Patients are often confused by seemingly conflicting findings of studies, or equally good doctors recommending different treatment plans. How are we to decide? Medical science is a process created by a “reality-based community” to help decide such questions. Science isn’t just hypothesis-testing with empirical observation, although that is a big part of it. It is also the consensus of a community of experts. In 1660, scientists led by Isaac Newton formed The Royal Society as the first institution designed to collect, encourage, and evaluate scientific knowledge. They published the first scientific journal in 1665 (which is still in publication). Were they ever wrong? Often! For example, for 250 years everyone wrongly believed Newton’s theory that gravity was a fundamental force of nature. And that is the point – knowledge is fallible and not subject to the personal authority of any one person. But over time, the arc of the universe of scientific knowledge bends towards truth.
There have been many improvements to the system of medical science since the Scientific Revolution. The first peer-reviewed journal was published in 1731. But peer-review as we now know it didn’t begin until the 1970s. The first randomized clinical trial occurred in 1747 (citrus for scurvy), but the rules for running double-blinded randomized clinical trials, and progressive Phase 1-3 trials weren’t systematized until Austin Bradford Hill and Harry Gold in the post-WWII era. Statistics entered medicine in the 1970s. Systematic reviews began in the late 1970s. Evidence-based medicine, as we know it today, was taught in medical schools since the 1980s.
Jonathan Rauch in “The Constitution of Knowledge: A Defense of Truth” describes knowledge as a funnel. At the top are all the guesses, the hypotheses, that drive scientific investigation. This would include (in order of increasing reliability) much of what is posted on any patient health forum every day: anecdotal “evidence” from patients; YouTube videos posted by Snuffy Myers, Mark Scholz, etc.; lab studies (mouse or test-tube); observational/epidemiological studies of patients; retrospective case-controlled studies, and systematic reviews/meta-analyses of them; cohort studies (people followed from before disease occurrence; e.g., Health Professionals Follow-Up Study, Mendelian Randomization Study). All of them are just hypothesis-generating. Most hypotheses are, and should be, wrong. Science depends on evaluating lots of hypotheses. There is no shame in guessing wrong; the only problems are when guessing stops and when one confuses a guess for a fact.
Large, well-done, and confirmed randomized clinical trials are at the bottom of the funnel; they are not just hypothesis-generating, they constitute truth in medical science. These categories were universally agreed upon after looking at which kinds of studies are likely to have conflicting results, and which almost never have conflicting results. All scientists believe in these categories; “pseudoscience” occurs when people claim to be doing science but ignore these categories. Here’s a fuller description:
Some institutions regularly GRADE prostate cancer research (NCCN, AUA, ASTRO, ASCO, SUO, EAU, CUA, PCF, and others). The institutional opinions (and not anyone’s personal opinion) are the standard-of-care. Until disproved, they constitute current medical truth. While even the best research doesn’t predict for the individual, one is foolish to ignore our best estimate.
There is no science without consensus by experts - science is a social construct. One can argue that there are and always have been objective truths, but we can only know what is in some way perceivable by humans. Did the Earth always revolve around the sun? Of course. But it did not enter the realm of science until Copernicus hypothesized it (1543), and Galileo (1609), Tycho Brahe (1573), Johannes Kepler (1609), and Isaac Newton (1687) proved it and showed how. That’s when astronomy became a science. There is no science without hypothesis-testing and empirical observers.
Part 2 (tomorrow): Loss of Respect for Expertise, Fundamentalism in Science, and Distrust of Institutions
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Tall_Allen
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Interesting post. Thank you. Question. You say “Large, well-done, and confirmed randomized clinical trials are at the bottom of the funnel”. How often are these type of confirmed trials later proven wrong and forced back up the funnel? I would guess not often but I feel certain it has happened a number of times. For example numerous drugs that have been approved via these types of trials are later pulled from the market for previously unseen safety reasons. If and when it does happen do you believe it’s due to badly designed studies, bias, or other reasons?
