Friday, January 31, 2014

Interesting Naval Aircraft

The X47-B (above is USN photo) is an unmanned carrier launched aircraft. The Navy has deployed it for tests. As they state:

The X-47B Unmanned Combat Air System Demonstrator (UCAS-D) conducted flight operations aboard the aircraft carrier USS Theodore Roosevelt (CVN 71), Nov. 10. The event, the most-recent in a series of carrier-based tests, demonstrated the integration of the latest in naval aviation technology with the most advanced and capable carrier.

 It is interesting in that Carrier Groups present powerful deployment platforms but are also vulnerable to sophisticated attacks.

As USNI reports they will potentially operate jointly with manned aircraft.

During the two previous X-47B at-sea periods onboard USS George HW Bush (CVN-77) and USS Theodore Roosevelt (CVN-71) in 2013, while the unmanned demonstrator had a Boeing F/A-18 chase aircraft, the two types did not operate together on the carrier flight deck. This time around the manned F/A-18 and X-47B will operate from the carrier together cooperatively.

This means that the reliance upon fixed deployment platforms may be diminished.

An Interesting Trial

NCI is proposing to do a randomized trial with selected cancer patients based upon genetic profiling of the specific cancers. Namely they state:

Patients with melanoma whose tumors have mutations in the V600E region of the BRAF gene should have received and progressed on a specific BRAF inhibitor therapy to be eligible for NCI’s M-PACT trial.

Patients with lung cancer should have had their tumors tested for the presence of EGFR and ALK gene mutations, and, if mutations were detected, they should have received and progressed on therapies targeting EGFR or ALK, respectively.

 The specifically state:

Patients with all types of solid tumors will be considered for trial eligibility. For the randomization, patients will be assigned to Arm A (they will receive a treatment regimen prospectively identified to target their specific mutation or relevant pathway) or Arm B (they will receive a treatment regimen not prospectively identified to target their specific mutation or relevant pathway).  Patients in Arm B will have the option to cross over to Arm A to receive therapy identified to target their specific mutation or relevant pathway if their disease progresses on their initial study treatment.  As of January 2014, the study is open for patient accrual.  

What is interesting is that this appears to be a great beginning to such a procedure. One of the concerns, however, is that with BRAF V600 we seem MEK mutations following and then we must treat that one. The challenge is to try to better understand the evolving mutations that result as the tumors proliferate and spread. Thus we may then better understand how to treat the patient progressively and even perhaps prevent subsequent mutations. But this is well worth the following.

However there is the question of epigenetic factors which should be considered as well. Methylation is a prime factor which we know plays a significant part in many cancers, such as prostate and others. Other epigenetic factors such as miRNA and lncRNA are also considered of import. Thus focusing on genes is but one step.

Therefore it would be of interest to further consider:

1. Progression of genetic changes by time and location.

2. Complexities and proliferation of epigenetic changes as well as benign somatic epigenetic factors.

3. Family genetic analysis could also be of help to determined any heritability predilection.

Thursday, January 30, 2014

Je parle Francais, un peu, je pense

The NY Times has a piece on the attempt to expand French as a second language in New York Schools. They state:

In the fugue of tongues on New York’s streets, French has never been a dominant voice. And as surging numbers of Asian and Latino immigrants continue to tip the balance of foreign languages toward Chinese and Spanish, the idea of learning French, to some, may seem kind of quaint, even anachronistic.Yet in the city’s public school system, the French dual-language program, in which half the classes are in French and the other half in English, is booming. 

Now more than half a century ago after my Latin and Greek I spent four years learning French. One had to since we were taught by the French Christian Brothers.  But has French been of any use? Well I had to translate several papers for my Doctorate, but that was harder than I thought since several were from the early 1900s and they were a bit arcane. Then I spent a great amount of time in France and as long as I was not in Paris things went well. In Paris my non-Parisian accent was instantly noticed and the Parisians switched to English so as to let me know of their dissatisfaction.

