Thursday, July 20, 2017

Most Influential Science Books



What can be influential in science, what books for example. The Guardian has run a piece and Richard Dawkins's Selfish Gene comes out on top. They note[1]:

Debates about the most influential science book of all time habitually settle into a face-off between Darwin’s Origin of Species and Newton’s Principia Mathematica. But a poll to celebrate the 30th anniversary of the Royal Society science book prize returned a more recent winner: Richard Dawkins’s The Selfish Gene. Dawkins took a decisive 18% of the vote, while Darwin was jostled into third place by Bill Bryson’s A Short History of Nearly Everything in the Royal Society poll of more than 1,300 readers. As interesting as the votes on the 10 books shortlisted for contention was the often passionate championship of titles that were left off the list. They were dominated by physics and cosmology. Silly not to include David Deutsch, sniffed one of many, who cited a range of works by the Oxford-based quantum physicist. Carl Sagan’s “mind-blowing” 1980 TV tie-in Cosmos garnered a clutch of votes from fans who described it as life-changing.

Now I thought about some of the works I have read over the years and especially the ones I have re-read, some several times. My most favorite is the two volume auto biography of Norbert Wiener. Each time I go through it I see more and more. It is the mind of a mathematician, a brilliant mind. Many think Norbert as a bit of an odd duck and in the Engineering world the folks like Shannon much more, but there is nothing like Wieners autobiography. It is a snapshot in time and a time when one could roam across the world and share ideas.

Now on to my list:

1.     Bell, Men of Mathematics
2.     Einstein, Relativity
3.     Einstein, The Meaning of Relativity
4.     Feynman, QED
5.     Feynman, The Character of Physical Law
6.     Gamow, One, Two, Three…Infinity
7.     Schrodinger, What is Life?
8.     Shannon and Weaver, The Mathematical Theory of Communications
9.     Watson, Double Helix
10.  Watson, Molecular Biology of the Gene
11.  Wiener, Cybernetics
12.  Winograd and Flores, Understanding Computers and Cognition

Just some thoughts.

Wednesday, July 19, 2017

CBO Numbers

The CBO issued a report on the savings when eliminating Obamacare. They state:

CBO and the staff of the Joint Committee on Taxation (JCT) have completed an estimate of the direct spending and revenue effects of the Obamacare Repeal Reconciliation Act of 2017, an amendment in the nature of a substitute to H.R. 1628, which would repeal many provisions of the Affordable Care Act (ACA). According to the agencies’ analysis, enacting the legislation would decrease deficits by $473 billion over the 2017-2026 period

Yet if you look at what they reported a day ago the savings would be almost $600 billion per-year! How can anyone believe these folks! What number is ever real! Well it is Washington after all.

Tuesday, July 18, 2017

Healthcare Expenditures

The CBO published a report containing the data below.
Let us examine the above:

1. Medicare is a paid for insurance plan. eight years ago we showed that any middle class person contributing for their 50 years would have paid into he plan, assuming interest at the FED rate in excess of any benefits. Thus Medicare is a paid up benefit. In addition Medicare still charges for participation and still one needs extra coverage. Thus for those who have never held a reasonable job and paid little into Medicare it is a free ride, for all others we pay well more than any benefit!

2. Medicaid is a free plan. The ACA double Medicaid coverage adding $250 billion to this plan. BUT, it was to stop and fall upon the states. As some Governors try to allege, falsely so, we are not expected to keep filling up their trough.

3. ACA Support is the $250 billion being spent for Obamacare payments on the Exchange. Add that to the Medicare expansion and we have $600 billion we never had before!

4. Insurance is what the working folks pay!

5. Out of Pocket is again the working folks.

6. Other is the working folk.

Thus almost $600 billion is added to our deficit and growing. The folks who pay their own way, including Medicare, will ultimately have to pay for this excess free riders!

Monday, July 17, 2017

Russian Intelligence

In the old days when the Soviets had a KGB and other intel agencies they were pervasive and managed to keep themselves well hidden from Western intel agencies. The classic example was the Philby clan who managed to keep themselves out of the MI6 and CIA radars. The Russians are quite intelligent and sophisticated and somewhat unlike Chinese intel have well established western outlets. There were thousands of fellow travelers in the old Soviet days and in today's world the need for promulgating a Soviet world view are no longer necessary. The interest is establishing a strategic advantage to maximize whatever Russia may have.

