MESOTHELIN AND EARLY DETECTION

A churchyard in the Yorkshire Dales

Note the beautiful dry-stone wall

And, of course, the beautiful Linda

 

I am plunging back into the scientific literature regarding early detection of ovarian cancer.  I am pleased to be able to boast that I understand one hell of a lot more now than I did 18 months ago, when I took my initial dip.  That is not to say that I have anything like a competent handle on the subject, nor that you should believe anything I say.  Probably what I say now should be taken with an even larger grain of salt than previously: earlier, I was afraid to conclude much of anything, because of the obvious fact that I would probably be wrong.  Now I am beginning to think that I know something I am more inclined to make judgments and even (gasp!) give advice. The original warnings still apply: I am a superannuated earth scientist, awash in an ocean of biochemistry.  Don’t trust me.

That said, I want to talk (once again) about early detection of ovarian cancer.  I believe it is commonly agreed that early detection is the best way to save lives.  There seem to be two approaches to this task: develop a symptom index (of which I have written many times before), or find a “marker” – a molecule of some kind carried by the blood (or urine) .  The symptom index has proven useful, but unfortunately symptoms usually kick in only when the cancer is in a late stage of development.  The same can be said of two protein markers that elevate along with cancer development: cancer antigen 125 (CA125) and human epididymis protein 4 (HD4).  These markers often vary in unison, with the newly validated HD4 (validated by my Hutch group) showing perhaps the greater promise.  My group (and others) has developed a way of using changes in an individual woman’s CA125 (and HD4?) levels as a more sensitive predictor.   We have also tried to use a molecule called mesothelin* as a marker, but apparently with no outstanding success.  I hope we keep on studying mesothelin.  You certainly remember Jack Andraka, the 14 year old kid who has invented a 3 cent, 5 minute test for elevated mesothelin.  Mesothelin also is known to be elevated  in ovarian cancer.  Part of the argument against screening the general population for OVCA is that its prevalence is so low that the screening would be prohibitively expensive.  If there are 25 million post-menopausal women in the United States you could screen them all every year, using Jack’s test, for $75,000.  This  is a rounding error in the fiscal burden of cancer. 

It also has been shown fairly recently that microRNAs of certain types elevate with ovarian cancer.  Micro RNAs are very short strands of the nucleic acid RNA.  They are mysterious to some extent, but one thing they do is regulate gene expression: turn genes on and off, as needed.  I have an irrational hunch that miRNAs are going to be a big player in future cancer research.  Muneesh Tewari, of whom I wrote a short time ago, is studying miRNA.

So, yes, I am trying to get serious about this cancer biochemistry stuff.  To do that,  I need to understand some basic statistical concepts.  I am going to put them in a Comment – so that you can skip them without shame or effort.  Maybe in a few days…. 



ALSO SPRACH THE ECONOMIST

Linda and Phil Montague

On a hike near Tucson.

Mid 1980s

 

Back on May 22, 2012, I wrote a blog entry about the conclusions of one Dr. Ioannidis of Stanford University, a respected biostatistician, that “It can be shown that most published research is wrong.”  I gave my own version of that dictat: “ It can be shown that most published conclusions are based on faulty statistics”, or something like that. Obviously, a proposition can be correct even though the statistical evidence is weak.  Unfortunately, it also is possible for a proposition to be false, even if it is backed by pretty good stats.  I don’t want to get into stuff like confidence intervals, statistical “power”, Type 2 errors, and other equally arcane and  unamusing topics; I can only get you to read these things if I keep them light and frothy.  But, anyway, it seems that Dr. I is to be taken seriously.  I base that on the observation that no less a serious rag than the Economist made his ideas their cover story this week.  (How Science Goes Wrong.)  I would urge you to read it yourself, but I know most of you won’t .  It’s not light and frothy,  that’s for sure.  So I sacrificed myself and read it carefully.  I think it boils down  to the following set of propositions:

There is too much crap being published.  This is a result of several mutually supporting forces:

                Publish of perish.  You can’t make full professor if you publish just one paper per year, even if it’s pretty good.  Six sacks of you-know-what outweigh one sack of the real stuff. 

                Nobody wants to publish negative results.  If you do an experiment and find out that it doesn’t work you are unlikely to publish it.  If you do send it to a journal,  most of the time they will reject it.