Never been wrong about efficacy to my knowledge. A few years ago, the FDA set up drug safety reporting sites so they could continue to collect safety data long after the RCT was over.
There are lots of mistakes made, but , over time, fewer, I think. I'm glad there are watchdogs like that. Many of the top trials in prostate cancer are done by groups like NRG Oncology or SWOG, who take care to get it right. However, even in some of their trials, reasonable people may differ, I think your point is spot on about the good intentions - everyone is trying to get it right.
Well, reproducibility is exactly why we do Phase 3 trials. Phase 3 trials have always been reproducible, as far as I know. But I am willing to look at counter-examples if you have any.
The Alzheimer's research is a problem with endpoints. The question is whether reduction of plaques is an appropriate endpoint. I don't think it is. But the trial they did is certainly reproducible.
I guess you missed the point that science is often wrong - but it is the institution that will end the end bend towards truth.
Yeah, a lot of this talk about reproducibility came out of the work of John Ioannidis. I don't reject what he says out of hand, but he's very much an advocate, and for that reason I don't consider him an impartial arbiter of the state of clinical research.
I didn't think it was personal. I think it is important to not throw out the baby with the bathwater. The epistemic institutions are strong enough to stand criticism and correction.
TA. I love you Man. I respect the Hell out of your knowledge and intellect. BUT…..I am firmly in the camp of “No Stone Unturned”. I do not think “CURE” will come from Pharmocology. Immunology, more likely. From the time a good idea is put forward, until a Double Blinded Phase 1,2,3 Human Trial (IF you can find funding….Big IF) can be a lot of time we don’t have. Many of us have a huge premium on time. I know we have Stage 4 Metastatic guys here that are 20+ years. But that is an exception.
Without rambling, let me summarize.
I love it when I see a double blinded Phase 3 Trial w Peer Review presented once per year at ASCO. You can count on that as solid. But let’s not make this site go in that direction only. Let’s have open minds to everything. What works for me, may only work for 10% of our community. We all present differently and respond differently to various therapies. I know you have seen this too.
Xtandi did not work for me. Zytiga did. I went from PSA 4.7 to 4.9, then 18 mos later during Covid to PSA 47. Everyone is different. If only one guy finds complete remission for even 3 years, I WANT TO HEAR ABOUT IT. My Life. Clearly the current SOC is extending life, but far from Cure. No Stone Unturned. Much Respect Always, Mike (Spyder 54)
Trials never predict for the individual, only for the group average. I don't blame you for grasping at straws. Let's just keep in prospective what is fact and what is a guess.
I understand, and agree. Your power is far reaching. “When given a long sharp sword, be cautious how you yield it.” If this site becomes info only for double blinded-phase 3, peer reviewed studies, many stones will go unturned. If someone here figures a combo that gives great results, they may be Boooed, or shamed off this site. We must be open for the possibility of CURE. It will come. No stone unturned is my hope. Thanks for listening Allen, Mike
If you've noticed, unless asked for my opinion, I generally do not comment when patients relate anecdotes - unless there is some problem attached to the treatment they used (e.g., toxicity, interference with or replacement of proven therapies. extreme diets/deprivations). I also do not read what does not land in my inbox. But I do stick up for science and always will. It has the best record of helping all of us.
The “consensus by experts” has been tainted. Our society has become highly capitalistic and predatory. Everything has become a commodity, even healthcare. Money has corrupted the American medical system. Peer journals and our praised medical associations are funded by special interests. Universities are afraid of losing funding and bow to their donors and government by hiring professors who toe the line. (read the Powell Memorandum, 1971). (where have I read that before?)
You know, there is good healthcare and good medical science, beyond the US. But even in the US, most doctors are caring and careful and are not corrupted. The conspiracies you see behind peer-reviewed journals and medical associations are just figments of your imagination. Universities compete to hire doctors who have a history of caring for patients and who have changed their field with research.
I was not addressing the quality of doctors. I was addressing your post on how science and the consensus of experts arrive at their conclusions. This is where money has tainted the process.
