This particular bit of news leaves your friend Doc Gumshoe shaking his head in puzzlement. To wit, in the US it is expected that there will be a substantial shortage of physicians in the upcoming years. The American Association of Medical Colleges predicts that this shortage may reach about 122,000 physicians by the year 2032 – about 56,000 primary care physicians and about 66,000 specialists.
How can this be? Physicians are well paid; their work is interesting and satisfying; they are among the most respected members of the community. On the other hand, the education and training of a physician is long and arduous, and many physicians are drained and frustrated by demands that have little relation to the healing arts, such as keeping electronic health records and navigating the complexities of the means employed by patients to cover their medical expenses, whether private or public.
A big part of it is demographics. Overall, the US population is growing at a moderate rate. The Census Bureau estimates that the population will have expanded by about 10% by the end of the next decade. However, the big change will be in the age distribution. The number of people over the age of 65 is expected to increase by about 48% during that same decade. And the aging population will affect the physician supply. About one-third of all active physicians will pass the 65 year marker by the end of the decade. Some of them may decide to continue practicing, but some will certainly hang up their stethoscopes.
Furthermore, large segments of the US populace are underserved when it comes to health care. Race, insurance coverage, and geographic location all have major effects on a person’s likelihood of receiving appropriate health care. If medical care were equalized across all population segments, we would need an additional 95,000 physicians immediately, and even more as time went on.
Can artificial intelligence (or what currently passes for AI) make up for the shortage of live human medical providers? Can we entrust our health to digital devices?
If the track record of the Apple Watch is an example, the answer appears to be a big “NO!”
The Apple Heart Study
This was, supposedly, a genuine clinical study, designed to produce information of value concerning the Apple Watch, which – again, supposedly – can detect episodes of atrial fibrillation. Atrial fibrillation, commonly referred to as atrial fib or afib, is a condition during which the contractions of the four chambers of the heart are irregular. The sequence of contractions in the heart, when it is functioning normally are:
- Blood from the venous system returning to the heart enters the right atrium, which contracts, pushing the blood into the right ventricle.
- The right ventricle contracts, sending blood into the lungs, where it will absorb oxygen.
- Newly oxygenated blood from the lungs enters the left atrium, which contracts, pushing the blood into the left ventricle.
- The left ventricle contracts, sending the oxygenated blood into the aorta, to be distributed throughout the body.
But in afib, the two upper chambers, the atria, contract rapidly and chaotically, and do not coordinate with the contractions of the lower chambers, the ventricles.
As a result, blood is not completely expelled from the upper chambers – the atria – and the lower chambers also do not expel as much blood as they are supposed to.
The greatest risk of atrial fib is that a certain amount of blood may remain in the upper chambers, where it pools and is more likely to form clots than blood that is circulating normally. As a result, the greatest risk from atrial fibrillation is that one or more of those blood clots will find its way into the brain and cause a stroke.
Clots may also circulate and wind up in other vital organs, leading to blocked blood flow and the potential for life-threatening harm.
The Apple Watch is supposed to detect cardiac arrhythmias and send information about the wearer’s heart rhythms to Apple for evaluation. Apple paid Stanford University more than $8 million to conduct the study, which was intended to determine whether the Apple Watch did indeed do what it was supposed to do. (This may sound like serious money, but it’s a small fraction of what a well-controlled clinical trial would cost, and also just a tiny nibble of Apple’s profits.)
Apple Watch owners were invited to participate in the study, and nearly 420,000 people did so. Of these, a majority – 219,179, or 52% — were under age 40. Of those, only 341, or 0.16%, were notified that they had a cardiac irregularity. And of those 341, only 9, or 0.004%, actually had atrial fibrillation.
Only 24,626 persons in the study were 65 years of age or older. Of these, 775, or 3.14%, were notified of an irregularity. But in that group of 775 who had been told that they were experiencing some kind of cardiac arrhythmia, only 63 people, or 0.26%, actually had atrial fib.
Comparing the percentages of people whose atrial fibrillation was actually detected by the Apple Watch with the prevalence of atrial fib in the American population tells us something about the Apple Watch that Apple probably does not want to acknowledge. Atrial fib is present in approximately 2% in people under the age of 65, and in 9% of people age 65 or more. But the Apple Watch study detected real atrial fibrillation in only about one quarter of one percent of the participants who were 65 or older. What happened to the other eight and three quarters percent of those 65-year-olds? Did the Apple Watch just fail to spot their atrial fib?
