, the mental exhaustion is replete with multiple rivulets of sweat pouring down your back. You pass your answer sheet back to the examiner and with one last look back at it, you figure, Okay that’s done! Three months later you get a passing grade and you go celebrating till the wee hours of the morning. Loaded with congratulations, inebriated from the slaps on your back and feeling immune to the vicissitudes of mortal life. Ah yes, another conquered!



But then you enter the hospital and there lies a frail, weakened human body, a shadow of its formal self as you can see the skin has since loosened off and hanging on the bones with very little musculature support. “What the…?” your words escape between your teeth. The breath from this shadow comes in slow uneasy cadence, yes there is life but it is struggling to maintain its domain within his shell. There is an odor that you have never encountered before. It isn't obnoxious or anything, just a mousey, old cat litter type, wafting through your senses. His eyes open and the whites of the eyes are patchwork of miniature blood vessels and a hazy dull yellow background affixed onto an equally weak sallow complexion as deep pits on a desert floor. There are some spotty blood marks on his arms that lie above the clean white sheets of his recently made bed. His utterances are feeble and devoid of meaning when you ask him questions. He does nod in affirmance and shakes his head slowly in the negative. Suddenly overcome with the complexity of his person, you open his hospital chart and gaze through the lab reports and his diagnostic x-rays. Ah! You think, here it is, the answers to the riddle. This man has “such and such” and with “Mr. So and So, we will get to the bottom of this,” you stride out of the room as fast as you can only to find that the same tests had been done in this gentleman’s previous admission. Now what?

And there fellow journeyman, reader of these words, lies the problem with gamification of medical education. Our entirety of purpose is not in the hospital rooms, but in the confines of the computer glows where we search for meanings, not in the operating theaters but in the virtual operations conducted within the binary logic of a computer console, not with a patient-understanding the look and feel of a disease but in the memory bank tied to a CPU, where a differential diagnosis is within reach and Sutton’s Law is practiced for the ideals of human care to safeguard finance and limit the use of limited resources. When all you need to do is spend that extra moment in spending with the ones with the ill health and recognize through expediency of critical thinking what the problems are and which ones to fix now and those that can be fixed later. It would limit running through the myriads of differential diagnostics (that cost an arm and a leg and in many cases literally) and it would put the resources to better use.



So here we are stuck in the conundrum of do little to save the limited resources but use the tools that expand their use.

Time to rethink!

Time to reevaluate!

And maybe if we do, we will find the answer that is obvious and time-honored…Spend the time with the flesh not with the automated binary logic. Understand the human body and not the logic of a multiple choice. Draft a memory of experiences that will recognize disease and help patients rather than harming them with a “House MD” type approach of “biopsy the brain” when fifty other things yield negative results in a span of one hour.

And about that EMR, there is nothing meaningful about it, except more population-based algorithms!

No, medicine is and will be for the near future be practiced with an art due in part to the humanness of humans and in part to the connectivity between us humans. A discordant approach between the mind-body and clicks leads to de-coherence, which is futile in healing the sick!


Saturday, December 13, 2014

AM I BIASED?

“The gentleman can see a question from all sides without bias. The small man is biased and can see a question only from one side.” - Confucius (c. 551 - c. 479 BC)
Am I biased?
Well, if I am honest with you and above all with myself, I would say, “Of course, absolutely, without a doubt, no if ands or buts about it, 100%!” (After all I do not want to be the small man – my bias there as well). You see, bias is our blind spot, a sort of a functional fixation and the curse of limited knowledge or transparency that remains a continual drag on the strivings of all human beings. This bias is enforced through parochial jargon, tortured reasoning and systematized metaconcepts of dubious integrity.

But if I am not honest about it, I would say, “Of course not. I am an expert!”

Seriously, think about this for a minute. Bias is a natural predilection to the plight of the human brain. It shimmers over every spoken word, caresses every thought with the prejudice of past experience and the phantasmagoria that is added on to that past; a bouillabaisse of ideas, thoughts and actions. The spry and tasty tart ultimately gets embalmed within the tea and toast-lost in translation.
Words that bump against the word bias include; prejudice, intent, inclination, tendency, bent, disposition, proclivity, predilection, slant, leaning, preference, bigotry and preconception. Just reading them one gets the message, loud and clear.