Now the two main languages seem to be Mandarin and Spanish. Frankly any New Yorker should just pick up Spanish as a second language on the subway alone, the signs are all in Spanish and half the conversations are as well. It is almost by osmosis that one gets to feel comfortable with it. 

Recently I remarked that my grandchildren are learning Mandarin whereas I learned Russian back in the 50s and 60s. My Mandarin speaking listener immediately asked if I was a "spy". "No", I replied and continued to explain that in that period much of the technical literature in my area was in Russian. In fact if I recall I may have been one of the last MIT PhDs to have to have some modicum of language proficiency, mine, for what it was worth, was Russian. 

So what is the worth of French? Almost everyone knows English, and English can be mangled totally and still be a manageable means of communications. Just speak to any New York Cab Driver, almost all of whom have some other language as their native tongue. English has so much flexibility, assuming you do further mangle it with an accent as with the Brits, and it can be understood. 

I cannot say about Mandarin, but Russian is also manageable, and Italian, well, just learn to stress all vowels and wave your hands and you too are from some part of Italy, love the language.

But French, one cannot make a mistake in syntax, form, or any part of the language, it grates the ear and mind. French has unalterable structure and is devoid of slang. You must say what you intend the way it is supposed to be said, and moreover you must remember the syllable to be stressed. So what its the value of French? Well you can read some of the worlds greatest novels, philosophers, political thinkers, poets, and the like, they are wonderful in French. In Normandy and Savoy they will listen to your attempts to pronounce it properly and are forgiving. But abandon all hope of ye who enter Paris!

So what is the best languages to teach in New York? It seems that Latin and Greek have seen better days. But Spanish and Mandarin can be fund on any street corner. The key to learning a language is the ability to integrate it to one's visual response. Russian finally made it when I could walk around Moscow and not translate words, just look at the Cyrillic collection and recognize apples, milk, bread, etc. New York presents that in Mandarin and Spanish, unfortunately not much if any French!

Wednesday, January 29, 2014

The One Trick Pony

For the past five plus years as I have watched Google prosper I have always suspected it is a one trick pony, a very good one trick pony. The announcement today that it is selling the Motorola Unit that is bout a few years ago seems to more than validate my view.

One need just look at Google's stumbling:

1. Nexus, now I have several Kindles, they work, they are reliable, and Amazon understands customer care. My Nexus broke in 6 weeks and I sent it back to the Chairman who I had co-chaired the Internet 2 Presidential Panel with. I sent a letter, a personal letter. Did I ever get a response, no, did I ever get a replacement, no. One suspects management has other issues that are more important than customers.

2. Google RSS Reader: Now this could have been a goldmine. Dead.

3. Google's Personal Health Pages: I saw this as a home run for the EHR requirement. Google's response, kill it.

4. Fiber to the Home: What part of my many analyses on cities did Google not read? Forget it guys, the Cable companies will bury you. How much did you wast on this one.

The list goes on. However, Android makes sense, but that was a natural extension of software to the customer, a platform. The other things were toys that the "kids" played with.

My advice to Google, "focus, focus, focus". Being under 30 and having a high IQ is not all in life. And yes, if all else fails please listen to the customer. After the NSA does, your customers at that!

Tuesday, January 28, 2014

What is the Purpose of the Navy?

Admiral Mahan was a distant cousin from the same village in Ireland in County Lietrim. So perhaps, as my Irish side would say, I have a wee bit of a concern.

 There is a strong proposal coming from the current Administration to reduce the size of the carrier fleet. As USNI states:

A bipartisan group of Congressmen have written a letter to the Secretary of Defense expressing their strong support for maintaining a fleet of 11 nuclear-powered aircraft carriers despite rumors the Pentagon is considering cutting the carrier fleet. “We write to reiterate our strong support that the United States Navy should continue to require a naval fleet of no-less than 11 nuclear aircraft carriers,” reads the Tuesday letter address to Defense Secretary Chuck Hagel.

Now generally there is only one third of the fleet out at any one time, thus about 3 or 4 carriers, covering the Globe. They are supported by a collection of other ships in what is called a Carrier Task Force. They are our way of protecting American interests, like getting help to Libya etc, which at times does not work.

