Sunday, April 21, 2013

(In Search of...) VARIABLES

In Search of Understanding Variables

What are variables” Are they some form of molecules, differing thoughts, concepts, ideas, behaviors, emotions, feelings, personalities or people? I guess the answer would be yes to all. Now wouldn’t it? Each one of us aspires to be different. We want to achieve, plan, create, modify, build, manufacture, harness or sometime merely express our inner most feelings. The variability in our expression and desires changes with the nuance of the day, the shades of reflections, the brightness of the sun or the silvery calm of the moonlight. Each moment bestows it’s own separate and distinct milieu that drenches thoughts and changes passion.

There are many variables, for instance; heat, volume, filters, position etc. each has a lasting value and impact on the ultimate result. And don't forget Lorentz "strange Attractor" in this wild and funky world. Yes, Indeed we are surrounded by variables. So when, some list one or two and forget the others without reason, I say bolder dash!

So how in the world can we as individuals, groups or organizations cater to the needs of the individual? How so?

In the days past, it was easy, there was little to go around and what was created was utilized. Today the world is awash with variability. There is literally something for everyone’s desire. You don’t portrait, we have a landscape for you. You don’t like desktops, we have a laptop for you and if you are a curmudgeon about laptops, why then we have a tablet for you. Every color of the rainbow and those other colors conspired by humans in between, is represented in clothes and objects. And yet with all this mass of commerce there is still a need for selective difference. That tiny wisp of individuality.

Big Data is here to fill in some of the salesman shoes that used to walk up to every door. Ah the computers are busy accumulating this information in large swaths of binary codes and storing them in large servers that hum cooled with the needed refrigeration to keep them from liquefying under enormous generated heat or worse through that heat, transmuting into a different frequency of the signal. Thus far it is the human that sits and uses his or her analytical smarts to decipher messages from these non-linear swarms. It is the analytical skills filled with Boolean Logic that determines the IFs that lead to the THENs. But soon we in our ever logical mind will be abrogating that decision-making process to the whir and whiz of spinning or solid state hard drives.

But lately Artificial Intelligence also a product of, you guessed it; human intellect is making its overtures. AI as it is called is slowly transforming our life.

It is!

You want some real life example? How about the driver-less cars zooming around the Google complex and soon to a neighborhood near you? Or, and this is near to the human Achilles Heal, the ubiquitously well known 16-terabyte phenom housed in New York, affectionately called “Watson?”  This machine is a giant repository of resource. But relegating the soft, yielding, compliant, argumentative, rebellious mind of the human to the even, linear, programmed, multiprocessing, cold, calculating 1 and 0s, residing within the set parameter machine, bodes a difference in the fortunes of the future is the difference between one that is naturally created through trial and error or the other crafted by the mechanized “soul” of a cold hard entity of yes and no and only calculated probabilistic in-between(s). One can only be reminded of the echoes from the past, “Dave, I am afraid, I can’t do that.”

You see, transformation in a society is a slow ooze of intellect, baked in the kiln of understanding, hardened to the cold biting air of the real world and then utilized. This is not meant to be pejorative by any means. There is a delightful repository of data that resides in Watson’s terabytes, indeed there is! But there is also the self-wielding algorithm couched by the human mind, the bromide, which would confuse Confucius himself by its selective bias. In all it is the number and kind of variables one uses to create such self-replicating chains of evidentiary information. It is in the intersection of the variables that real truth exists. Can we then know all the variables? Yes, If you can know the mind and body of the 7 billion people! Other than that we are playing with the play-dough of uncertainty and probability.

So what is a variable? It is a logical set of attributes. It may be dependent and thereby change as a result of other values within the system or strictly independent, messianic, authoritative and deliberate. But these nuances change the meaning of the meaning.

You might have heard the term “Multivariate” analysis! This implies that in doing the analysis many variables were considered so that the results were robust and not likely to be confounded by artifact. But just naming “multivariate” analysis does not release the chain of burden on the author nor the reader. For in that term the variables so chosen have to be specified and it is up to the reader to determine if from the reader’s perspective the utilized variables are enough to warrant the validity of the results. However no matter the result they will always be bounded by the confines of the "Confidence Intervals" called "CI." This CI has limits to about 95% in most scientific and medical literature because a probability is never the absolute reality and therefore suggests in a polite manner that outliers outside the confines of this 95% boundary do exist! For instance, I came across a well-referenced scientific paper that suggested that the benefits of a drug were superior to the standard treatment in a particular cancer. Okay, that is good. But reading further through the jungle of the graphs and the Tables and Boxed algorithms, I realized that the variables did not include ethnicity breakdown within the trial methodology. Now that would seem nit-picking wouldn’t it? But dare I say that there was a relevant piece of information about the disease suggesting that the ethnicity had a major impact on the survival of patients. So if one were to artificially bunch the ethnic details on one “Arm” of the study, the results would pleasingly benefit the "other" treatment arm, now wouldn’t it?