Take for instance the recent episode of “glibness” and  “I am sorry” from the MIT professor Jonathan Gruber, who admitted that he was prejudiced in his own statements that he made to the policy-makers. He used words that would be acceptable to the Congress to pass the healthcare legislation. He was not concerned about the American people, because they would not understand the complexity of the financial jargon within the document. Clearly Dr. Gruber’s bent was to influence. His preconception about the “stupidity” of the American population was an ideal tabula rasa upon which to imprint his masterpiece. His inclination towards the type of healthcare reform was in keeping with the official mind set, hence his slant was met with equal measure of prejudice within the beltway. Oh, I am not here to pass judgment, as it might seem to some, I am merely making a reference to the recent past events. This particular plaque of concern that reverberates within the chambers of my mind seems to stand out as a beacon of internal bias. “What was he thinking?” One might ask. The problem deeply imbedded in that “thinking” based on conjecture alone, would be the sweet, penetrating, sickly but fleeting taste of the praise from his audience.

Biases stem from reconstructed experiences. They are difficult to remove. For example, my bias to trust individuals implicitly was severely violated and thus trust comes to me with difficulty. The verification process takes time and is tedious and I am learning to employ it in full embrace.
Bias has many faces: optimistic, pessimistic, attribution, selection and a catalog full of them can be found in books, yet all seem to stem from a personal prejudice. Color bias is easy to see. Ask a child what color she likes (even in that statement, I am biased by using she, because as a society we are fighting the bias of the male dominated gender) and she will say, pink, red or blue. Ask an adult the same question and they will hesitate to answer (thinking about all the ramifications in this politically correct word not to offend others with different color likings). We might call this the “Compassionate bias.”
Optimistic bias is the mother lode of all biases in the human mind. We survive, because of our instincts to survive. Our optimism sees the future and dresses the present accordingly. There is perpetuity of hope over experience in most times, even to the detriment of the exposed reality. Tali Sharot a neuro biologist points out, 
“The capacity to envision the future relies partly on the hippocampus, a brain structure that is crucial to memory…directing our thoughts of the future toward the positive is a result of our frontal cortex's communicating with subcortical regions deep in our brain.” 
So, deep in the cognition factory of our brain, the neurons in our hippocampus faithfully encode the required information that is processed via the emotional amygdala and then rationed through the pre-frontal cortex (rostral anterior cingulate cortex). We are fed with information, we process it through the filters of our experience and the cognitive output matches our inherent bias, in other words.
Now here is a conundrum worth mentioning in full disclosure; my introspection of realizing there is a bias within me also predisposes me to think that there is a similar bias in everyone else. This meta-bias that permeates in the thinking process creates the dynamics of the “Prisoner’s Dilemma within the Game Theory.” In fact all contracts between entities are based on some form of internal bias.
Moving quietly to the scientific world, one finds an equal rudderless boat adrift in the ocean of bias. The boat is being pulled and pushed by the ebb and flow of currents divined by human thought. Interestingly in spite of the bias behind any experiment the rudderless boat continues to move and as it does, so does society as a whole changes. Our current love for all things internet is transferring a monstrous new 1,826 petabytes of digital jargon and creating 5 exabytes of new data daily (here ). That is an enormous amount of data/information. Manipulation of cherry-picked data analysis can offer a whole host of literary/financial/scientific rewards through monetization in the short term, even though in the long term these outputs are meaningless. But this world that has transformed itself from tomorrow to today to now, the future has become immaterial. Such short-term biases have brought the economies of many nations to their knees. The current account deficits and the rising national debt of $18 Trillion in the United States, is inconceivable to foster future growth and wealth. Meanwhile the spenders create charts and graphs and tables to persuade the laity about the rosy future and the savers worry and worry. The Keynesian door remains ajar and capital continues to flow… out.
 Medicine as one of the disciplines that deals strictly with human health is also filling the coffers of that digital realm with equal fervor. Alas most of the data is subject to bias. The professor/scientist/doctor wants to publish about his or her experiment. Everything is funneled through the loose sinews of statistics. If the experiment is not successful (fails) a positive spin describes the benefits. If the experiment is a success, it is raised to the highest bar of recognition. Less than half of the patients achieve similar results as are proffered in the glowing scientific literature. What gives?  Unfortunately when the rigor of caution and careful analysis is undertaken more than 54% of the scientific papers fail validation (under close scrutiny). Yet some still try to persist in their endeavor by claiming the value of the p-value as the determinant of all successes
“Here we adapt estimation methods from the genomics community to the problem of estimating the rate of false positives in the medical literature using reported P-values as the data. We then collect P-values from the abstracts of all 77,430 papers published in The Lancet, The Journal of the American Medical Association, The New England Journal of Medicine, The British Medical Journal, and The American Journal of Epidemiology between 2000 and 2010.” ---( here )