As the Navy currently reports there are 4 carriers at sea.  They are:

USS Carl Vinson (CVN 70) - Pacific Ocean
USS Theodore Roosevelt (CVN 71) - 5th Fleet
USS Harry S. Truman (CVN 75) - 5th Fleet
USS Ronald Reagan (CVN 76) - Pacific Ocean

That leaves 7 in port. In the event of a problem in the Atlantic or even northern pacific we have a problem. Currently the total focus is the Middle East and the South China Seas. We have substantial exposure elsewhere. Not to mention the problem of littoral threats.

Perhaps a rethinking of the strategic need for a well deployed Navy, including submersibles, littorals and a well equipped Marine Corps is essential.

Monday, January 27, 2014

Prostate Cancer Overdiagnosis?

Prostate Cancer is the number one occurring cancer in men in the U.S. At the same time there is an ongoing debate as to the need to screen for this cancer. The problem is that most cases of PCa are indolent and will not be the cause for a man’s demise. On the other hand we know that a significant number of cases, 5-15% of them, are aggressive and will result in a very painful death in a short period, two to six years or less. The problem is that there is no gold standard test to determine which is which.

Various genetic profiles have been proposed wherein they measure the expression of a panel of genes and then calculate a metric, usually some number, which if in a certain range means indolent and outside of the range is aggressive. The problem of course is; what cells are you making this measurement on? If you are doing it on the encapsulated prostate cells then you may be missing the already metastasized cells which have moved to the bone.

Now a recent paper by Gulati et al state[1]:

The chance that a prostate cancer detected by screening is overdiagnosed (ie, it would not have been detected in the absence of screening) can vary widely depending on the patient’s age and tumor characteristics. The purpose of this study is to use age, Gleason score, and prostate-specific antigen (PSA) level to help inform patients with screen-detected prostate cancers about the chances their cancers were overdiagnosed.

First I would be concerned with the definition of overdiagnosed. It states; “it would not have been detected in the absence of screening”. One should examine this. If one screens and detects a PCa then that is an overdiagnosis. If, however, one gets a patient who comes into your clinic with massive back pain and dysuria, then that patient is not overdiagnosed. The latter patient is however terminal. Thus I would strongly quibble with this definition of overdiagnosed.

They continue:

A computer microsimulation model of prostate cancer natural history was used to generate virtual  life histories in the presence and absence of PSA screening, including an indicator of whether screen detected cancers are overdiagnosed. A logistic regression model was fit to nonmetastatic patients diagnosed by screening with PSA less than 10ng/mL, and a nomogram was created to predict the individualized risk of overdiagnosis given age, Gleason score, and PSA at diagnosis. The calibrated microsimulation model closely reproduces observed incidence trends in the Surveillance, Epidemiology, and End Results registries by age, stage, and Gleason score. The fitted logistic regression predicts risks of overdiagnosis among PSA-detected patients with an area under the curve of 0.75. Chances of overdiagnosis range from 2.9% to 88.1%. The chances of overdiagnosis vary considerably by age, Gleason score, and PSA at diagnosis. The overdiagnosis nomogram presents tailored estimates of these risks based on patient and tumor information known at diagnosis and can be used to inform decisions about treating PSA-detected prostate cancers.

Now I would also have concern as regards to such a model. We have been examining them in several cancers and they are complex and require data which we are yet able to provide. Moreover a logistic analysis is rant with many problems; it merely hypothesizes a relationship based on a correlation model which may bear no resemblance to reality. In its place one really needs a tempero-spatial model which includes genetic mutations in some Markov manner. Also I would be concerned with an overdiagnosis range of from 2.9% to 88.1%.

Now a comment by Rathner in the same issue states as follows[2]:

Using a nomogram that incorporates age, Gleason score, and prostate-specific antigen (PSA) level at diagnosis, individual risks that a screen-detected prostate cancer has been overdiagnosed can be estimated, according to a new study published January 6 in the Journal of the National Cancer Institute . The authors used a standard definition of overdiagnosis to refer to a cancer that would not have become symptomatic or clinically identifiable if it had not been detected by screening. Overdiagnosed cancers do not pose a risk to the patient and do not require treatment, which is associated with significant risks of impotence and incontinence.