So, in sum, what did the Apple Watch do in this very large study? Mostly, it frightened the 1,116 people that supposedly had a “cardiac irregularity,” while only 72 of them had anything of medical consequence. And at the same time, the Apple Watch missed identifying thousands of people with real atrial fib. If the global prevalence data applied to the 420,000 participants in the Apple Watch study, about 8,400 of those persons would have had atrial fib.
My take on the Apple Watch is that it’s worse than useless – worse, because it frightens people needlessly by reporting a “cardiac irregularity” of zero clinical significance, while providing false comfort to others by supposedly being able to detect atrial fibrillation while missing the real thing.
I hope it can at least tell time.
The deficits of the Apple Watch do not mean that all healthcare devices that depend on super-sensitive detection and algorithms are doomed to failure. Diabetics these days wear devices that continuously monitor their blood sugar and administer correct doses of insulin as needed. Pacemakers to control heart arrhythmias have been around for decades, and persons with ventricular (as opposed to atrial) fibrillation are sometimes furnished with defibrillators.
Flaws in the algorithm
On the other hand, reliance on artificial intelligence, as a substitute for actual face- to-face doctor-patient communication and consultation, can be a distinct menace. For example, it was reported in the Journal of Pediatrics that reliance on a “consultation” where the patient communicates not with a live human physician, but with a computerized algorithm, results in, among other things, a huge over-reliance on antibiotics where antibiotics are not needed.
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Some doctors like reliance on these automated consultations because they take much less time than an actual office visit. When Timmy’s mother calls the doctor because Timmy is feeling poorly, the doctor him/herself does not have to conduct the consultation, and does not actually examine Timmy. Frequently, deciding whether an infection is due to a bacterium or to a virus is a judgment call, and the safer bet is to prescribe an antibiotic. Timmy’s mom is happy, because the doctor did something. And the doctor is happy, because the interaction did not chew up valuable time. But if Timmy’s ailment turns out to have been a virus, and Timmy’s mom doesn’t complete the course of antibiotic treatment as prescribed, there is a good chance that some bacteria lurking in Timmy’s system will have developed resistance to the antibiotic, definitely not a good outcome.
So, perhaps it’s time to turn to somewhat more cheerful news, not only for the population that is menaced by the particular disease, but for those of us who sometimes doubt the ability of the health-care profession to solve really tough problems. I’m talking about the recent news that means have apparently been found to significantly improve survival in a particularly deadly disease.
A drug combo that works fairly well in Ebola
These are interim results from a continuing clinical trial, but the signs so far are unquestionably positive. The trial, called the PALM study, demonstrated that two therapies made from Ebola antibodies are clearly improving survival rates in the individuals who were receiving the drugs. PALM stands for Pamoja Tulinde Maisha, which in Swahili means Together Save Lives. In the trial, three therapeutic agents were tested against ZMapp, the first monoclonal antibody to be used against Ebola, developed by Mapp Bio. ZMapp had shown signs in a previous clinical trial that it was improving survival in patients with Ebola; however, that trial was cut short because the Ebola outbreak at that time ended before the trial could conclude.
The original plan for the trial PALM trial called for enrolling 725 patients. However, the trial’s data and safety monitoring board, which has conducted sporadic reviews of the data, recently analyzed findings based on 499 patients and made them public.
Two agents in particular demonstrated improved survival rates. Those two were REGN-EB3, a cocktail of three monoclonal Ebola antibodies made by Regeneron, and mAb114, a single monoclonal antibody initially developed by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. Further development of mAb114 will be carried out by Ridgeback Therapeutics.
Based on the data available at this point, the mortality rate for patients treated with REGN-EB3 was 29%; for patients treated with mAb114 the mortality rate was 34%. These rates compare with a mortality rate of 49% for patients treated with ZMapp and 67% for the Ebola outbreak as a whole.
Left behind in the trial was Gilead’s remdesivir. The mortality rate in patients treated with remdesivir was 53%, trailing the other three active agents.
Commenting on the PALM trial, Dr. Anthony Fauci, director of NIAID said, “It means that we do have now what looks like treatments for a disease which not too long ago we really had no therapeutic approach at all. We feel that with agents such as these that we may be able to improve the survival of people with Ebola and might even make people more enthusiastic about coming for care. Because when you have something to offer an individual, it makes it much more likely that you might get to them early. And the earlier the better, as in any disease.”
Speaking of “the earlier the better,” that seems to apply also to the time of day when patients see their physicians.