Well, doctors are the experts in medical science. If you look at the committee writing the guidelines for, say, NCCN or AUA, it's all the top doctors in their fields. I don't think they are corrupted by money, they are brilliant and caring people.
The doctors that sit on those boards do have to follow AMA and other guidelines or face loss of license or stature in the medical community. I have witnessed a good doctor run out of his practice for teaching the mind/body connection to patients. Innocent enough, we all know attitude and outlook can help healing.
Big pharma does have influence on the FDA and these boards that make decisions on the standard order of care.
There is a revolving door between those in the pharmaceutical industry and the federal agencies that are charged with regulating them. After leaving government service some are hired by the same companies they were supposed to be regulating and for outrageous salaries. I do call that collusion and not a good basis for science.
But you present no evidence of wrongdoing. You just think it's bad that the same people work for both government and private industry. What problem has that caused?
The article states, a staffer was hired by the company after "successfully" managing their drug review. I don't think that is not just a happy coincidence.
When I worked for the government, it was my job to manage the success of our vendors. Why hire vendors only to have them fail? What is wrong with having successful vendors?
Well, it certainly implies a conflict. I don't know if Clarence Thomas's wife unduly influenced his vote in an emergency application to dissent in the Court's decision not to block release of White House records, but it smells. Whether the public trusts regulatory agencies like the FDA, EPA etc. does matter, in my opinion. I was particularly troubled by the FDA approval of Aduhelm.
So I take it that you admire the USPSTF 'experts' -- the ones who now suggest that prostate cancer screening, utilizing very inexpensive PSA tests be left entirely to the patient's discretion and not even recommended? That kind of 'scientific' 'expertise'? Wouldn't want to trouble someone with a frightening test result would we? No, better to wait until patient is symptomatic and beyond the curative stage. If this is your idea of science in action, I'll take the common sense approach of rigorous annual screening and the USPSTF be damned. The real problem isn't with over-screening, it is with over-treating.
Really, oh great and wonderful advocate for science? More men are showing up symptomatic and metastatic for lack of adequate screening using a simple and inexpensive test and that's the best you can do? Your rail about deferring to 'science' and 'experts' and when confronted by their failings you dismiss it as a bogus argument? Try harder.
Your link..... " Recommendations made by the USPSTF are independent of the U.S. government. They should not be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services. "
That position makes sense to me....from the stories I hear on this site and others, the problem is not that the advice is that the man make the decision after being informed of the pros and cons. The problem seems to be at least twofold (1) men who state that their Docs never discussed the pros and cons of the test, and in fact some men claim the topic was never mentioned (2) Docs who mention the test, but who bring their own biases to the discussion with the patient.
In my own case, my GP knew that I read quite a bit re basic medical stuff....not the deep dive many men here do though.... and she offered the test more than twice, and I took her up on the offer at 65 and 70. She did not press me , and she did not take the time to much discuss pro and cons......I mentioned that I knew of the many false positives involved with the PSA test, and CR's less than shining review of the PSA test.
Note that the task force did not advise against the test...we can argue about the decision to advise against for men 70+.
Are you opposed to patients in our system , in other than emergency situations, being well-informed about proposed tests and treatments, both the pros and cons, and making informed decisions with their Docs...rather than a system where patients simply salute whatever the Doc says?
Independent of the government but very much representative of the US medical establishment. They are the body that practitioners, especially medical school related, are obliged to follow. My medical school affiliated doctor refused to order a PSA test for me; my urologist was more than a little surprised at that.
Being part of a medical school faculty he was following USPSTF guidelines. That's the whole point I am making. Experts dictating weird rules following their interpretation of science.
were you 70+ ? even if you were, not obliged to follow a D evidence opinion.......which is what it is, NOT a dictate......provide a source confirming it is a dictate, and not just your viewpoint??? If you were below 70, then certainly he didn't follow the task force suggestion.