Unlike China which has an economic dependence on the West, Russia sells its extraction elements, oil and minerals. You really can't buy any "Made in Russia" stuff at Walmart. So why doe Russia do what it does? Simply it is the Russian mindset of having a presence, a seat at the table. It is doubtful that Russia wants to overthrow the United States. Frankly they have enough problems at home without taking on more. International influence, yes, international "respect", yes, recognition, yes.

Now as to Russian Intelligence Operatives. What do they seek? Sources of information, strategic advantages, weaknesses of the other side. If a target can be compromised then a target can be manipulated. Yet to compromise one must know something the target wants kept secret and then let the target know that they are vulnerable. Classic extortion. To work, the Operative must be invisible, yet present to the Target.

What are the rules for an Intelligence Operative?

There are three simple rules:

1. Never put it in writing

What does this mean? Simply never leave a discoverable trail. Clearly when one enters Trump Tower or any other major building in New York one is captured on video hundreds of times and one must register to enter the building, one is photographed, one must submit valid IDs etc, pass through Secret Service filters. Thus, any meeting at Trump Tower is a major violation of Rule 1! Let us assume that the Trump folks were just naive. They took a meeting which may after the fact have poor optics. Let us assume they were smart. They took a meeting knowing that any operative would never appear in such an open venue. Operatives meet in obscure locations like forests, mountain paths, under bridges, or anywhere where they chance of being seen is as near zero as possible. Operatives do not meet at a location under Secret Service control, like Trump Tower. Unless the Secret Service has also been compromised in toto! That is a tale going too far.

2. Trust no one

As an Operative you must trust no one, not even your father (or mother as the case may be). Anyone can be anything at any day. Trust is a non-entity. Counter Intelligence relies of building trust with a target. If the target is themselves an Operative then the target knows enough not to trust anyone. In fact any attempt to build trust may be a sign of a Counter Intel Operative. I have seen Counter Intel Stasi and Cuban Operatives, very attractive but they scream beware!

3. Always have a second exit.

This is a critical one. It covers a lot of ground. From that of a simple Plan B to the use of third parties to do messy jobs and seeing that they are expendable. Never hold the knife, you may get caught. Have plausible deniability, be transparent. Have another identifiable as the Operative, always have a delaying plan while escape can be made.

Is Russia a Major Threat?

In the old days we worried about a Soviet nuclear attack, really! There were plans for various options such as the RISOP plan[1]. We still live on a remnant of RISOP. Russia has ready nuclear forces, and the US maintains its triad forces. The past Administration let the weapons remain un-updated, but there are still more nuclear weapons to destroy the earth many times over. Russia likewise has active capabilities. But both Russian and American key players understand the end game of any nuclear engagement and would thus mitigate against any. China is a bit uncertain but its focus has been on economic warfare. Thus Russia may at the extreme be a threat but not in any day to day environment. One may then ask why they are acting as they do? The answer is simple. It is the tale of the frog and the scorpion. The scorpion walks to the edge of a raging river and seeks to cross. He asks a frog who at first refuses, after all it is a scorpion. The scorpion promises not to sting. The frog agrees and halfway across the raging river the scorpion stings the frog, now both will die. The frog asks in his last breath; why? The scorpion replies: I can't help it, I am a scorpion. Thus one understands the Russian mind.

Is Russia more of a threat than China?

Now here we have a concern. This is an economic player. A large military but one suspects to keep peace at home. But a massive player in world economies and growing. Perhaps more time on this issue would be better spent than on the scorpion!

Sunday, July 16, 2017

Prostate Cancer Mortality: Fact or What?

In a recent paper by Wilt et al the authors state:

After nearly 20 years of follow-up among men with localized prostate cancer, surgery was not associated with significantly lower all-cause or prostate-cancer mortality than observation. Surgery was associated with a higher frequency of adverse events than observation but a lower frequency of treatment for disease progression, mostly for asymptomatic, local, or biochemical progression. 

Put aside the adverse events since it is well known that any surgery has such a risk. We would focus on survival alone. The authors continue:

In conclusion, radical prostatectomy was not associated with significantly lower all-cause or prostate-cancer mortality than observation through 20 years of follow-up among men with localized prostate cancer that was diagnosed during the early era of PSA testing. Absolute differences remained below 6 percentage points. Death from prostate cancer was very uncommon among men with low-risk disease who were assigned to observation. Surgery may be associated with decreased mortality among men with intermediate risk prostate cancer, depending on the pathological classification. Surgery resulted in substantially greater long-term urinary incontinence and erectile and sexual dysfunction than observation and was associated with a significantly lower risk of disease progression and additional treatments, most for local or asymptomatic biochemical progression.

