The consequences of casual concepts of causation

Exposure to X-rays can cause cancer, so their use as a routine and repetitive screen for tuberculosis (and, for readers old enough to remember, to look for the fit of shoes at a shoe-store), or for routine CT scans, and so on, is questionable.  Dental x-rays seem to be so safe that their risk, which is probably not zero, is nearly unmeasurable and presumably worth the dental problems they can find (hopefully, though not certainly, they are not taken too often as a source of profit).

Developing breast tissue in young girls is vulnerable, so they were not routinely given chest x-rays.  But breast cancer is common and serious, so mammography was seen for a long time as clearly a valuable life-saver, if used on peri- or post-menopausal women.  But recent studies have raised questions.  Interestingly, this is not because of new cancers that may be caused by the screening (though the number may not be zero).  It was because they could detect small anomalies that were then followed up.   Some would turn out to be cancer, even if in an early stage.  But the follow-up is psychologically traumatic and has its own unexpected consequences.  And even more, studies have shown that some of these cancers would regress on their own.  So mammography, despite so many being convinced of its value, is now under scrutiny:  when and how often and on who is this false positive risk too great to justify routine mammographic screening?

PSA testing has become routine for finding prostate cancer in older men, because prostate cells that are too active churn out PSA (prostate specific antigen), so high PSA levels, just as with suggestive mammograms, have been considered indicative of the need for follow-up.  Again, that has its own morbidity--including, gulp, impotence!--so it, too has come under scrutiny.  Indeed, as with mammography, studies have shown that the intervention's risk and the fact that many of the tumors would regress, or would stay silent until some other cause took the poor guy away, suggests that routine PSA testing be stopped.

Now, a new report suggests the same thing for ovarian cancer screening.  The reasons are the same, and surely there will be as much controversy.   What is this all about, and what is one to do, and why do we see this?  Surely and hopefully, it cannot be all, or even primarily, due to the profitability of screening services and follow-up.

More likely this reflects the belief in technology, fed by and into the hunger for early diagnosis and treatment of very nasty diseases that threaten the quality of life or even life itself.  Is it that early ideas about what might be early risk factors, based on some first rounds of studies, lead researchers anxious for important findings, and clinicians anxious for effective detection, to believe what are not very sound results?  This must be the case, unless the early studies were seriously flawed in their methodology.

Probably more importantly, this reflects a profound modern-day problem in science: the way that complex, multi-factor causation is studied by statistical studies, and the difficulty of getting good enough samples, well-enough understood, to generate reliable results.  Plus, many factors are lifestyle-related, and they change over time.

But could these findings be a reflection of a point we often wonder about, and that applies to evolutionary reconstructions as well--namely, that the assumptions underlying statistical studies of these types make and test assumptions?  Is it that the methods assume a type or level of regularity that simply does not reflect how things really are?

If that is the case then we have to await the next brilliant insight that will transform  how we think.  Meanwhile, we are apparently stuck not knowing why results and opinion change so often, or whether we can trust the latest study more than the previous studies it overturns.....or whether we have to believe that the latest study, too, will shortly be overturned.

Either the situation is straightforward but we just haven't done the right studies, or we're in a deeper epistemological hole than most people would like to think, calling for the kinds of creative thinking that no grant or research 'system' can order up, but simply depend on the lucky arrival of the required genius.

Mammography: Grim tales of real life.

The use of x-rays to detect breast cancer, known as mammography, started around 1960. The idea was that x-rays could give an in-depth picture of the breast that would be superior to palpation for detecting small tumors that had not yet become obvious or symptomatic. It seemed like a very good idea that could save many lives, and became not just widespread but formally recommended as part of preventive care.

This was based on the belief, or perhaps even dogma, that tumors are 'transformed' cells that are out of control and will continue dividing without the normal context-specific restraint. The tumors induced vascularization that nourished its cells, and eventually cells flake off into the blood or lymph systems, to be carried along to other sites where they would eventually lodge, spreading the tumor (this is called metastasis). If anything, treatment or just competition would lead this distributing clone of transformed cells to gain an increasing evolutionary advantage over the woman's (and, in much rarer instances, men's) normal tissue: tumor cells would continue to accumulate mutations at the regular or even an accelerated rate, that would give them even further growth advantage.

Sometimes tumors seemed to regress, but this was difficult to explain and often it was thought that perhaps the initial diagnosis was wrong. If the tumor had escaped immune destruction when it was only a single or few cells large, what could then later make it regress?

Thus the general dogma in cancer biology that the earlier it was caught, the less likely it would spread. That also meant the earlier in life one was screened, the better. Local surgery could then cure the disease.

But there was a problem: the same x-radiation used to detect different cell densities between tumor and normal tissue, is also a very well-known mutagen and cause of cancer!

Worse, the more actively dividing cells were, the more liable to mutation and thus transmission to increased numbers of a descendant line of daughter cells in the tissue. Since breast tissue grows every menstrual cycle, pre-menopausal women would be particularly vulnerable to iatric carcinogenesis. Yet the idea was that earlier screening was better!