Science is supposed to remain pure because “truth” is only ascertained after an initial experiment is duplicated.  Also, purity theoretically is enhanced by the process of “peer review”, involving several experts in your field reading your paper with a critical eye, and then telling the editor whether or not it should be published.  However:

                Many clever “experiments” have demonstrated that most referees, as these folks are called, are lazy bastards who don’t really do the job right.  And why not? – they have their own papers to write.  Nobody gets promoted for being a good referee.  I was a referee on many a paper, and I should be ashamed of myself.  Besides, referees don’t get paid.

                Nobody wants to repeat an experiment that someone else already has done.  If you get the same result, well –Whoopee!  If you get a different result, who knows who is right?  You get no merit increases or promotions for checking other peoples’ work.  They pay off on original discoveries. 

                Funding agencies are very unlikely to give you a big grant just to check on the work of somebody else.  They want something new, cutting edge, roll back the frontiers -  stuff like that.  Besides – your colleagues won’t like you if you spend all your time trying to prove them wrong.  Nobody will have lunch with you at the annual scientific conference.

Most scientists are poor statisticians.  (That goes for me, in spades.)  Increasingly, researchers are called upon to tease meaning out of enormous data sets.  This is particularly true in biomedical research, but also in some branches of physics and psychology.  Often the result sought is hidden in an enormous amount of noise.  If it were obvious, somebody would have found it long ago.

So, the Economist suggests a bunch of quick fixes.  Some the granting agencies are beginning to insist upon, which is good.  Others, though, are pie in the sky.  We will continue to muddle through, I fear.  Maybe the Jack Andrakas of the world will clean up the mess.  My generation never will.

 

P.S. Was this the most boring thing I ever wrote?  Probably.

 



How about ovarian, Jack?

Borrego Springs

She liked hiking, quilting, gourding, & just sitting in the sun

 

I used to watch the TV show “60 Minutes” years ago, but I stopped because I was put off by their frequent resort to what I call “gotcha journalism”.  They would ambush some poor chump and pummel him so badly that I would feel sorry for him, no matter what he was reported to have done (or said or thought, or represented)  But now, after Florence DiJulio alerted me to this segment I may have to start watching again.  Check this out, and stifle your disbelief.  This kid is real.. 

http://www.cbsnews.com/8301-18560_162-57606995/boy-wonder-jack-andraka/

Jack Andraka is 15 years old and a high school freshman.  He has invented a method for detecting pancreatic cancer early.  The test costs 3 cents, and takes only minutes to perform.  I’m not going to try to tell you how it works: I don’t quite understand myself, I would garble what I think I know in the telling, and you probably don’t care, anyway.  Suffice it to relate that it involves detection of a rise in the abundance of the protein mesothelin.  Pancreatic cancers are associated with an abnormal concentration of mesothelin, apparently from an early stage.  If you can detect pancreatic cancer before it spreads you have a good chance of saving the life of the patient.  Otherwise, no.  Jack may just have saved thousands of lives.

 

Of course, Jack’s test has to get FDA approval, and this involves massive clinical trials extending over several (to many) years.  If I understand the situation correctly, Big Pharma (Pfizer, I think) stands ready and eager to shoulder the costs of such a test.  And why not?  If the test costs 3 cents and they sell it for a dime, and if everybody in America gets it, the gross profit would be something like $2.45 million.  (Better check my figures; I did that in my head.)  Anyway, profits would be enormous.  And, guess what?  Jack patented the idea!  At  that age all I could think about was girls and basketball!

 

It is well known that Bill Gates and, I think, Steve Jobs dropped out of college and went on to be billionaires.  Jack Andraka may be the first billionaire to drop out of high school.

 

To show you just how badly we need an early detection device for pancreatic cancer I’m going to try to attach a graph.

 

Hell, I can't figure out how to make this damned thing bigger

CAROLYN!

                 Oh, I see.  Just click on it and it gets bigger.  Who would have thought!  Duh!

Damn!  How I do hate dumping ice water on my own enthusiasms, but I must.  In reading about the cancer marker  mesothelin - that which Jack detects - I find that there is considerable doubt about  usefulness for detecting pancreatic cancer.  I will dig deeper and report.