Marx and Politics

Upon rereading Marx and Engles, always an interesting thing to do on Christmas Eve, they state their ten point plan:  

1. Abolition of property in land and application of all rents of land to public purposes.

2. A heavy progressive or graduated income tax.

3. Abolition of all right of inheritance.

4. Confiscation of the property of all emigrants and rebels.

5. Centralization of credit in the hands of the State, by means of a national bank with State capital and an exclusive monopoly.

6. Centralization of the means of communication and transport in the hands of the State.

7. Extension of factories and instruments of production owned by the State; the bringing into cultivation of wastelands, and the improvement of the soil generally in accordance with a common plan.

8. Equal liability of all to labour. Establishment of industrial armies, especially for agriculture.

9. Combination of agriculture with manufacturing industries; gradual abolition of the distinction between town and country, by a more equable distribution of the population over the country.

10. Free education for all children m public schools. Abolition of children's factory labour in its present form. Combination of education with industrial production.

Well we are not there yet but perhaps we can judge the progress by examining the actions of our Politicians but more importantly of our Government Administrators.

Just a few of the above:

Centralizing Credit and Banks, well we are on our way there.

Centralizing means of communications, well the NSA has really helped out there.

Cultivation of Wastelands, that has been the EPA, Marx never asked for productive "cultivation"

Mao tried the "all to agriculture" thing in the "Great Leap Forward". I find it interesting that perhaps we could get all those folks in DC out in the fields working crops. Just a thought as we move towards a new year.

Alan Turing

The Queen has given a rare Royal Pardon to Alan Turing for his alleged personal practices. As the BBC reports:

"Turing deserves to be remembered and recognised for his fantastic contribution to the war effort and his legacy to science. A pardon from the Queen is a fitting tribute to an exceptional man."
The pardon comes into effect on 24 December.

Turing died in June 1954 from cyanide poisoning and an inquest decided that he had committed suicide. However, biographers, friends and other students of his life dispute the finding and suggest his death was an accident. 

 Although Turing was known for his seminal ideas on computers and his work on code breaking, my personal appreciation was his work on tessellation and flower coloring. This essentially was the development of the understanding of inter-cellular communications which only now is being fully understood. I often wonder what would have happened if Turing had lived and had the chance to understand what Watson and Crick had done just up the road a piece from where he was at the time.

The Phone System

The NY Times has an Editorial regarding what they term the "phasing out of the phone system". The say that what we have now we have had since Bell. Not even close guys. I love it when people who know nothing of what they speak on a specific topic prognosticate, especially on the Editorial pages of the Times. It appears all too often that lawyers and journalists are all too prone to do this, and yes, economists as well.

There has been a revolution in telephone architectures since 1984 with the official breakup of AT&T. Competition and market forces, fettered at times by the FCC, opened the market. To some degree wireless would not be what it is today if we still had Bell Labs and vertical integration. Steve Jobs would have been in prison for violating Federal Law. And most likely we would have more people in AT&T than employed by the Federal Government.

As of now the US does not have a single telephone switch manufacturer left. They have moved elsewhere, including China. What we have a a high capacity wireless network along with extremely clever end user devices working on an IP based network.

As the Times states:

Some telecommunications companies like AT&T argue that the country needs to begin moving away from the traditional system, in which copper wires connect phones to big machines known as switches, to a more efficient Internet-based system that work over wireless or fiber-optic technologies. 

The F.C.C. is expected to authorize AT&T and other phone companies to replace conventional telephone wires with wireless or fiber-optic connections in certain neighborhoods or a large rural area to see how such a change would work in practice. 

Frankly what right does the FCC have to tell companies how to offer their service.  It arguably is the authority Congress gave them for Universal Service. Now the Times in its brilliance states:

Phone companies maintain backup batteries and electricity generators at their central offices to make sure service is uninterrupted during blackouts. But consumers have to plug in devices to use cellphones and Internet-based services, which means there’s a risk of losing service if the electricity goes out. 

As the F.C.C. deals with new technology, it needs to keep in place safeguards that have long ensured that the phone system serves everyone. Today, Americans who cannot afford regular phone service can get a subsidized wired or wireless connection. That should continue even if the underlying technology changes. 

 Batteries in COs are all too often environmental hazards. Just look at 140 West Street, the basement was filled with batteries, then flooded and now being rented out as upscale condos. Perhaps because they cannot tear it down due to the battery deposits. Just a thought. 

But must we keep "horse stables" when we have automobiles, must we keep the buggy whips factories going when we have the same new means of transportation. Cell phone have batteries, they battery lasts a long time unless you are using it excessively. Thus I am really aghast as to the Times demanding we keep all those toxic battery vaults so the "poor" can use their cell phones and Internets during a temporary power outage. Just to let the Times know, most people get Internet via a wireless or Cable feed and not over copper! Those Hayes modems just do not do a great job anymore.