Here there is a clarification of overdiagnosed as meaning indolent. Indolent means slow growing and of de minimis risk of death from the lesion. However it is highly problematic to make such a determination unless one uses genetic metrics on a whole body basis. Techniques using exosomes may be beneficial if the profiles are stable.

Previous studies have estimated the risk of overdiagnosis for the U.S. population, with results ranging from 23% to 42% of screen detections. However, risks of overdiagnosis can vary considerably depending on the patient’s age and tumor characteristics, highlighting the need for a personalized tool to predict the likelihood of overdiagnosis. … The authors used a microsimulation model to generate virtual life histories for a representative population of u S men between 1975 and 2005. Men who develop cancer can be detected based on elevated PSA levels or development of symptoms. ,,,,

 A prediction model was then developed to predict individual chances of overdiagnosis (i.e., the chance that other-cause death would precede diagnosis in the absence of PSA screening) given information known at screen detection. The prediction model estimates that the chances of overdiagnosis range from 2.9% to 88.1% depending on patient age, PSA, and Gleason score. …

Freidlin and Korn question whether the Gulati et al model of the risk of overdiagnosis is useful in guiding treatment decisions of patients with screen-detected prostate cancer: “...once an individual has been screened and found to have prostate cancer, the relevant question is the outcomes of various treatments (treatment morbidity, prostate cancer symptoms and death), and not the probability of an event [detection of prostate cancer] that could have happened if the individual had not been screened.”

One then must ask if it is ethical to perform a fully blinded randomized trial to ascertain the predictions made herein. As much as I am a fan of models, this is not a phenomenological model. It merely uses data from previous diagnostic tests to ascertain the importance of certain metrics. As such it lack what I believe is a sine qua non to approaches like this, a physical model with predictability.

Now comments in Healio state the following[3]:

Researchers assessed risk for overdiagnosis — defined as a cancer detected through screening that otherwise would have been asymptomatic or clinically unapparent— using a microsimulation model of virtual life histories of men aged 50 to 84 years from 1975 to 2005.
Researchers then applied SEER prostate cancer incidence and PSA screening data to the virtual models. Results indicated that the odds for overdiagnosis increased by 12.9% (95% CI, 12.2-13.6) for each additional year of age at the time of diagnosis.

One of the concerns is that using SEER from 1975 to 2005 may insert a bias in age since PSA was not used to any extent until 1995 at the earliest. Thus half the data was without PSA testing and thus the older men may very well already have PCa.

A Gleason score of at least 7 was associated with a 19.5% (95% CI, 11.7-26.5) decrease in the risk for overdiagnosis when compared with a Gleason score of 6 or lower (P<.001). The odds of overdiagnosis decreased by 16.6% (95% CI, 14.2-18.9) with each additional 1 ng/mL of serum PSA up to 10 ng/mL.

A Gleason of 7 on biopsy may be really a Gleason of 8 upon prostatectomy. It may even be higher. PSA is also an issue related to age, prostate volume, BPH, and the better measurements are those reflecting temporal changes. Single PSA measures have the same problem as spot blood pressure measures. Researchers found age to be the most statistically significant risk. Among men with a Gleason score of 6 or lower and PSA levels from 4 ng/mL to 4.9 ng/mL, those who were aged 50 to 54 years had an 11.6% risk for overdiagnosis, whereas those who were aged 70 to 74 years had a 59.9% risk and those who were aged 80 to 84 years had an 83.4% risk.

Age has always been a significant factor and the results presented here in my opinion just reiterate that fact.

The question is; does such a nomogram have any clinical value? That is in my opinion problematic. The handful or so of first line Urologists at major centers will have thousands of cases where they can ascertain based on a plethora of data a patient’s prognosis, yet even they are wont to go too far. Patients, in my opinion, may find such an approach as just another element to add to an already confusing pile of suggestions.