In a society that massages the numbers and clothes them in words, selects the perfect scenario, applies the arbitrary values and changes the necessary variables, the output from the digital interface will be anything but unpleasant; a boon for the doers and a bane for the followers. We are being governed by the bias of some to the detriment of the many in small and large ways. It is up to us to recognize and critically manage such misinformation overloaded biases.
Our headstrong passions shut the door of our souls against God.´ - Confucius (c. 551 - c. 479 BC)

Thursday, December 4, 2014

"ABIM has Lost its Way"

“ABIM has lost its way.”

-so said Charles Cutler, MD the former Board of Regents of the American College of Physicians.
Now you rarely come across such a glaring comment from someone who has been a shepherd in guiding medicine and medical care.

The monologue started and the ugly facts started to show up on the screen one by one and as time marched on, they got uglier. I will share some of those with you. Oh, before I forget, let me say this was at a debate between the aforementioned Charles Cutler, MD and Richard Baron, MD the President and CEO of ABIM (American Board of Internal Medicine), held by the Pennsylvania Medical Society on December 2, 2014 in Philadelphia. I was there.



Dr. Baron started his protagonist “Maintenance of Certification” (MOC) viewpoint by visiting the history of medicine and the importance of education, from circa 1600s to the present, trying to tie in the time-honored need for physician education. He mentioned that in the 1980s when it was voluntary almost no one engaged in the process. But then it obviously became involuntary/mandatory through fiat, coercion, forced hospital and insurance buy-in!



He then cited MOC “studies” that confirmed the need for the MOC-process as a means to improve physician knowledge; namely make physicians better doctors in improving patient care. His fifteen minutes were laced with a mix of “Here is history and thus the need and MOC is the perfect tool.”

http://youtu.be/1H8NOCcHpw4


Dr. Cutler the antagonist to Dr. Baron’s point of view, started by visiting the revenue stream of the ABIM.


As Dr. Baron watched as his hand slumped on his pad and his eyes gazed at the floor. A lot was going to be revealed, he worried. Dr. Cutler meanwhile quiet and charming always holding a genuine smile on his face,  showed evidence of the ABIM-largess derived from the onerous MOC and showed how it was being used to pay high salaries to the Board of Directors of the ABIM. Dr. Cutler cited extravagant spending by the ABIM (its Foundation) to purchase a $2.3 million town-home in Philadelphia and paid taxes on the town-home annually.


He showed that the Board had meetings that were held at the Four Seasons Hotel, a few blocks away from the ABIM headquarters in Philadelphia with a luxury Mercedes Benz limousine parked in front of the majestic entrance ready to cater to the travel needs of the guests.



 Dr. Cutler revealed the salary of the previous President Christine Cassel, MD and associated other incomes from various agencies totaling $1.2 million a year, much to the growing dismay of the slightly reddened persona of Dr. Baron.



Dr. Cutler also mentioned other non-MD members of the ABIM staff who worked as assistant to the President making salaries in excess of $600,000.


But the dagger in the heart was that there was no real evidentiary proof that the MOC process itself has changed patient care except through tortured articles from the conflicted ABIM authors who had published their articles in journals that, well, kind of are subservient and beholden to the ABIM.