Another “brilliant” study suggested a human anatomical difference suggests the risk of a certain “disease/illness.” But here the variable used was a questionnaire handed over to the subject to see if he thought there was an apparent discrepancy between the anatomical regions. These subjects were everyday lay people and some with known medical illnesses and others without any. Given the filled in forms by the two cohorts of with and without the specified medical illness were cross tabulated with the subjectively-filled forms of anatomical differences. And voila there was a correlation determined and then using the probability function, a risk was derived at and the paper was published in a “peer-reviewed-high-impact” journal. An utter travesty, don’t you think?

So you say, “Variable, What Variable?” Slow down Watson, there is more than meets the eye. Be careful in your variable evaluation, in your analysis and thus in your thoughts for future actions. And you know what the “experts” dearly love to avoid? The “confounding variables!” These confounding variables create substantial aberration in results and thus can negate the premise being expounded, exploited, expressed or otherwise being shoved down the throats. Oops! Too strong eh? I am reminded of the Challenger disaster where the cold rings were never cross-tabulated and it took a Feynman to figure it out (watch below).

You see from a mathematical perspective, the additive values of the variables change the downstream results. They do. The formula is 
Here “i” is the summation variable that calls upon each of the integers and “n” is a non-varying parameter.

In Physical phenomenon, the Institute of Physics defines investigations under this light, “When investigating physical phenomena, there are two strands to thinking about variables: the difference between independent, dependent and control variables; 
the intrinsic nature of the variables, i.e. continuous, discrete, or categorical variables.”

Countering physical phenomena, Algebra however defines Variables as, “A Variable is a symbol for a number we don't know yet.”

However in medicine variables loom large (from California State University, Fresno),

Demographics – Examples: Age, sex, race, religion, income, etc.
Physical Characteristics – Examples: Height, weight, etc.
Physical and Mental Health – These concern the presence (vs. absence) of physical and mental disorders, along with their symptoms.  Examples: medical diagnosis, psychiatric diagnosis, number of headaches per week, number of panic attacks per week, etc.
Personal History – These concern experiences that people have had.  Examples: number of lifetime sexual partners,
Individual Differences – These include standard personality traits (e.g., the Big Five), along with other relatively stable psychological characteristics.  Examples: Extroversion, intelligence, financial responsibility, self-esteem, etc.
Beliefs and Attitudes – This category also includes knowledge, opinions, and judgments.  Examples: attitude toward divorce, opinion of the President’s job performance, beliefs about the seriousness of the AIDS epidemic, etc.
Affective Variables – These include emotions, moods, and feelings about the goodness or badness of a stimulus.  Examples: depression, subjective well being (i.e., happiness), anger, how much one “likes” a photograph.
Performance Variables – This refers to people’s performance on all sorts of physical and cognitive tasks.  Examples: number of points on a final exam, number of errors on a memory test, time taken to recognize a stimulus, etc.
Naturally Occurring Behaviors – These include essentially all other behaviors that people might engage in and that might be of interest to psychologists.  Examples: whether or not one person helps another, number of hours of television watched per week, whether or not use public recycling containers, etc.
Treatments – These are actions that are taken (vs. not taken), which are intended to have a positive (i.e., beneficial) effect on another variable.  Although the term treatment comes from medicine, neither the action nor the effect needs to be medical or biological.  Examples: taking a drug (vs. not taking it) to reduce anxiety, using cognitive therapy (vs. psychotherapy) to treat depression, using a new method of studying (vs. the standard method) to improve exam performance, etc.
Other Situation / Task Variables – This is an enormous catch-all category that includes anything about a person’s situation or the task he or she is performing.  Number of people in the room, difficulty of a test, noise level, time allowed to complete a task,  
And others dependent on the stated premise being evaluated.