I was 66. He performed a DRE but refused to add PSA to the lab work order. What other reason than following this task force's guidelines could there be? Not an insurance issue, not for a once a year physical. He's a doctor attached to a medical school. He had to set an example -- of following the rules set down by this advisory board.
You should have asked him....as obviously you had some idea of the benefit of the test and asked him about it. I disagree with your unproven assertion of the reason for his "refusal". Insurance should never be a consideration when an MD believes something will be beneficial for you...he/she should discuss the test/treatment, and if he/she knows, also any knowledge of insurance coverage for that test or treatment. ALL MHO obviously. I wholeheartedly agree that, being human, MDs often disappoint us. Then again, I've disappointed a few folks during my lifetime!!!
Depending on the year, the task did change their advice several times re PSA....but NO MD is bound by their guidance....the good ones will review the evidence and decide for themselves!! Also experienced MDs cannot help but be influenced by what they have observed in their practices re a certain test or treatment!!
I have my own problems with a RO who has not agreed with what seems to be pretty standard practice for radiation treatment these days.....fiducial markers and the use of Spaceoar gel to separate rectum from prostate. Done my best to find clarifying studies, but have been unsuccessful .....at least using my standards for meaningful studies. I don't like to do such, but seems I'm at point of feeling necessity of confronting him on this and asking for his guidance on studies supporting his position. he is an older RO, and simply a matter that he has not pursued training for those newer procedures. Or, does he know of studiess showing the benefit not worth the risk for either treatment. H e seemed to be quite confident of good results using CBCT imaging, without fiducials, only tattoos and bony and soft tissue for daily guidance/adjustment, along with quick actual RT session of under 3 minutes with VMAT technology/equipment. He has been doing this since late 80s, spent 90s as professor at U chicago, and been at Kaiser 20 years I guess. He said he tired of the academic and wanted to feel the benefit of all his training by actually working with many patients. I believe he may even do brain SBRT??? Who am I to 2nd-guess him???
Note...I believe they grade the evidence as part of their report???? If I recall, for PSA , no more than C grade. Anyway, men who are unaware of the PSA test must have been living in a cave??? The guidelines say that a man can ask for the pSA test, and also that their GPs should mention availability of tests, along with pros and cons, and patient, in consultation, can decide...of course...patients ultimately decide on treatments and tests in most cases.
Is it reasonable to expect a medical scientific answer to every question that comes up about treatments? In Sweden we have medico-legal concept of “science and proven experience”. If there is a lack of scientific evidence caregivers must rely on proven clinical experience and own judgement. "Proven experience" should be constantly re-examined and questioned. The art of doubt must be kept alive.
This is so important. The research guys build an hypothesis - its not a guess but an informed argument based on theory and tests that some new treatment "may" work. Less informed people can also build an hypothesis based on anecdotes without understanding the molecular activity involved. But neither of them are proven before they go through a Random DB Phase3 trial - and even then we might end up with percentages - works on 70% of patients with statistics giving + . Our main problem is jumping onto a prognosed solution with all sorts of supplements. The human body is a highly intricated machine - and we usually dont know all the interactions involved. Maybe one substance is good when combined with another, or at certain minimal concentrations. Cant really fix much by taking huge doses of a particular supplement - has to be scientifically tested in clinical trials.
Having said that it is highly unlikely that most of the stuff we eat on a daily basis will be tested at phase 3 level - so we are left to work with the facts where we have them - and our favourite untested hypotheses beyond that. When it all comes down to it we cant even state that this or that supplement helped my cancer fight - cos we dont know how it would have been without a well known scientific problem - too many variables.
So keep the hypothesis coming - but dont forget to give the details of why this is a good idea
The success of Einstein's theory of General Relativity (e.g., the transit of Mercury, gravitational lensing) proved that the Newtonian theory of gravity was wrong (although good enough for most calculations). Newton believed that masses attract one another (F=GMm/r2) -- they don't. In fact, mass causes distortions in space and time, and inertia creates the illusion of attraction. The speed of massive objects in motion is dependent on the fabric of spacetime they travel through (mostly because of changes in the time dimension). In the gravitational lens, massless photons (which have no time dimension) are simply taking the shortest path through the space they travel through - space is distorted by mass. Space and time are not what we intuitively think they are (as Kant said in 1781).