The early bird gets more of the physician’s attention
One would think that it wouldn’t matter in the least at what time of day our appointments with our doctors took place, other than the doctor’s convenience and our own convenience. But it does really appear to make a difference.
A study in JAMA Network Open reported a large difference in the number and percentage of patients referred for cancer screening depending on the time of day of their physician appointments. Patients with morning appointments were significantly more likely to be referred for colorectal and breast cancer screening than patients with afternoon appointments.
The study was based on the records of 33 medical practices in Pennsylvania and New Jersey, examining 19,254 females eligible for breast cancer screening (which included mammograms) and 33,648 male and female patients eligible for colorectal cancer screening (which included colonoscopy, sigmoidoscopy, fecal immunochemical test, fecal occult blood test, or a multi-targeted stool DNA test).
Screening test order rates for breast cancer dropped from 63.7% at 8 AM to 47.8% at 5 PM. Similarly, screening test order rates for colorectal cancer decreased from 36.5% for 8 AM appointment times to 23.4% at 5 PM.
The study authors speculated that this significant decline in the screening referrals might be due to a number of factors: the cumulative burden of screening discussions on physicians during the day; also the stress due to trying to keep up with schedules, and a factor which the authors designated as “decision fatigue.”
I would suggest additional sources of stress: the pressure in many group practices on maintaining “through-put” resulting sometimes in arbitrary time limits on consults; also, the attention to the demands of electronic medical records, which may require the physician to pay as much or more attention to the computer than to the patient.
The same factors affected the rates at which patients actually completed their screening tests. Screening test for breast cancer completion rates were 33.2% at 8 AM. and decreased to 17.8% at 5 PM. For colorectal cancer screening test orders, completion rates were 28.0% at 8 AM and decreased to 17.8% at 5 PM.
It is almost a cliché to point out that early detection, followed by prompt treatment, significantly improves cancer prognosis. However, about two out of three US patients who have a regular physician and insurance that could pay for the test have never been screened for colorectal cancer, which is the third leading cause of cancer-related deaths both in men and women. Similarly, the CDC estimates that 28% of women who meet guideline recommendations have not been screened for breast cancer.
This same pattern of suboptimal care related to appointment times later in the day has also been found in several separate studies. Higher rates of inappropriate prescriptions for opioids or antibiotics for back pain were given to patients with later appointments, and also vaccination rates for influenza declined in the afternoon.
Having urged you to get up early in the morning and see your doctor before the morning dew is off the vine, am I now going to tell you to watch your BMI for the sake of your heart health?
At least in cancer patients, BMI is not a good predictor of cardiovascular risk
A population-based study published in JAMA Oncology studied the relationship between BMI and major adverse cardiovascular events (MACE) as well as the relationship between other indices of body composition and MACE. The major adverse cardiovascular events were stroke, cardiovascular death, and heart attacks. BMI, in case you’ve forgotten, stands for body mass index, which is calculated by dividing the body weight in kilograms by the square of the height in meters. It is a quick and convenient way of sorting people into very broad categories, from underweight to obese, without having to take into consideration a great many other factors that affect health.
The study evaluated patients with colorectal cancer. Such patients are at four times the risk of MACE than the general population. All 2,839 patients in the Kaiser Permanente Northern California cancer registry ages 18 to 80 years who were diagnosed with stage I to III invasive colorectal cancer and underwent surgical resection were evaluated.
The mean age was 61.9 years, and 51.3% were female. Many patients were current (12%) or former (40%) smokers and had type 2 diabetes (20%), hyperlipidemia (49%), and hypertension (55%).
In this cohort, a BMI in the obese range, which is 35 or greater, was not associated with significantly greater risk of MACE than a normal weight BMI, which is 18.5 to 24.9.
What MACE did correlate with was muscle density and visceral fatty tissue, both indices of body composition rather than the relationship between weight and height. The highest quintile in muscle density had about a 33% lower incidence of MACE compared with the lowest quintile, while the highest quintile in visceral fatty tissue had about a 50% higher incidence of MACE.
What this study demonstrated was that it’s not so much your weight that is a factor in your heart disease risk, but the composition of your body – the balance between muscle and fat. Even though this particular clinical study was based on colorectal cancer patients, Doc Gumshoe is fairly confident that that same factor applies to the rest of us.