So before you take the next step of doing a trial, evaluating a premise, exploiting an idea, understanding the world around you, contemplate your methodology, before critics start running you out of town after your 15 minute of fame.

Wednesday, April 10, 2013


So there we were, heralding the onset of a new dawn, drunk into a stupor with the insight of two men, Watson and Crick, who had just seen the X-ray diffraction images, projected by a woman named Rosalind Franklin. The fabled cloaked life of what made humans tick had been revealed. The DNA that carried the codes that made us, us, had been discovered. Now there was no end to the treatments that this knowledge would spawn. All those inimical diseases would be eradicated. Ah but that was such a long time ago, back at the dawn of genetic time in 1953.

And then again, our senses took leave, spread across the vast vistas of exotic thoughts of human life extensions into two or even three centuries. Oh yes, there were expert scientists who paid no heed to the term exaggeration. And on and on they boasted till there was no place on the front pages of the newspapers. Ah yes, a consortium of intellectuals had finally mapped the entire genome of a human being. A big and grand achievement worth celebrating indeed! They had found between 25,000 and 30,000 active genes on the DNA helix, not the 100,000+ that had been predicted. Well now! There would be little in the way of barriers in achieving the cures of cancer and other lamentable chronic diseases. Yes, truly the era of modern medicine was here. The Human Genome Project after 10 years and $3 billion had succeeded and every thing would be wonderful soon. That was 50 years after Watson and Crick, in 2003. A lot has transpired since then.

Every new discovery details a new path towards winning the war against disease, but every new discovery also brings with it questions. When I was 10, I thought there was nothing left to discover. When I was 20 that was really true. In my 30s it was really, really true, but then as time elapsed, none of it was true. Discoveries will keep coming as we try to figure out the mechanisms that keep us alive and eventually put us to a permanent sleep, "where dreams may come." Somewhere in there is the holy grail of a real understanding and if one would just stand a little far back, one can see that the intricacies are infinite.

The intricacies are infinite, because humans are constantly at war and peace simultaneously with their environment and life is in a flux of the ravages of storms and the glistening smooth calm of a silent sea.

And that brings me to the little pixies that create ruckus in our lives and simultaneously protect us. Sound familiar from a few paragraphs ago?

We’ve all heard the term Epigenetic, here “epi” the prefix means “upon” and quite literally that is true. The epi on the genetics is the rule of the meek over the mighty. Victor Ambros and colleagues Rosalind Lee and Rhonda Feinbaum discovered the first miRNA in 1993. The microRNA with only 18-24 nucleotides in their arsenal can wreak havoc on the function of a gene. In other words, put a miRNA on top of a gene and it can accelerate its function, decelerate it or completely silence it. Yup, the tiny maestros within, stand and shake their arms with aplomb!

Now that is called oomph! 

They do that by base pairing with the target messenger RNA or mRNA and inhibit heir expression through translation, or destruction. Humans have around 400 or so miRNA genes encoding their behavior ~ the guards, guarding. And if that wasn’t enough each miRNA sequence can mess with dozens if not hundreds of genes at one time, or the power of one! To boot, about 30% of the genes or more seem to be driving under this influence. These supervisory “little beings” if we can call them that, have taken on the responsibility of life and death decisions in the affairs of humans. They act as specific regulators of gene expression. In humans 3% of human genes encode for miRNAs, and up to 30% of human protein coding genes may be regulated by miRNAs. 

(The biogenesis and function of miRNAs. a Primary miRNAs (pri-miRNA) are transcribed from longer encoding DNA sequences (miRNA genes). The pri-miRNA contains one or more stem-loop structures of about 70 bases. In the nucleus, the ribonuclease enzyme Drosha excises the stem-loop structure to form the precursor miRNA (pre-miRNA). b After export into the cytoplasm, the pre-miRNA is cleaved by the ribonuclease Dicer to generate a short RNA duplex (miRNA:miRNA*). The mature single-stranded miRNA is incorporated into the RNA-induced silencing complex (RISC), while the complementary strand (miRNA*) is usually rapidly degraded. The miRNA incorporated into the silencing complex can bind to the target messenger RNA by base pairing, causing inhibition of protein translation and/or degradation of the target messenger RNA) Stephanie Sasson et al. Virchows Arch. 2008 January; 452(1): 1–10

Naturally, we as humans can’t sit around and party all day in oblivion. So we have created a set of double-stranded synthetic miRNA called siRNA or small interfering RNA that have the ability to degrade the mRNA. And they can target specific ones to achieve the purpose of silencing or activating to cool down an active oncogene or heat up the tumor suppressor gene. Human ingenuity is always nearby to exploit and defend its turf.