I think it’s useful to recognize the usefulness of a particular “model” depending on the context.
We have a Newtonian model where gravity is a force, and this one is proven “correct” in many but NOT ALL situations. Frankly, it’s “good enough” in almost ALL situations we’ll ordinarily experience.
There is another Einsteinian model (GR = General Relativity) where changes in velocity (i.e. acceleration, like when you “fall” towards the ground) stem from the way that mass distorts spacetime. This one is proven to be “correct” in basically ALL situations, as far as I’m aware.
However, in the spirit of TA’s post and comments about how science evolves, this does not mean that GR is the final truth about gravity. It’s just the best we’ve done so far.
Newton’s view of gravity as a force has been, and will continue to be, extremely useful … even for things like sending astronauts to the moon. Using solely Newtonian gravity (which assumes gravity to be a “force”), one calculation shows that the error in transfer orbit, compared to using GR, is only 1.3 cm. So, yeah, useful. Here’s that math-heavy discussion if you’re so inclined:
You’ll also see that, until more advanced physics/science courses, students even today are taught there are four fundamental forces (including gravity). It’s a very useful way to get started on things until students can handle the higher levels of math, concepts, etc needed to deal with the fabric of spacetime…
GR is, however, indispensable for situations where there are very high levels of gravity (e.g. black holes, Mercury’s proximity to the Sun, etc), or where there are very high velocities (approaching the speed of light, e.g. muon lifetime on approach to Earth), or there’s a need for very high precision in time synchronization between two objects moving at velocities that differ by a “large enough” amount (e.g. GPS).
Since GR’s curvature in spacetime model can reproduce everything Newton’s force of gravity was able to do, but has also been able to explain things that “gravity as a force” could not, it is currently the best model we have.
💯 The Newtonian model is very good and gives highly accurate answers (not accurate enough for GPS as you correctly point out though). So far, the Einsteinian model has stood up to about 100 years of very active scientific testing. It doesn't tell us how mass alters spacetime. Maybe the Higgs Boson will (but I suspect I am being reductive in looking for an easy answer)? Perhaps Bell's Theorem and the violation of the Einstein-Podolsky-Rosen paradox are the first cracks? It certainly tells us that spacetime isn't what we intuitively think it is. David Hoffman in "The Case Against Reality" puts forth the hypothesis that our perception of reality evolved to help us be fit to survive, but that true reality, which he calls "veridical reality" is very different from "fitness reality." Quantum entanglement may provide our first peek at veridical reality.
Right, it was never necessary for survival for us to understand physics at the quantum level. So we don’t. Richard Feynman doesn’t. It is … challenging to accept.
So when you say “how mass alters spacetime”, I think you’re asking the same question as “why”, am I right?
Physics Forum is another resource I like…someone asked this “why” question there, and one answer is “because it does”. Kinda like if you’re at the foundations, at the most fundamental theory, then you can’t go any deeper to explain its mechanisms. It’s just the way it is.
If we can find how to reconcile quantum and spacetime (as I think you’re alluding with Higgs, Bell and EPR), perhaps we get there. “Theory of Everything”, right? But then, we’d have to explain the why of THOSE mechanisms. Turtles all the way down.
So, yeah, entanglement. We’re gonna need a bigger forum.
Thank you Allen for such an in depth review and analysis of how and why medical studies become validated and discredited. It is certainly difficult for many here, myself included, to sometimes avoid the enticement of an easily understandable medical article , whether indicating positive or negative "results" of a study.
Your clear and concise description is very useful, though I expect I will still have questions about both legitimate and pseudoscience research studies to understand how to interpret their results.
Very well written and immensely helpful. Thanks again.
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