Monday, June 20, 2016

Cakes and Bakes by Keller

At the other end of grandsons is Keller and his baking business; Cakes and Bakes by Keller, try it out!
Go try them out! He has mastered the art of fine eating!

Another Eagle Scout

Terrence IV received his Eagle Scout award Saturday, having spent a total on nine years in the process. Congratulations!

Tuesday, June 14, 2016

Is AI Helpful or is it Merely the Opinion of Millennials in California


McCarthy defines AI, Artificial Intelligence, thus:

Q. What is artificial intelligence?

A. It is the science and engineering of making intelligent machines, especially intelligent computer programs. It is related to the similar task of using computers to understand human intelligence, but AI does not have to confine itself to methods that are biologically observable.

Q. Yes, but what is intelligence?

A. Intelligence is the computational part of the ability to achieve goals in the world. Varying kinds and degrees of intelligence occur in people, many animals and some machines.

Q. Isn't there a solid definition of intelligence that doesn't depend on relating it to human intelligence?

A. Not yet. The problem is that we cannot yet characterize in general what kinds of computational procedures we want to call intelligent. We understand some of the mechanisms of intelligence and not others.

Now in contrast my definition of AI is as follows:

If A=B
            Then C
            Else D
End

That’s is, no more no less. But the key question is; what is A, B, C, D? You see we are dealing with computers and we must use numbers, namely bits. Therefore, ultimately each is some binary number in a memory location. They are to reflect some reality. Thus the issue is:

1. Who selects the reality?
2. What measures of the reality are used?
3. What weights on the measures are employed?
4. How does one relate the measure of one's perceived reality with the actual reality, whatever that is?

One can see from the above that a great deal of human judgement is used. That is even the case if we "adaptively" change weights and measures. For example, one can use a first level system, namely one where the programmer assigns weights and measures. Namely we measure x and we weight it by y to generate z which we call A. Or we could use an adaptive system. We all like adaptive systems because they allegedly adapt to reality. But they are ultimately just the first level system pushed down one level. The adaptive system adapts its variable but by another selected measure called w. That is, we look at x and y overs some data space and weight it adaptively by w to get z which we no call A. This of course can be carried on forever but we still have some human making some value judgement somewhere. Thus that human value judgement stays with us forever! It can become immortal.


Consider a case from NEJM a few years ago. The answer was "rabies". From a Bayesian perspective, its probability of ever occurring would have been zero, and the diagnosis is not definitive until autopsy with the identification of Negri bodies in the brain. The question of how does one develop an algorithm, an AI procedure if you will, to identify something that would generally have zero probability until after death is problematic. Obviously there are many A, B, C, D, and they may operate sequentially or in parallel. Furthermore, they may also adapt, namely the weights that map diagnostic variables into some binary number may change.

Consider the initial presentation in the NEJM article:

The patient had been well until 4 days before admission, when aching developed in the left elbow, which improved with ibuprofen. The next day, right-elbow discomfort occurred, and he had decreased appetite. Two days before admission, he noted difficulty forming words, mild light-headedness, and mild recurrent pain in both elbows. An attempt to drink a glass of water precipitated a gagging sensation. He had difficulty breathing and could not swallow the water. The choking sensation resolved when he spat out the water, but it recurred with subsequent attempts. He stopped drinking liquids and became increasingly anxious. One day before admission, he was unable to shower because of increased anxiety and noted intermittent decreased fluency in his speech and pruritus at the nape of his neck. He was concerned that he was having a stroke, and he drove to the emergency department at a local hospital.

Now if one were in a region where rabies was pandemic one would immediately think of rabies. But in Massachusetts where there had not been a case for 80 or more years that would be the last thought. Thus how would one "program" this decision.

