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.

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