The problem with this analysis is as follows:

1. It is clinically well known that a small percentage of all PCa is of a highly aggressive form.

2. The highly aggressive form almost always results in death.

3. The highly aggressive form occurs early in the onset of the disease and metastasis is almost immediate.

4. The specific genetic makeup of this highly aggressive form is currently undetermined. Moreover there may be a pleiomorphic genetic presentation.

5. However, whenever it is suspected, such as presented in the above paper, the detailed genetic makeup of the cancer cells should and must be determined. It was not apparently done here. Not all PCa is the same.

Thus we examine the data from the perspective of the putative existence of a highly aggressive form.

The Press does take this report to arguable extremes as is usually the case. Science Daily states[1]:

Prostate cancer surgery offers negligible benefits to many men with early-stage disease, a major 20-year study demonstrates. In such men, who account for most cases of newly diagnosed prostate cancer, surgery did not prolong life and often caused serious complications such as infection, urinary incontinence and erectile dysfunction…In men with early prostate cancer, the study compared surgery with observation. With the latter, men only were treated if they developed bothersome symptoms, such as urinary difficulty or bone pain. Such symptoms may indicate progression of the cancer.

Many men in the observation group received no treatment at all because early-stage prostate cancer often grows slowly and rarely causes symptoms. To evaluate any potential benefits of surgery, the researchers randomly assigned 731 men in the U.S. with localized prostate cancer to receive either surgery or observation at one of 44 Department of Veteran Affairs Health Care Centers or eight academic medical centers, including Washington University. The average age of men in the study was 67 at the time of enrollment. Of the men who had prostate cancer surgery, 223 (61 percent) died of other causes after up to 20 years of follow-up, compared with 245 men (66 percent) in the observation group -- a difference that is not statistically different. Further, 27 (7 percent) men in the surgery group died of prostate cancer, compared with 42 men (11 percent) in the observation group, but that difference also is not statistically significant.

However, the data show that surgery may have a mortality benefit in some men, particularly those with a long life expectancy and intermediate-risk prostate cancer. (Such men generally have PSA scores of 10-20 ng/ml and a Gleason score of seven. The latter score signifies tumor aggressiveness.)

One of the major concerns here is that there is a limited amount of data on each patient. Since the progression of PCa can be dramatically different depending upon a plurality of factors at presentation, it is essential that such details be incorporated in such an analysis. Moreover, if such an incorporation were included then the size of the sample is easily an order of magnitude larger than what was done here.

Herein we examine some of the elements of this paper and consider critiques which require some attention. All too often papers like this end up as significant elements of policy and limiting care to men who require it. The definitive conclusions are in my opinion at best speculative.

Let us begin with several definitions used and referred to in the paper. Namely the definitions of risk. The Table below is from Rodrigues et al and presents a list of Low, Intermediate and High risk criteria.

The D'Amico specific criteria are summarized below.

Institution/
organization
Low risk
Intermediate risk
High risk
D'Amico


T1-T2a, Gleason less than 6, PSA less than 10T2b, Gleason equal to 7, PSA between 10 and 20 Greater than T2c, Gleason between 8 and 10, and PSA greater than 20

Note that for the low case we have Gleason score of less than 6 which is quite low and no Mets and a PSA less than 10. Most urologists are aware that even here there may be a small number, say 5%, who despite this favorable set of measurements go on to an aggressive cancer.
 
Let us also briefly summarize the issue of Staging[2]. This we do below:
Primary tumor (T)
  • TX: Main tumor cannot be measured.
  • T0: Main tumor cannot be found.
  • T1, T2, T3, T4: Refers to the size and/or extent of the main tumor. The higher the number after the T, the larger the tumor or the more it has grown into nearby tissues. T's may be further divided to provide more detail, such as T3a and T3b.
Regional lymph nodes (N)
  • NX: Cancer in nearby lymph nodes cannot be measured.
  • N0: There is no cancer in nearby lymph nodes.
  • N1, N2, N3: Refers to the number and location of lymph nodes that contain cancer. The higher the number after the N, the more lymph nodes that contain cancer.
Distant metastasis (M)
  • MX: Metastasis cannot be measured.
  • M0: Cancer has not spread to other parts of the body.
  • M1: Cancer has spread to other parts of the body.
We summarize these in the following Table. Note that for th prostate HG PIN is considered CIS. This is despite the fact that some HG PIN resolve uneventfully to a benign state. This has been noted in other cancers as well such as breast and melanoma.