The added results were as follows:

On examination, the patient appeared anxious, with dry mucous membranes. The blood pressure was 171/80 mm Hg, the pulse 86 beats per minute, the temperature 36.4°C, the respiratory rate 16 breaths per minute, and the oxygen saturation 98% while he was breathing ambient air. Other findings included ptosis of the right eyelid, mild facial twitching, postural hand tremors, and dysmetria on finger–nose–finger and heel-to-shin testing, without truncal ataxia. Deep tendon reflexes were symmetrically hyperactive throughout; plantar reflexes were flexor. There was mild difficulty with tandem walking. The patient’s speech was rushed and fluent, except for occasional slurred words and pauses for word finding; the remainder of the general and neurologic examination was normal. The hematocrit, platelet count, erythrocyte sedimentation rate, and levels of hemoglobin, C-reactive protein, and troponin T were normal, as were tests of renal and liver function

Each result has to be added to some metric and some decision point.
 
One of the biggest problems in any AI is the judgements made when developing the primal metrics. The recent discussion regarding the alleged Facebook new bias is a prime example. AI is not politically neutral. It can be and remain as such highly biased by the very means by which selection bias is made. This is the case even if adaptive learning is utilized because even then the learning algorithms are also elements of bias perforce of their developers input.

To quote Drucker, who paraphrased McLuhan;

 "Did I hear you right," asked one of the professors in the audience, "that you think that printing influenced the courses that the university taught and the role of university all together." "No sir," said McLuhan, "it did not influence; printing determined both, indeed printing determined what henceforth was going to be considered knowledge."

Thus this led to McLuhan's famous phrase that the medium is the message. Specifically, as we developed a new medium for human communications, we dramatically altered the nature of the information that was transferred and the way in which the human perceived what was "truth" and what was not. The television generation of the 1960's was a clear example of the impact of television versus film in portraying the war in Vietnam as compared to the Second World War. The perception of these two events was determined by the difference of the two media that displayed them to the pubic masses. Television allowed for a portrayal that molded more closely to the individual human's impact of the events as compared to films overview of the groups involvement's. Both media deal with the same senses but they are different enough to have determined two different outcomes of the wars. This conclusion is a McLuhanesque conclusion but is consistent with the changes that McLuhan was recounting in the 1960's in his publications.

But a corollary to McLuhan and the medium, is the use of putative AI techniques to present to humans certain facts. The AI becomes the new medium, it is the filter between the facts, whatever they are, and the perceived reality. For example, if one were to be tracking News on politics, then perhaps the AI presenter, the new medium if you will, may present you negative only facts on say Trump and positive only on Clinton. The result is strong medium reinforcement. We know that is the case in print, we clearly can see this say in The New York Times, hardly a Trump fan, but we know the sources and can weight it accordingly. However, if there is some AI engine in the background, hidden behind some curtain, written and architected by the feelings of some unknown person or persons, then how do we interpret that.

For example, we are now all told that Silicon Valley is the hub of the new entrepreneurial gestalt. However, this reality is a reality of apps, and software manipulations and social networking. In contrast we have a massive entrepreneurial present in Cambridge, here we have genomic engineering and lifesaving technology. We seem to weight a new app or social network well above a new pathway inhibitor or monoclonal antibody. Why? Perhaps because the social networks are self-reinforcing.

Thus our concern is that when we have humans developing AI algorithms say for medical diagnosis or news presentation the algorithms are inherently biased. Again in medical diagnosis, does a machine respond as a human when by misdiagnosing the patient dies. For the machine it is just another data point. For the human is can be mind altering.

Machines do not make data mistakes, humans do. Yet machines do not weight their mistakes in such a drastic fashion as humans do. Also humans are always inserting their value judgements. The result may then, as Drucker noted, be perceived as the new truth. Thus if we have some group of Millennials in California writing algorithms called AI, it really must be understood as nothing more than complex multi-layer opinion pieces, and pieces which may have long lives. Do we really want their value judgements telling us what is reality? One would hardly think so. Thus AI poses a significant danger as nothing more that propaganda from privileged protagonists.

Reference

Greer et al, Case 1-2013: A 63-Year-Old Man with Paresthesias and Difficulty Swallowing, NEJM, 2013;368:172-80.

Drucker, Peter F., Adventures of a Bystander, Harper Row (New York), 1979.

Monday, June 13, 2016

What is the Value of the SATs?