The last paragraph is truly amazing for its Luddite tones:

America has a long history of telecommunications innovation since Bell made the first call to Watson nearly 140 years ago. The issue is not whether the phone system needs to be upgraded. It’s how. 

 First, the US telecom technology was suppressed until the breakup of AT&T. Bell Labs designed capital intensive systems since its profit was a return on investment. The motivation for cost effectiveness was non-existent. The change started with McGowan and MCI and took hold only in 1984. Secondly, technology moves at its own pace. Once started the Times and the FCC can only be temporary roadblocks. So for those "poor" with their free Government supplied, taxpayer supported, phones and Internet, try charging it before the storm! Let technology evolve naturally, not the way our elite wants it to.

PCa Genetic Tests: Do They Make Any Sense?

The recent report on such a cancer prognostic model such as Oncotype DX by Knezvic et al is a putatively prognostic method used in prostate cancer. Fundamentally what they do is examine cancer cells for the expression of various genes and examine three sets; baseline expressions, excess expressions and reduced expression. They use the baseline to set levels for excess and reduced. They then use the excess or reduced in a one dimension expression to determine a prognostic measure. This seems to be in contrast with work we reported on a few months ago[1].

Like PSA measures, CA125, CEA, and the like, they try to reduce everything to a single number. We argue here that such an approach is problematic at best. Furthermore they fail totally to demonstrate any internal pathway influence. There is no predictive basis for their approach predicated upon the actual dynamics of the cell. It is purely correlative and there may be substantial confounders involved. This approach is an example of what we fell to be the poorer aspects of genomics applied to cancer prognostics.

In a recent study the authors develop a score called the GPS score which is based upon know malignant PCs cells and then argue that then score has significant prognostic value. The authors state:  

The Oncotype DX Prostate Cancer Assay has been clinically validated, demonstrating that the GPS, assessed in diagnostic biopsy tissue, can predict the likelihood of the presence of adverse pathology (high-grade and/or high-stage disease), and that it complements existing pre-treatment risk assessment tools such as PSA levels, Gleason Score, and clinical stage. The assay is intended to help guide treatment decisions in early-stage prostate cancer, including the decision between immediate therapy and active surveillance. As evidence that the analytical assay was designed well for its intended use to test RNA from small biopsies, in a clinical validation study, valid GPS results were generated for more than 95% of samples requiring 1 mm and 30 microns of tumor tissue…

They continue:  

Optimization of the Oncotype DX platform has enabled the development and analytical validation of the Oncotype DX Prostate Cancer Assay for use with prostate biopsy specimens. This RT-PCR assay has been clinically validated to predict the risk of high grade and/or non-organ confined disease at radical prostatectomy using biopsy samples containing as little as 1 mm of tumor tissue. The Oncotype DX Prostate Cancer Assay complements traditional clinical and pathologic diagnostic features and will assist clinicians to discriminate patients with indolent prostate cancer from aggressive prostate cancer to help make the most appropriate treatment decisions. 

The approach is as follows as shown in the Figure below. Basically take the malignant cells and measure the expression of certain genes via their RNA using a baseline reference gene expression level.

Now the genes they have selected are categorized as follows. They have four categories related to PCa and one category for the purpose of setting a reference level.

Stromal Gene	Cellular Organization Group	Androgen Group	Proliferation Group	Reference Genes
BGN	FLNC	FAM13C	TPX2	ARF1
COL1A1	GSN	KLK2		ATP5E
SFRP4	TPM2	AZGP1		CLTC
	GSTM2	SRD5A2		GPSI
				PGK1

Now based upon the levels of expression of these genes against the gene reference level they have proposed a metric which they term the GPS metric which is a measure of prognostic value related to the aggressiveness of the cancer. The GPS metric is given by:

The higher the GPS measure the arguably the greater the virulence of the cancer. The internal value above is given by:

Finally the specific value calculations by class are given by: 

We summarize this below:

Group	Genes	Weight
Stromal Gene
	BGN	0.527
	COL1A1	0.457
	SFRP4	0.156
Cellular Organization Group
	FLNC	0.163
	GSN	0.504
	TPM2	0.421
	GSTM2	0.394
Androgen Group
	FAM13C	0.634
	KLK2	1.079
	AZGP1	0.642
	SRD5A2	0.997
Proliferation Group
	TPX2	1.00
Reference Genes
	ARF1
	ATP5E
	CLTC
	GPSI
	PGK1

We present graphically below thevalues as shown above, namely the weights:

From an earlier Press Release there was reported the results of a study stating[2]:

Results showed that the test, developed in collaboration with UCSF and Cleveland Clinic, strongly predicted disease aggressiveness (p=0.002) offering information beyond currently available clinical factors, such as PSA and biopsy Gleason Score, to help physicians and their prostate cancer patients confidently choose the most appropriate treatment based on an individualized risk assessment.

Furthermore, this first-of-its-kind, multi-gene test has been validated to guide treatment decisions using the prostate needle biopsy sample taken before the prostate is removed -- thereby providing the opportunity for low risk patients to avoid invasive treatments such as radical prostatectomy or radiation.