Even further, early onset cases are more likely to be or to become bilateral (both breasts) or multiclonal (more independent tumors), and it was suspected and is now known that some of this, at least, is due to inherited susceptibility mutations (in BRCA1 and BRCA1 and a few other genes). These mutations put a woman at very high risk, so earlier and more frequent screening--but higher total radiation doses!--could be important.

Especially after the atomic bombing of Japan in World War II, and the subsequent fallout from nuclear reactors and bomb tests, and the proliferation of diagnostic x-rays, many extensive studies were done to document the risk, and for example chest x-rays used in routine tuberculosis screening were shown to be a risk for cancers including breast cancer.

So, to screen or not to screen? The obvious answer to this Hobson's choice was a grim cost-benefit analysis: how many cancers are detected and cured vs those that are caused by mammographic screening? Even grimmer, this could be evaluated by age, so that recommendations could be made based on a judgment as to how favorable the age-specific balance between cause and cure was. And there's more: radiation-induced carcinomas take years to develop before they would appear as clinically detectable tumors, so evaluating and attributing risk was (and is) not easy.

Breast cancer is unfortunately quite common, but the differences being considered, among many additional variables known and unknown, are small. That means very large, long-term studies needed even to come to a tentative rational ('evidence-based') conclusion. The result was recommendations of occasional mammograms for women in their 40's, with more frequent screens in 50's and beyond.

This made sense....until a few studies recently began to appear with curious results. Several studies showed that the number of cancers in women not screened was lower than those in women who had been screened. How can this be? The answer appears to be that screening leads to detection, reporting, and treatment of tumors that would eventually disappear on their own. So screening led to interventions of various types, some rather grim in themselves, in a substantial fraction of cases that would go away without any treatment with its associated cost and trauma.

The same has been found recently in PSA testing of men for prostate cancer, so it's not a fluke of the study design. Scars of remitted tumors have been found, showing clearly that they regressed without diagnosis or treatment.

So now a panel of experts has recommended backing off, and doing screening less often (except in those who, in a grim kind of good luck, know they carry a high-risk mutation and hence need to be checked carefully, and often, where early detection can more clearly be effective).

Now if that isn't 'evidence' what is? Yet this is controversial, because it goes against accepted practice. In the Wednesday NY Times it's reported that some physicians don't plan to change their recommendations (what will insurance companies, our most noble citizens, and the entities that will actually drive this decision, do?). The NIH Secretary also backed away from this new report. This is curious to say the least and relevant, of course, to the notion of 'evidence based' medicine that we discussed in a recent post, and why we think the notion of evidence is actually rather slippery.

This strikes close to home for many of us, who have very close relatives who have died of breast cancer. For us, research on this subject could hardly be more important. If you're a young woman you face these grim or even terrifying choices. But in real life, rather than fairy stories, there's no easy answer.

If genetic causation is complex, why should risk factors be any less so?

Every day, it seems, the forces of biological simplism -- the hunger for, and vested interest in simple answers to complex questions -- suffer a setback. Today, it's large-study results that show that screening for a simple marker for early prostate cancer detection seems to be ineffective ( New York Times prostate cancer article ). It may be harmful in the sense of leading to the detection of benign cases, and then some intervention with its associated risk of morbidity. Earlier this year somewhat similar results appeared for mammographic screening for breast cancer. The point is not to coldly denigrate attempts at early detection, but to show the importance of recognizing nature's complexity. Those who suffer from cancer--and we all know such people, and many of us will be such people--deserve all the care and concern that can be mustered. But can we think of better ways to approach this genetically complex problem? Is standard reductionism, trying to identify individual risk factors, or even single risk factors, the way to go? Or will some smart young researcher give us the benefit of conceptually innovative ideas?

For most risk factors, genetic or otherwise, the situation is similar: cholesterol, blood pressure, even obesity have complex and poorly understood associations with subsequent disease outcomes, and with prior genetic risk factors. It is already known, however, that the most effective way to head off chronic diseases is not to smoke, get exercise, and eat a moderate, balanced diet (including even to have a drink now and then!).

But, that conceptually innovative idea is not going to come anytime in the next month or so -- biology is on holiday. This is not like France, where everyone goes to the seaside in August. No, it's because of our 'stimulus' package's ad hoc grants program. Like lemmings to the sea, or hogs to the trough, every scientist and his relatives (living or deceased) is charging headlong for the new money. Whether this is a moral way to spend these funds is an open question. But everyone's now too busy putting together their hoped-for bonanza grants to do any actual scientific work. Ironically, the stimulus package's 'challenge grants' may turn out to be a NON-work initiative for science!

Presumably, the crush will end and we'll all get back to work. One can predict that, due to the gold rush the funding percentages won't be any better, and they may be worse for this 'easy money'. Time will tell.