The Admissions Office of UVA notes:

3. Scores from different exams aren't combined.We don't mix sections from different exams together. So we wouldn't put a math score from the ACT together with a reading/writing score from the SAT. Similarly, we won't mix sections from the old SAT and the new SAT. The College Board directed colleges on this last summer. They said it isn't appropriate to mix old and new because the exams are different.

Thus read that last sentence again. Well then what is the purpose of the SAT. It is to measure just what again? I gathered that some of the senior folks there came from the current Administration. That ought to pan out well, just look at their overall record.

SATs are like any other multiple choice exam. Drill Drill Drill. It is the low end equivalent of say the Chinese National Exams. You could have sequences several genomes, modeled successfully cancer pathway dynamics, or solved a few of Hilbert's challenges, but if you do not conform you are in my experience and in my opinion going to do poorly.

I truly feel sorry for some smart kids. If their profile does not meet the new world order then...but after all the Facebooks need some programmers...

Cancer Stem Cells: A Philosophical Look


The recent book by LaPlane on Cancer Stem Cells is a brilliantly well-crafted introduction to the field from is a philosophical perspective. Such an approach is significant since it was Galen who promoted the use of logic, and in fact the full trivium, as an integral part of the practice of medicine. Words do mean something and the term "cancer stem cell", the CSC, has been used by many over the last decade and a half oftentimes for multiple and possibly conflicting purposes.

As LaPlane initially notes the somewhat accepted definition of a CSC is (p. 2):

"Cancer stem cells are, as their name suggests, cells that combine two identities; they are both cancer cells and stem cells."

Thus starts the debate. For one must then ask what is a cancer cell and what is a stem cell. There is also a somewhat adjunct issue of the Cancer Cell of Origin. This construct is one that states that the initial change occurs in some cell. Then the CSC states that there may very well be another cell which carries on the proliferation. The questions then are: what are the characteristics of that cell, how can it be identified, how can it be targeted, and what are the therapeutic strategic that should be pursued? This is what the author examines.

The author's approach is philosophical in that she is concerned about definitions and the words that are applied. It is a bit of a return to the Trivium and even to Boethius. Words have meaning and what do we really mean by them. Furthermore, the author examines the meanings in terms of the phenomenological basis of each. As such this is a unique and frankly brilliant approach to a complex area.

It is not clear is this an exclusive coverage but it logically appears to be. It does assume that the CSCness is defined and immutable. On p. 4 the author raises the concern:

"Stem cells and CSCs raise philosophical questions regarding their identity because we still do not know exactly what they are."

Thus we are beginning to read an analysis of things for which we have a great deal of uncertainty as to their very nature.

On pp 28-31 the author starts to provide some structure to the definition of a CSC. She initially uses the definition by Reya from 2001 and she appears to give a definition (p. 29) as follows:

"If a cell is capable of self-renewal (a) and differentiation (b) then it is a stem cell."

The above describes stemness. Yet there are two other requirements. One requires that it is a CSC is a tiny amount of the total cancer growth and that, this is critical, that (p. 30):

"…cancers are initiated and maintained by cancer stem cells."

Just what and how the terms initiated and maintained are to be interpreted is yet to be determined. Now this word study albeit being philosophical is essential. Somehow to study something we must be able to define it in a universally accepted manner so that phenomenologically it is consistent. The author keeps driving this critical point.

The author, in summary, thus divides CSC into several categories. First is:

1. Intrinsic: CSCs are CSCs and that is all. Once a CSC always a CSC. Once a cell has CSCness it always retains that character, and thus is intrinsic to the cell.

2. Extrinsic: CSCness may be dependent on where and when the cell resides. A CSC may become a CSC and then change back to something else depending on some yet to be defined extrinsic factors.

Then for Intrinsic we have (Chapter 7):

1.1 Categorical: It is in its very essence. It is what it is.

1.2 Dispositional: It depends on some extrinsic factor. It has a potentiality but it must be activated by some externality.

and for Extrinsic we have (Chapter 8):

2.1 Systemic: It can be determined from any niche. As the author states on p. 169:

"…at least two kinds of processes can induce stemness: stochastic events affecting gene expression and cell population level regulations. In both cases stemness appears to be regulated at the population/system level suggesting stemness would be a "systemic property""

2.2 Relational: This is purportedly analogous to Dispositional but it is for the extrinsic mode. Namely some extrinsic niche element.