"The results of our study showed that the individual biological information from the Oncotype DX prostate cancer test tripled the number of patients who can more confidently consider active surveillance and avoid unnecessary treatment and its potential side effects. The test also identified a smaller number of patients who, despite seemingly low-risk clinical factors, had more aggressive disease and, would suggest that they consider immediate treatment," said Peter Carroll, M.D., MPH, professor and chair, Department of Urology, UCSF and principal investigator of this validation study.

"With these new study results, I believe we may be able to significantly increase the use of active surveillance, which has been limited to some extent by the absence of a validated genomic tool to more accurately distinguish low and high risk disease at the time of biopsy." Active surveillance is a treatment plan that employs careful and consistent monitoring of the cancer in a man's prostate without removing it. Under active surveillance, patients have regular check-ups and periodic PSA blood tests, clinical exams and potential biopsies to closely monitor for signs of prostate cancer progression.

The Oncotype DX prostate cancer test measures the level of expression of 17 genes across four biological pathways to predict prostate cancer aggressiveness. The test results are reported as a Genomic Prostate Score (GPS) that ranges from 0 to 100 and is combined with other clinical factors to further clarify a man's risk prior to treatment intervention.

Now there are many significant issues in this analysis.

1. The weights are arguably chosen to maximize the risk of missing an aggressive PCa. However I have not yet seen adequate clinical evidence to that effect.

2. Prior proposed genes and the ones included herein are shown below, one from the study currently in discussion and the other from a prior study of a Myriad genetic profile:

Target Genes Oncotype DX	Housekeeping Genes Oncotype DX	Target Gene Myriad	Housekeeping Gene Myriad
AZGP1	ARF1	ASF1B	CLTC
BGN	ATP5E	ASPM	MMADHC
COL1A1	CLTC	BIRC5	MRFAP1
FAM13C	GPSI	BUB1B	PPP2CA
FLNC	PGK1	C18orf24	PSMA1
GSN		CDC2	PSMC1
GSTM2		CDC20	RPL13A;LOC728658
KLK2		CDCA3	RPL37
SFRP4		CDCA8	RPL38
SRD5A2		CDKN3	RPL4
TPM2		CENPF	RPL8
TPX2		CENPM	RPS29
		CEP55	SLC25A3
		DLGAP5	TXNL1
		DTL	UBA52
		FOXM1
		KIAA0101
		KIF11
		KIF20A
		MCM10
		NUSAP1
		ORC6L
		PBK
		PLK1
		PRC1
		PTTG1
		RAD51
		RAD54L
		RRM2
		TK1
		TOP2A

It should be obvious that these two tests are dramatically different. Yet they claim similar results. The question is; what genetic expression has gone astray? Why, for example, do we see such a massive disparity? Frankly, other than CLTC we see no other commonality. What causes these disparate expressions? The answers are left hanging. At least with PSA we have some clear cause and effect. Here, at best, we have some correlative values.

With such disparate sets of genes one wonders why and how can these tests be compared if at all. Or, are these results just suggestive and are neither causative or resulting from the lesions.

3. In the current test under discussion the cells used for extraction are arguably from the prostate biopsy. The Myriad appear to be more wide spread.

4. Are these tests worth anything? Furthermore, groups are offering tests to assess risks based upon genetic profiles. As stated[3]:

Myriad also rolled out new tests. In September, the company launched its myRisk Hereditary Cancer™ test, a 25-gene panel covering eight major cancers (breast, colorectal, endometrial, gastric, melanoma, ovarian, pancreatic, and prostate) at an average selling price of $3,700. In October the company introduced myPlan Lung Cancer, which carries a $3,400 list price; followed in November by myPath Melanoma, which has an average selling price of $1,500. By 2015, Myriad has said, it expects to discontinue several current tests, including the BRACAnalysis test at the center of the Supreme Court case.

Just because some genetic profile may have some correlative relationship the genetic profile is not causative. Tests like these can be costly and of yet to be fully justified clinical value. Take a melanoma, if one has a suspect pigmented lesion then a simple excision and competent path study should suffice. That is an order of magnitude less than the genetic profile. In fact if one were to do a profile it should be of the melanocytes and not of the cells in general.

References

Knezvic, D., et al, Analytical validation of the Oncotype DX prostate cancer assay – a clinical RT-CR assay optimized for prostate needle biopsies, BMC Genomics 2013, 14:690.

http://www.telmarc.com/Documents/White%20Papers/98%20CCP.pdf

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[1] See http://www.telmarc.com/Documents/White%20Papers/98%20CCP.pdf   Note that this study was based upon a different vendor with different genes.

[2] http://investor.genomichealth.com/releaseDetail.cfm?releaseID=762874

[3] http://www.genengnews.com/insight-and-intelligence/the-10-biggest-events-of-2013/77899986/