Gulati R et al, Individualized Estimates of Overdiagnosis in Screen-Detected Prostate Cancer, JNCI J Natl Cancer Inst (2014) doi: 10.1093/jnci/djt367 First published online: January 7, 2014

Rathner, Z., Nomogram to determine individualized estimates of screen-detected prostate cancer overdiagnosis, JNCI J Natl Cancer Inst (2014) doi: 10.1093/jnci/dju001 First published online: January 7, 2014

Hypermethylation and PCa

Methylation is an epigenetic process which often results in the silencing of genes and for example in the case of hematologic cancers is often the driver for loss of proper maturation of cells and to the proliferation of blast cells. The MDS condition is a prime example. This precursor of AML is often a result of hypermethylation which in turn can be treated by demethylating drugs.

In PCa there is still a debate as regards to the cell types initiating the process, luminal vs basal, and also the existence and significance of the PCa stem cell. In a recent paper by Pellacani et al the authors note[1]:

Prostate cancer (CaP) is mostly composed of luminal-like differentiated cells, but contains a small subpopulation of basal cells (including stem-like cells), which can proliferate and differentiate into luminal-like cells. In cancers, CpG island hypermethylation has been associated with gene downregulation, but the causal relationship between the two phenomena is still debated. Here we clarify the origin and function of CpG island hypermethylation in CaP, in the context of a cancer cell hierarchy and epithelial differentiation, by analysis of separated basal and luminal cells from cancers.

For a set of genes (including GSTP1) that are hypermethylated in CaP, gene downregulation is the result of cell differentiation and is not cancer specific. Hypermethylation is however seen in more differentiated cancer cells and is promoted by hyperproliferation. These genes are maintained as actively expressed and methylation-free in undifferentiated CaP cells, and their hypermethylation is not essential for either tumour development or expansion.

We present evidence for the causes and the dynamics of CpG island hypermethylation in CaP, showing that, for a specific set of genes, promoter methylation is downstream of gene downregulation and is not a driver of gene repression, while gene repression is a result of tissue-specific differentiation.

The observation is interesting since it differentiates hypermethylation from cause to effect.

As stated in the article in Medical Express concerning the above article, the writers note[2]:

Scientists at the University of York have discovered that a process called 'methylation', previously thought to drive the development of cancer, occurs in cells that are already cancerous. The findings mean therapies aimed at reversing this process might not be effective against cancer stem cells, allowing the cancer to return…The work, … reveals a major difference between the cells normally treated in cancer and the underlying 'stem' cells.

The discussion of stem cells in PCa is something we have examined for the past few years. There is as of yet no clear definitive demonstration of such stem cells and even more so there is no description of what a stem cell is especially as regards to any genetic changes. They continue:

Dr Pellacani said: "To develop cancer, certain proteins found in healthy cells need to be switched off”. Sometimes this is caused by methylation - a process where DNA is changed to block instructions for making a specific protein. "There are obvious differences in the methylation of genes in prostate cancer cells and non-cancer cells. This previously suggested that the process could be driving the progression of cancer, and that this could be reversed by using specific drugs, but our research has suggested that this may not be the case."

Methylation is a powerful and ubiquitous process. It has only been understood as a significant epigenetic factor in the past decade and even now is going through a steep learning curve. Methylation is often found in cancer cells and like so many of the suggested genetic profiles one wonders if it is cause, effect, or just correlative. One may even wonder if methylation is some archaic attempt by the cells to deal with the genetic changes causing the cancer. It is not yet clear just what the function may be.

The authors continue:

Prostate cancer is made up of two types of cell; rare basal cells, including stem cells, from which the tumour is formed, and luminal cells, which form the tumour mass. The team found that a change from basal to luminal cells – a process called differentiation – is strongly linked to the methylation difference, suggesting that the methylation in prostate cancer cells is not the primary driving force for the cancer.

This is a strong statement which some may not fully agree with. There have been many studies which we have reported on here that question whether we have a basal or luminal cell origination of PCa. In fact one might even imagine some other cell altogether. Yet the methylation factor in basal to luminal change is interesting.