Stage
What it means
Stage 0
Abnormal cells are present but have not spread to nearby tissue. Also called carcinoma in situ, or CIS. CIS is not cancer, but it may become cancer.
Stage I, Stage II, and Stage III
Cancer is present. The higher the number, the larger the cancer tumor and the more it has spread into nearby tissues.
Stage IV
The cancer has spread to distant parts of the body.

 Let us begin by examining the Wilt et al data. Our focus is on Table 2. Cumulative Incidence of Death from Prostate Cancer through 19.5 Years. The data for that Table can be summarized as below:


Radical Prostatectomy
Observation

Low
Medium
High
Low
Medium
High
Total
148
129
77
148
120
80
Mean
4.100
8.500
13.000
5.400
15.800
18.800
Low
1.900
4.800
7.200
2.800
10.400
11.700
High
8.600
14.600
22.300
10.300
23.400
28.700
Sigma
1.675
2.450
3.775
1.875
3.250
4.250

We have added percent numbers to the data for clarity. They are percent mortality.

Let us examine a simple case. First for the Low Risk we have a mean death from PCa as 4.1%. In the Observation class the death was 5.4% The probability density for these are shown below:



There clearly is a greater risk in just Observation. Now consider the High risk case. This we show below:


Again there is a substantially high rate of death.

Assume there are two distinct types of PCa. In each generic class there are these two genetic classes. We first limit to one class of patients, say the Low Risk Class. This can be readily generalized to include all. Our goal is to try to determine how large a sample we need to determine the two means from a sample containing a mix of the two. We further assume we do not know the genetic difference that makes one in a class.

A Simple Example

Thus consider the following simple thought experiment. Let us assume we have 100 cases of Low Risk PCa. Let us assume that 5% of these or 5 cases are of the highly aggressive form. Namely no matter what one does they will lead to death. Let us further assume that we can perform a prostatectomy or observe.

Then if after some period, say 20 years, we find the following:

a.      Prostatectomy yields 5 deaths.
b.     Observation yields 8 deaths.

Then we could say that even if we were to remove the tumor, in the 5 cases after prostatectomy the patient would still die of the disease.

In contrast in observation, in a similar 100 cases, 5 also would die of the disease as well as an additional 3 because of non-treatment.

The question then is; can we use the data to examine such a hypothesis? Secondly; how does the inclusion of such a hypothesis change the results from the NEJM paper?

Thus let us consider the data as follows. Assume that in the Low Risk Prostatectomy case we have a percent death caused by PCa as given but assume that is due to a genetic only risk of highly aggressive tumors. Then remove that from the samples and consider what remains. The data we show below.


Radical Prostatectomy
Observation

Low
Medium
High
Low
Medium
High
Total
148
129
77
148
120
80
Initial Data
4.100
8.500
13.000
5.400
15.800
18.800
Mean
0.000
4.400
8.900
1.300
11.700
14.700
Low
1.900
4.800
7.200
2.800
10.400
11.700
High
8.600
14.600
22.300
10.300
23.400
28.700
Sigma
1.675
2.450
3.775
1.875
3.250
4.250








The conclusions from the above seem to be:

1. If you do not have a genetically aggressive form, then the risk of dying from a Low Grade PCa is about 2.5%

2. If, however, you have a High Grade form at presentation, and not an aggressive form, then you have a 7% chance of dying from PCa versus an 18% chance with Observation alone.

3. The question is; are you willing to forego a 2.5:1 risk while avoiding surgical issues?


Observations

The data presented in the paper raises more questions than can be answered. For example:

Mortality is Lower

If we examine the data as presented and look at Prostatectomy vs Observation, for each of the three risk categories there is a clear advantage in lowered mortality in a prostatectomy. The authors further state:

Reducing overtreatment is needed. Men with low-risk and PSA based screening–detected disease can safely avoid harms and costs of early radical intervention or of biopsy-guided active surveillance with delayed radical treatment. Observation, PSA-based monitoring, and active surveillance with delayed radical intervention remain infrequently used, even among older men, despite a frequency of metastatic progression of less than 3%, prostate cancer mortality of 1% or less, and cost-effectiveness that is superior to that with early radical intervention. PSA-based monitoring and biopsy based active-surveillance programs should reduce the frequency of surveillance biopsy and increase biopsy and PSA thresholds that trigger radical interventions.

We now comment on this conclusion.

It is not at all clear that the data makes any sense.