Another squabble about prostate cancer screening
In previous posts, I have looked at – and discussed with you – prostate cancer and the best way to detect it and treat it. The limitations of the prostate-specific antigen (PSA) test are acknowledged, as well as the likelihood that it leads to too many unnecessary biopsies. But at the same time, the decrease in the number of men who have the PSA test (because of the negative recommendation of the US Preventive Services Task Force) has led to a smaller number of prostate cancer diagnoses, but a larger number of prostate cancers that are not diagnosed early enough and therefore become metastatic.
A new diagnostic test for prostate cancer, the prostate health index (PHI) was introduced a few years ago specifically to attempt to distinguish between, on the one hand, men whose elevated PSA results would have led them to undergo biopsies even though their cancers are not threatening, and men with more advanced prostate cancers that should be treated.
The PHI does not replace the PSA test. On the contrary, it has been approved by the FDA only for men who have taken the PSA test, and whose PSA levels are between 4 and 10 ng/mL. It is in men with initial PSA levels in that range that a great many “unnecessary” biopsies are performed. These biopsies are characterized as unnecessary because the great majority result in a Gleason score of 6 or lower, indicating that if a tumor is present, it is not threatening and does not call for immediate treatment. Most men with those characteristics are counseled to adopt a policy of “watchful waiting.”
“Watchful waiting” might mean nothing much more than “let’s keep an eye on how you’re doing” – annual PSA assays when the patient has his physical examination, and perhaps a biopsy if the PSA level has gone up too much or too fast. It’s the biopsy that the PHI test was developed to avoid.
Further research has shown that PSA can be measured in three isoforms: total PSA, free or unbound PSA, and a form designated as p2PSA. Starting in the 1990s, it became evident that in men who had a greater percentage of free PSA in the total PSA levels, there was a greater likelihood that the cause was a condition other than prostate cancer.
The PHI combines all three forms of PSA into a single score that can lead to an informed decision about how to proceed in patients with an elevated initial PSA reading. PHI is calculated using a formula in which the ratio of p2PSA to free PSA is multiplied by the square root of total PSA.
PHI has been compared directly with PSA and with assays of the individual component of total PSA and found to be about 50% more accurate in detecting prostate cancers with Gleason scores of 4+3 and above. PHI scores are also valuable in that patients with PHI score below 27 are unlikely to have elevated Gleason scores and a less than 10% probability of having cancer.
In patients with higher PHI scores, the probability of having cancer increases. Patients with PHI scores from about 27 to 35 have a 17% chance of having cancer. In those with PHI scores from about 36 to 55, that probability increases to about 33%, and in those with PHI scores higher than 55, the cancer probability increases to 50%.
The studies of the PHI described above attempt to evaluate the accuracy of the PHI by determining the Gleason scores of patients with PHI scores in a certain range. However, that can only be done by performing biopsies on those patients, since Gleason scores are obtained through biopsies only. But perhaps the main selling point for the PHI over the PSA is that the PHI provides a more accurate estimate of the probability of cancer requiring early intervention.
The biopsy reveals the state of the cancer cells in the prostate and assigns grades of 1 to 5 to the cells. Not all the cancer cells are at the same stage of development, so the Gleason scores are generally the combination of two numbers; the first of the two numbers is the grade of the cells that occupy the greater amount of space in the gland, while the second of the two is the grade of the rest of the cells. Cancer cells evaluated as grade 1 or 2 are considered to be non-threatening at that stage. At the other end of the scale, any cancer cells evaluated at stage 5 call for early treatment, since metastasis is likely when the cells reach that stage. A Gleason score of 3+4 is considered less threatening than a score of 4+3, since the latter indicates that more of the cancer cell population is genuinely threatening.
The squabble was kicked off by a paper published in April of last year supporting the usefulness of the PHI in arriving at a decision regarding whether to biopsy men with an elevated PSA. (White J et al. Prostate Cancer Prostatic Dis 2018:21(1):778-84) The paper reported a study in about 1,000 men, half of whom had received a PHI test to determine the need for a biopsy. The authors concluded that PHI testing reduced the rate of biopsies in the PSA “gray zone” of 4 – 10 mg/mL and nonsuspicious digital rectal exams. In those who had a PHI test, 36% had biopsies versus 60% of those who had not had the PHI tests. Thus it appeared that the PHI tests spared a lot of guys from unnecessary biopsies.
But were those biopsies really unnecessary? Two researchers at the Memorial Sloan Kettering Cancer Center wrote a letter to the journal pointing to data that were missing from the paper as published, and demanding that the missing data be made public. The data in question related to the number of men with lower PSI scores, supposedly pointing to a lower probability of cancer, who actually did have prostate cancer. The MSK researchers, both MDs, asserted that the PSI missed as many as one in three prostate cancers.