Dr Pellacani continued: "There are clear implications for the effectiveness of new drugs currently being developed to change the methylation pattern in cancers. At the moment we only treat a proportion of the cells. By breaking the cancer down into its component cell types, we get insights into why cancers come back after treatment. Only by treating all the cells in a cancer will we approach long term treatment or even cure." Professor Maitland and his team at the YCR Cancer Research Unit achieved international recognition in 2005 when they were the first to identify prostate cancer stem cells, which are believed to be the 'root cause' of prostate cancer.

This discussion is of interest and it blends well with our model of cancer cell propagation. The two observations are critical. They are: (i) that there are various cancer cells characterized by specific gene expressions or lack thereof, (ii) that there exists a cell called the stem cell which has characteristics we have discussed at length. The hypermethylation, and even hypomethylation, are but two characteristics of epigenetic changes. We would also expect to see miRNA, lncRNA and the like to also play roles.

The problem still is; what cells are we profiling? Are we profiling cells proliferating in the prostate or one which have already spread elsewhere?

Overall this is an interesting and compelling report.


Pellacani, D et al, DNA hypermethylation in prostate cancer is a consequence of aberrant epithelial differentiation and hyperproliferation, Cell Death & Differentiation, (24 January 2014).

Sunday, January 26, 2014

It is Good That We Are Not in the Middle Ages

The Guardian reports that when the Bishop of Rome let loose some white doves from his balcony that they were attacked by seagulls and crows. If this were say 1092 we might have the source for some bad omens.

The Guardian states:

...thousands of people watched in St Peter's Square on Sunday, a seagull and a large black crow swept down on the doves after they were set free from an open window of the Apostolic Palace.

 One wonders where this may fit within the message. It could be a great basis for some novel.

Income Inequality: What Does It Really Mean?

The current concern on the issue of Income Inequality is really not new. As I have noted before it started in the early 19th century and seemed to peak during the first Progressive era from 1890 to 1920. The issue then was that with the influx of immigrants and the extreme wealth of a few, that the country was going to Hell in a hand basket.

Recent authors such as the left wing Irishman at the New Yorker states:

Now for the bad news: the Horatio Alger myth is still a myth. Relative to many other advanced countries, the United States remains a highly stratified society, and most poor kids still have few prospects of making big strides. I’ve already mentioned the finding that the odds of a child moving from the bottom fifth of the income distribution to the top fifth are less than one in ten, and have been that way for decades. For children who are born in the second fifth of the income distribution, those who might be categorized as working class or lower-middle class, the probability of moving up to the top quintile has fallen significantly. For someone born in 1971, it was 17.7 per cent; for someone born in 1986, it was 13.8 per cent.

 Frankly to see that this does not really add up all one has to do is to look at the backgrounds of the top earners at Goldman Sachs. Unlike the UK we in the US do not have a Constitutionally mandated Aristocracy. The UK does and they believe there is a Divine right to, well money. Here in the US frankly any person if they are smart, so inclined, and can fast talk themselves to the right places, can get to Goldman.

In a similar fashion, I look at the many students from China who come here and with just a bit of searching one finds near poverty a generation or so in the past.

The problem as I see it is what we expect of our children. When I approached college it was; what was I going to do for a living? In the late 1950s most kids in Catholic Schools in New York saw the police or fire departments as a path forward. Many looked for union jobs, sinecures that guaranteed high pay for low yield. Only some 20% or more went to college. A few of us looked past the good Brothers and even Vatican 2 and saw opportunity. Thus one got a degree, by hook or by crook, so as to get a well paying job, not to be "educated". The problem today is we seem to send our children to college and seem never to ask them how they will earn a living.

The kids coming out and going to Goldman had asked that question early on and were directed to go there. Goldman and the like are one of the many opportunities available. Entrepreneurs have a much better chance than when I started with my first start up in 1969. There were at best a handful of venture companies, if such was even an appropriate term. Now, there are still thousands. And there are globalization trends. There are very few silver spoons. This is not the UK. Fortunes are made and lost. Then they are made again. That is the glory of the United States.