Let us examine total mortality, namely from any cause, over the 20 year period. This is summarized below:


Prostatectomy
Observation

Events
Percent
Events
Percent
Low (Local)
82/148
55.4
(47.4 to 63.2)
83/148
56.1
(48.0 to 63.8)
Intermediate
77/129
59.7
(51.1 to 67.8)
89/120
74.2
(65.7 to 81.2)
High
55/77
71.4 (60.5 to 80.3)
59/80
73.8
(63.2 to 82.1)
Low (Central)
58/111
52.3
(43.0 to 61.3)
67/122
54.9
(46.1 to 63.5)
Intermediate
97/155
62.6
(54.7 to 69.8)
99/139
71.2
(63.2 to 78.1)
High
55/78
70.5
(59.6 to 79.5)
63/85
74.1
(63.9 to 82.2)

Note that almost 75% of the High Risk patients died of something in the 20 year period. Not knowing the age data and normal mortality data this is relatively meaningless. In contrast these deaths in the High Risk cohort due solely to PCa are between 19% and 26%. Thus the other causes of death are 3 to 4 times greater. One wonders what that means. The Table below is the PCa death only data.


Prostatectomy
Observation

Events
Percent
Events
Percent
Low (Local)
6/148
4.1
(1.9 to 8.6)
8/148
5.4
(2.8 to 10.3)
Intermediate
11/129
8.5
(4.8 to 14.6)
19/120
15.8
(10.4 to 23.4)
High
10/77
13.0
(7.2 to 22.3)
15/80
18.8
(11.7 to 28.7)
Low (Central)
1/111
0.9
(0.2 to 4.9)
8/122
6.6
(3.4 to 12.4)
Intermediate
14/155
9.0
(5.5 to 14.6)
12/139
8.6
(5.0 to 14.5)
High
10/78
12.8
(7.1 to 22.0)
20/85
23.5
(15.8 to 33.6)

Here one wonders that those with High Grade at presentation have a disease cause mortality of such a small rate over this period. It is a large Gleason grade plus Mets! One knows that PCa Mets rapidly to the bone and from there one all too often sees IDC occurring which is fatal.

Moreover, if a patient presents with >T2c, or PSA >20, or GS 8-10, then one would expect a rather dire result from the PCa. Instead we see after 20 years a modest death rate. This data does not conform to certain realities.

There is clearly a complex underlying dynamic at play here and it clearly demands a deeper analysis.

How Big is Big

The size of the samples is small, just over 100 patients. In view of the potential for an even smaller size of the subset of aggressive types which would be as small as 5%, then frankly a much larger sample is demanded.

What is the Genetic Makeup?

The results are totally devoid of any genetic makeup of the cancers. Not only is the nature of the spread missing but the genetic makeup is now considered as an essential element of any analysis. What genetic flaws were in the cells of the patients who died of PCa and what in those who survived.

Dynamics of Survival

There is a somewhat complicated analysis on survival or mortality. If as this study states, for example, only 20% of the patients died of PCa but 80% died of any cause, then depending when this occurred, the percent of PCa deaths could be misrepresented. Namely if the 80% occurred short term, then the size of the sample is reduced by that number and if the 20% died when the 80% were dead then the death rate would be much higher. The denominator would be lower. Without such dynamic data one is hard put to understand the results.


A Bayesian Analysis

Any analysis of PCa must include a Bayesian analysis. Namely one must consider disease caused death subject to underlying facts. First important fact is that not all PCa is identical. There are genetically different classes and any analysis that disregards this fact is fundamentally flawed. Namely if we have several classes then we need to have mortality by class. This has been grossly neglected in this analysis and it thus provides results which are fatally flawed.

For example. If for each patient one had; family history, PSA velocity, previous biopsy history, and the like, then one could segment the results to ascertain some reasonable a priori risk factors. Secondly the same would be the case if the tumors were sequenced for a set of reasonably well know genetic markers. Third, the time to death, that is from diagnosis to death is essential. Fourth, the tumor status of those surviving, over time, is also essential.

Devoid of any of this data the results are in my opinion of questionable use.

1.     D'Amico et al, Biochemical Outcome After Radical Prostatectomy, External Beam Radiation Therapy, or Interstitial Radiation Therapy for Clinically Localized Prostate Cancer, JAMA, September 16, 1998—Vol 280, No. 11
2.     Hald, Statistical Theory, Wiley (New York) 1953
3.     McGarty, T., Prostate Cancer, A Systems Approach, DRAFT 2014 http://www.telmarc.com/Documents/Books/Prostate%20Cancer%20Systems%20Approach%2003.pdf
4.     Rodrigues et al, Pre-treatment risk stratification of prostate cancer patients: A critical review, Can Urol Assoc J 2012;6(2):121-7.
5.     Wilt, et al, Follow-up of Prostatectomy versus Observation for Early Prostate Cancer, NEJM, 377;2 July 13, 2017