Some specifics for those who love specifics:

Colorectal Cancer: In Cancer Epidemiol Biomarkers Prev; 20(7); 1272–86. Hermann Brenner states, “A total of 160 miRNAs were found to be dysregulated in CRC. MiR-20a and miR-31 were found to be significantly upregulated in more than one study, and miR-143 and miR-145 were found to be significantly downregulated in CRC tissue in six or more studies. MiR-92a was significantly upregulated in CRC patients in two of the plasma-based studies and in CRC tissue in one of the tissue-based studies.”

Breast cancer: In Genome Biol. 2007;8(10): R214, Blenkiron  et al. state, Of 309 human miRNAs assayed, we identify 133 miRNAs expressed in human breast and breast tumors. We used mRNA expression profiling to classify the breast tumors as luminal A, luminal B, basal-like, HER2+ and normal-like. A number of miRNAs are differentially expressed between these molecular tumor subtypes and individual miRNAs are associated with clinicopathological factors.” (Supervised hierarchical clustering over selected miRNAs 

(Pearson correlation, average linkage). Heatmap colors represent relative miRNA expression as indicated in the color key for each panel. Brackets in the right margin indicate members of the same miRNA family. (a) Clustering of 51 tumor samples that could be classified as basal-like (red), HER2+ (pink), luminal A (dark blue), luminal B (light blue) or normal-like (green) over 38 miRNAs with Benjamini-Hochberg adjusted Kruskal-Wallis p < 0.05. (b) Clustering of 24 tumor samples classified as luminal A (dark blue) or luminal B (light blue) over 9 miRNAs with Benjamini-Hochberg adjusted Wilcoxon p < 0.05.)

Lung cancer: In Journal of Experimental & Clinical Cancer Research 2012, 31:54 Peng Guan states, “A total of 184 differentially expressed microRNAs were reported in the fourteen microRNA expression profiling studies that compared lung cancer tissues with normal tissues, with 61 microRNAs were reported in at least two studies. In the panel of consistently reported up-regulated microRNAs, miR-210 was reported in nine studies and miR-21 was reported in seven studies. In the consistently reported down-regulated microRNAs, miR-126 was reported in ten studies and miR-30a was reported in eight studies. Four up-regulated microRNAs (miR-210, miR-21, miR-31 and miR-182) and two down-regulated mcroiRNAs (miR-126 and miR-145) were consistently reported both in squamous carcinoma and adenocarcinoma-based subgroup analysis, with the other 14 microRNAs solely reported in one or the other subset… In conclusion, the top two most consistently reported up-regulated microRNAs were miR-210 and miR-21.”

Prostate Cancer: In Methods Mol Biol. 2011; 732:69-88, Tang et. al state, “As an example, profiling of miRNAs in four prostate cancer cell lines has revealed that a set of miRNAs were differentially expressed between androgen-dependent and androgen-independent metastatic prostate cancer cells. Among them, the differential expression of miR-205 and miR-200c were further validated by Northern blot analysis in these two types of prostate cancer cells.”

Epethelial-Mesenchymal Transition: In Journal of Hematology & Oncology 2012, 5:9, Oudai Hassan  et al. state, “Generally, the importance of miRNAs in cancer is emphasized by the fact that around 50% of all miRNA genes are positioned in the so called 'fragile sites', the cancer associated genomic regions which are repeatedly changed in cancer. The miRNA 143 and miRNA 145 are other two miRNAs that are assumed to play a role in EMT. In Prostate Cancer, miR-143 and miR-145 are deregulated in primary cancer compared with normal prostate tissue. The up-regulation of miR-143 in prostate cancer cells represses mesenchymal markers (vimentin and fibronectin) and increases the epithelial marker E-cadherin, while the up-regulation of miR-145 leads to the same effects except for vimentin."

Chronic Lymphocytic leukemia: In Proc Natl Acad Sci USA 99:15524–15529, Calin et al, “found that two miRNA genes, mir-15 and mir-16, were located within this 30-kb deletion. They subsequently analyzed the expression of miR-15 and miR-16 in blood samples from patients with CLL. Both miRNAs were absent or downregulated in the majority (68%) of cases when compared to normal tissue or lymphocytes. This finding suggested that these two miRNAs were causally involved in the pathogenesis of chronic lymphocytic leukemia.”