Perhaps, as I suppose, the drop in some incomes, is because we failed to ask, "What are you going to do for a living?" Instead we allowed a generation or two to take up their interests never worrying about their lives!

Left Hand Pocket to the Right Hand Pocket

In a recent announcement, PCORI, the Government sponsored and funded entity which get about $500M pa from the added taxes on our new health care plans has awarded some $5M contract to NIH to fund work on its internal PRO system. They state:

The Patient-Centered Outcomes Research Institute (PCORI) has approved $5 million in funding for research focused on the Patient Reported Outcomes Measurement Information System (PROMIS) of the National Institutes of Health (NIH). “Funding PCORI projects focused on PROMIS will allow us to substantially advance the use of these tools in comparative effectiveness research,” said PCORI .... “Working with the NIH allows us to build on its investment in a comprehensive, flexible, and patient-centered measurement system.”

 Now this means that the money we all pay for our health care now has a tax which is collected by the Government and then handed over to PCOR which then as a non-governmental entity adds its costs and then transfers the $% M to NIH a governmental entity. One wonders how much money there was before it got down to the $5 M going to NIH. Why not just give NIH the money outright rather than burdening the taxpayers with the added overhead. Only the Government could conceive of this mess.

But read the words, "advance the use of these tools in comparative effectiveness research" Namely, this is a CCE tool, and although it focuses on PRO information it will be used for CCE or CER results.

Now just a remark on CCE. FDA does randomized trials using well accepted gold standard statistical techniques. CER examines procedure in a real life clinical setting. Patients just do what they want. That means if we compare weight reduction to metformin for Type 2 Diabetes, we all know that most people just do not do what they are supposed to in managing food intake. Thus we know a priori that there is a bias. Also the people will not tell the truth, they fear being criticized. Thus CER has at best highly questionable results.

So why do this work? If NIH is doing this for drug approval support then we have the FDA involved. If it is for CER/CEE work then PCORI is now the new kid on the block. But somehow this flipping the money around so everyone gets a bite is rather silly, and wasteful of the taxpayers money, but alas it is what we have come to see in the ACA. Just a little corner of the effort.

Now let us examine what this $5M may cost the Taxpayer. Below is a reasonable flow chart of what Government entity handles each step.
The money is paid by the Taxpayer. It is collected and validated by the IRS who hands it to the Comptroller of the Currency, who pays PCORI. Remember PCORI us guaranteed a minimum of $500M per year!. Now PCORI works through RFPs etc and ultimately the $5 million goes to NIH. Along the way I estimate that the Taxpayer had to pay in $25 million to get the $5 million out the other end! Why not just give it directly to NIH? Simple, ACA will not allow that! And folks, you are just seeing the beginning. Don't say we did not warn you!

Cancer Genes

In a recent paper by Lawrence et al in Nature the authors present a structured collection of genes elated to a selection of cancers. We summarize them above. The details are in the paper.

The details shown above are another way to view the results. This is interesting in that it demonstrates steps in cancer formation, proliferation, and metastasis. Although the paper does present a mass of unconnected genetic markers, one suspects that the spatio-temporal characteristic can be somewhat readily ascertained.

As the authors conclude:

Although a few cancer genes are mutated in a high proportion of tumours of a given type (>20%), most are mutated at intermediate frequencies (2-20%). To explore the feasibility of creating a comprehensive catalogue of cancer genes, we analysed somatic point mutations in exome sequences from 4,742 human cancers and their matched normal-tissue samples across 21 cancer types. We found that large-scale genomic analysis can identify nearly all known cancer genes in these tumour types. Our analysis also identified 33 genes that were not previously known to be significantly mutated in cancer, including genes related to proliferation, apoptosis, genome stability, chromatin regulation, immune evasion, RNA processing and protein homeostasis. Down-sampling analysis indicates that larger sample sizes will reveal many more genes mutated at clinically important frequencies.

It is worth following this in some detail.