Thus there are four models of the CSC and each has some element of plausibility. Frankly perhaps all exist. The author then proceeds to examine each with both phrenological analyses as well as logical. She further posits possible therapeutic mechanisms for each. This is exceptionally well done and understandable.

Overall this is a unique and highly valuable contribution to the literature as well as to the discussions on the field of CSCs. Phenomenologically we seem to be obtaining new insights each day and having a framework to consider them is essential.

There are several areas where the author should have explored more. Let me name a few.

Mitosis: We know that cells divide by a process of mitosis. Generally, the cell divides and the resultant two cells are identical to the parent. Unless of course if some aberrant change occurs in copying the DNA as it splits.  Thus it would be useful to demonstrate phenomenologically how this process would work so smoothly in CSCs. How does mitosis occur with a CSC so as to enable this bifurcation into a duplicate and an aberrant albeit non-CSC cell? What is the phenomenological steps that allows this? Thus far it appears to be some magical process which is just skipped over.

Dynamics of CSCs: In the classic CSC model each CSC divides creating a single copy of itself and a copy of some type of non-CSC cancer cell. Then somehow this collection of non-CSC cancer cells increases. If they do not divide, then growth rates are dominated by the CSC. For example, in the simplistic clonal theory where a single cell mutates and thence this cell just multiples the resultant populations grows exponentially. This may be modified by some form of apoptosis or lack of cell progression but it states that it is just a clonal explosion. We now know however that cancer cells as they go through he body are highly heterogeneous. Thus cancer is not purely clonal.

Epigenetics: We now understand that epigenetics plays a key role. However, their cellular dynamics is relatively little understood. Certain cancers such as MDS are really methylation disorders, that is epigenetic, and yet they often progress to AML.  

Ensemble Models: In physics such as in statistical dynamics and in engineering in large scale stochastic adaptive control systems one develops ensemble models. Namely one could consider cancer as ensemble of cell states with transitions occurring between these states. A cell state would be the expression state of the genes, namely what genes are functioning and which are not. This of course is suggestive. Then one could consider a model for a space time spread of this new organism, the cancer states, and instead of looking for a CSC one could look to identify the "control elements" of this new quasi organism. This would be an adaptive system approach based upon a totally different view of the cancer. Thus is the CSC a transient artifact or a fundamental target for cancer?

Coverage: Are the epistemological models posited by the author complete? Do they cover all possible options in which a putative CSC can take? The four seem to be so: internal with internal control, internal with external control, external with internal control, and external with external control. It appears that these cover all options. Yet is it too all encompassing? Or as an Ockhamist is each CSC just another representation of how cancer can develop. Is the attempt by the author to categorize to be defeated by nominalism?

Overall this is a superb book and should be read and consumed by those in the field. The debates still continue but having such an approach brings new insight and discipline that is of great value.

Thursday, June 2, 2016

More on Bats

The CDC reports a troubling case of a death from rabies. They state:

Rabies is a nearly universally fatal zoonotic disease, but is preventable if exposed persons receive postexposure prophylaxis (PEP). During recent decades, most domestically acquired human rabies cases in the United States have been associated with bat exposures; however, in the majority of these cases, no bite was reported. In 2015, a Wyoming woman aged 77 years died from infection with a rabies virus variant enzootic to the silver-haired bat. The patient had contact with a bat while sleeping, but she and her husband, her primary caregiver, were unaware of the risk for rabies in the absence of a visible bite wound; they did not seek medical evaluation or receive PEP after the incident. The patient’s family had reportedly contacted several local agencies about bats near their home over multiple years, but had not been informed about the risk for rabies.

 Rabies and bats are always paired. Bats are invasive and seek home for their settings. Bats also are as noted the most significant carrier and transmitter of rabies. How any physician missed this is unthinkable. Prophylactic treatment is essential even is a minimal exposure is considered.

The problem is that the vaccine is expensive and often not covered by insurance and further most Health Authorities are not attuned to the risk.

Hopefully the CDC can address this issue. Death from rabies is preventable if only one were to act.