As equally as the miRNA are implicated as causal factors, their absence presages similar calamity, “A global decrease in miRNA levels has been observed in human cancers, indicating that small RNAs may have an intrinsic function in tumor suppression.”

Untangling the web of this deceitful malady called cancer, we learn a little and find out that we need a lot more to learn. For every one answer, more questions pop up, needing further investigation.

The human body is amazing evolving machinery. The beauty in it is the leaps of faith towards perfection and with each leap the unintended consequences leave us slightly more imperfect, more fallible, more in need of more information. Thus the cycle of profligate proliferation of the human race, like the viruses and their counterparts; bacteria, the race, is always on to survive the vicissitudes of out environment one piece of information at a time!

Tuesday, April 2, 2013


To-morrow, and to-morrow, and to-morrow,

Creeps in this petty pace from day to day,

To the last syllable of recorded time;

And all our yesterdays have lighted fools

The way to dusty death. Out, out, brief candle!

Life's but a walking shadow, a poor player,

That struts and frets his hour upon the stage,

And then is heard no more. It is a tale

Told by an idiot, full of sound and fury,

Signifying nothing. _Shakespeare

In the finite existence of humans, man is destined to inquire into the infinity of life. Yet in this very endeavor, he cannot escape being mortal. After all what is life? Except for existence amidst survival in the best of times and the worst of times. It is the slow tick of the clock edging ever close to the limits of its mechanism, the minute hand slowly and inexorably moving towards that fateful hour. And what of this life, except within short term memories of a few generations, extinguished as the hour hand sweeps to the next day.

The tale hangs by a tenuous thread.

There was a man in his forties, who was fastened to the horrors of a disease, always contemplating his survival. His dream was that he would build a magnificent house, buy a boat and speed across the ocean on a summer’s sunny day and barbecue at the edge of land with all those he loved and cherished. That was his dream. He would not listen to reason, for reason had treasonous intent and had betrayed him. He would not listen to limits, for they were self-imposed, in his mind. He would not listen because he did not want to listen. His, was a mind that defied rules of existence. He wanted to, nay, he believed that life limits were self-imposed and that death came when you let it enter the front door.

He accomplished some of his dreams. The summer of pain was mollified by the warmth of the sun and as surely as the sun rises each morning, the hope and dreams of one were drowned by the setting sun in the fall. The house he had desired, remained as nothing but an architects rendering. yet the door in those drawings had been left open.

Life is predictable! It always ends!

As humans we know that there is a predictable end to living, yet we cannot, do not and will not comprehend it and there lies the paradox. Death only comes to others. Loss is ours but we cannot comprehend our own exit. We can imagine it but always as a hovering presence of the third person. Can you imagine what death would be like? Is it a black void? Or is it an endless sea of light? Or is it just blank? What is it? What happens when the brain fails and the mind stops and one enters the “undiscovered country from whose borne no traveler returns?” Are there trumpets announcing arrival? Or as the Mortality Paradox forces us humans to say, “This is getting dense, let me change the channel.”

The Dying Gaul

This mortality paradox has drawn a more vibrant color in present day society. It appears to have become an imperative, that death can somehow be circumvented forever for me, even though it marches on consuming others. That disease is a function of the past and ridding it must be the exclamation of the present. As humans, we think that our capabilities transcend the vagaries of disease and the exclamation of death. In this metaphor ordained, quasi-scientific culture of a self-interest society, the denial of reality is the new norm, steeped in false hope and unfounded in reality.

Confronted with mortality, an 80-year-old will now evoke a sense of missed opportunity, missed expertise or just wrongful curtailment of his or her rights. Because we have cultured our culture with the false residue of life-extended perfect survival even in the face of the grim reality, denial is an easy retort.

British philosopher, Stephen Cave writes in his book, Immortality: The Quest to Live Forever and How It Drives Civilization (Crown 2012), “Death therefore presents itself as both inevitable and impossible,” and defines this as the Mortality Paradox.

While Woody Allen wants to achieve immortality “by not dying,” Christopher Hitchens on a more realistic tone, said at a lecture once, “I’m dying, but so are all of you.”

What about Shakespeare’s idiot? Are we him? Since he is telling the tale and ultimately whether an idiot or an intellectual be, we all share the same fate that eventually life, “signifies nothing?”