The questions from the audience that followed were mostly directed at Richard Baron, MD the supporter and beneficiary of the MOC process. His answers were mere deflections, usually “rehearsed talking points” and little else. He alluded to the fact that the $2.3 Million Condominium was for sale if anyone was interested, to a muted chuckle from the crowd. But defended his salary by saying that the organization revenues are $60 million a year and to get someone of caliber to head such an enterprise requires high salaries as all such companies need to do, to attract good managers. Huh? ABIM is supposed to be a 501(c)(3) organization and composed mostly of volunteers. Yet in Dr. Baron’s mind the high salaries are justified. He also pointed out that medicine currently is under significant regulatory pressures and physicians are lashing out at ABIM as a consequence, a nuance only a well-oiled bureaucrat can express. On questions about the ABIM’s need for a secure certification examination relating to the need for closed exam instead of an open book examination, Dr. Baron cited the “psychometricians” as the determinants of the rule, stating that when viewed from the “psychometricians” point of view, there was no difference in the outcomes between “open” and “closed” examinations. Further on the topic of making examination questions available to those physicians who need to assess their personal failings, Dr. Baron pointed out that the questions were made by the “psychometricians” and that ABIM had invested 14% of its revenue to craft the questions “ because it is a very difficult process to ask the right question?” was the answer. But there was no response as to ABIM sharing such information. If you are wondering about psychometricians and what they know...



What is telling is that the MOC process requires physicians to lay bare their patient records to the ABIM and all other personal information including the number of patients being cared for by the physician, in the era of “transparency” and yet the ABIM itself is quite opaquely mum about their data, financial and otherwise. Sort of a one way street, like the Roach Motel! You spend your time completing MOC (that you should be spending with your patients) and your earned income to get this certification process and then forever (professionally) you are embroiled in the imbroglio that robs you of both on an ongoing annual basis. There are no such determinants of knowledge, capability etc. utilized for lawyers, engineers, manufacturers, technicians or any other profession that bar an individual from pursuing a living without a continuum of recertifications. (Restriction of trade comes to mind). Yet ABIM through its tentacles is attempting to make this MOC, Certification and Recertification process, from which they benefit greatly, a necessity and requirement for the physicians. Failing or not pursuing such an endeavor the physicians would find it difficult to practice medicine.

In the quest for elevating human understanding there are infinite large spaces between information and knowledge and between knowledge and understanding. Information is passing. The Certification examination is chock-full of information gathering that has little basis in the understanding that is required in the art of medical decision making. These gulfs that exist are the exploits that ABIM wishes to undertake, yet it succeeds only in arming the regulatory forces that demean the physician, it succeeds only in arming itself as the body of repute from which flow all recognition and laurels but without foundation and thus it fails in pushing the needle of understanding by even a whisker with all its undertakings. Patients are lost in the equation. Maybe there is a better way? Maybe there is a better pursuit? Maybe there is a better understanding among those that seek to improve it, but so far it is sorely lacking for want of serious intellectual desire.

Interestingly mentioned at the meeting was that 71% of the 780 patients surveyed by one practice had no idea about Board Certification. And equally a survey of 600+ Physicians of varying specialties revealed that 97% thought that the MOC process was a waste of time and resource with no benefit to patient care. There is p-value there somewhere that screams against the null.

Speaking of stats, the Distribution Curve with its two tails clearly focuses on the risks (left tail) and benefits (right tail) of every probability assignment. In the case of MOC sponsored by the ABIM the left tail is fatter than an otter and the right tail is slimmer than a nematode. Skewing doesn't change a thing. Neither does changing the information variable, because the understanding of the knowledge remains a virtue of experience, intuit and wisdom.

The Pennsylvania Medical Society is to be commended for bringing up the subject and presenting it to the rank and file members and visitors. The official video is referenced below.



The frustration on the faces of physicians and bubbling up in every question asked, was palpable, but it did not seem to have any effect on the stony determined face of Richard Baron, MD President and CEO of ABIM.

I guess Dr. Cutler is right about ABIM having lost its way. The question then is, will the ABIM organization under the clutter of new found wealth, plush carpets, regal curtains, regency and gobs of money find its way back?

Only time will tell.

 “We have met the enemy and he is us!” 

Sunday, November 30, 2014

LINEAR REGRESSION

y = mx + c


What is it about Y
Not why about Y
But what.
It sits at the door waiting
For the chime
But inherently
Remains dormant.
If the C was less
and added to the gain
It would change the Y
But only by a little
You see additives
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
And gradient within
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
Nor degrade the meaning
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
Your words that soothe
And eyes that sympathize

What happened
O Physician
With transforming skills
A frown is affixed
The hands barely touch
Your words are hurried
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
To gather your love
For all you hold dear
Before your vessel hardens
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.