The best that the authors of the original paper could answer is that their study was
“not powered” to provide that information. They then alleged a conflict of interest, pointing to work that the MSK researchers were supposedly doing on a competing assay. As far as I know, the dispute has not been satisfactorily resolved to date.
I find myself questioning why there is such a fuss about a prostate biopsy. I had a prostate biopsy almost 20 years ago, and it was by no means a big deal. The procedure is done under a local anaesthetic. It takes a few minutes, after which you get up from the operating table, get dressed, and go about your business. There is some blood in the urine for a few days, but not much. In my case, I had been having annual PSA tests at the suggestion of my primary care physician. The PSA levels hovered below 2.5 for several years and then jumped up to 4.2, still at the lower end of the scale. What raised my PCP’s eyebrows was the rapid change from the year before, so he insisted that I consult an urologist, who performed the biopsy. The excellent urologist, currently the head of urology at a major medical center, had indicated that the result of the biopsy would most likely be negative, but it didn’t turn out that way. My Gleason score was 4+3, pointing the needle in the direction of intervention. After looking at the range of likely outcomes following the alternative interventions, I opted for prostatectomy.
The prostatectomy was uneventful. I had what they call “clean margins,” meaning that no cancer cells had escaped the prostate capsule. I continue to have annual PSA tests, and those levels have continued to be in the “undetectable” range. But if I had not had that biopsy, who knows what the outcome might have been.
False positives / false negatives: which is more dangerous?
When it comes to a disease or condition that can kill you, a false negative is much, much more dangerous. The U. S. Preventive Services Task Force stated their opposition to PSA testing in most men on the grounds that the PSA test results in a great many false positives, such that huge numbers of men undergo biopsies of the prostate, while only a small fraction of those men actually have prostate cancers that would likely progress to the fatal stage. It is true that prostate cancer, in most cases, progresses very slowly, such that many men who do actually have prostate cancer live out their lives before the cancer results in any adverse consequences. The common wisdom is that these men die with the cancer, but not of the cancer. This line of reasoning leads to the conclusion that since the PSA test produces so many false positives, and that even in many of the instances where the test leads to the detection of an actual cancer, the connection between the PSA test and the need for treatment is tenuous. So, why bother to have the test?
The answer is that although the PSA test produces a lot of false positives, the false negative rate is tiny. A negative PSA result, let’s say under 4 ng/mL, really does signal an “all clear” at that time – but the test will be repeated as part of the next annual physical. But a positive PSA result means only that a biopsy needs to be performed. And the biopsy is highly definitive – it either finds cancerous cells or it doesn’t. Not only that, the biopsy is highly informative as to the stage of the cancer.
The USPSTF’s recommendation has had a non-trivial effect on the rate of metastatic prostate cancer: fewer men have PSA tests, fewer early-stage cancers are diagnosed and treated, therefore more cancers progress to the metastatic state. A recent study by researchers from the National Cancer Institute notes that from 2004 to 2007, the incidence of metastatic prostate cancer was steadily declining at the rate of 1.45% per year. Then, starting in 2008, the incidence started to increase, accelerating to 2.45% per year following the USPSTF’s publication of its anti-PSA recommendation. The annual burden of metastatic prostate cancer is expected to increase by 42% by 2025, with an additional 15,891 cases compared with alternative forecasts based on the trends prior to 2012. (Kelly SP et al. Eur Urol Focus 2018:4(11)121-127) Says Doc Gumshoe: “More work for the undertaker.”
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I had it in mind to end this long and serious sermon with something more cheerful, and was going to put in a bit about an “age reversing youth switch” that can make us go back in time without the need for a time machine, those being expensive and illegal in most jurisdictions. But then, on further sleuthing, the switch turned out to be those telomeres on the ends of our DNA strands that I’ve already mentioned a few times, and the magician who would guide us through the process of turning back the clock was none other than our old friend Dr Al Sears. So maybe I’ll skip the age reversing youth switch for now. In the meantime, my Alzheimer’s folder is getting stuffed, so I’ll clear it out soon and exhibit the contents to Planet Gumshoe. In the meantime, best to all, Michael Jorrin (aka Doc Gumshoe)
[ed. note: Michael Jorrin, who I dubbed Doc Gumshoe many years ago, is a longtime medical writer (not a doctor) who writes for us about topics in health and medicine a couple times a month. He does not generally comment on investment specifics, but has agreed to our disclosure and trading rules. You can see all of his past columns here.]