Questions re: statistics and testing accuracy

[Della66]

Like the rest of you, I've read a ton of information on the Internet regarding APOE and Alzheimer's disease, with much of it being a bit too technical for me to fully grasp. One issue I've found that drives me crazy is the disparity in numbers, for example, one article states APOE4 appears in 10-15% of the population, while another states it's 20-30%. That's quite a difference. Who to believe? Moreover, how can scientists present a statistic when the great majority of the population has not been tested? Those who have been tested either already have Alzheimer's or are tested because of family history....can those numbers alone be accurately extrapolated to the entire population? What about those APOE4's who have never been tested because they have no family history and no one in their family has ever developed dementia? Is there a statistic regarding these lucky folk? If so, how do scientists calculate the percentage of APOE4's who never develop dementia from among the entire population? I've also read that 40-60% of Alzheimer's patients are APOE4. Isn't that a remarkably large spread? If we take the number of 30% of the population having APOE4, but 40% of Alzheimer's patients have APOE4, isn't that a much lower risk than saying APOE4's consist of 10% of the population but represent 60% of Alzheimer's cases? I don't understand how risk factors are determined with such varying numbers and wide ranges being presented. Can you put it into layman's terms for me?
Also, I have a question regarding the actual testing accuracy ten years ago. As I originally posted, I was tested by a lab that ended up being sued by the government and several insurance companies for fraudulent business practices and was subsequently forced to go bankrupt. The lab was paying kickbacks to doctors who used their services (the lab called them "processing and handling fees", but the government called them kickbacks, which is illegal). The lab was also accused of doing unnecessary testing. The bankruptcy trustee is now in the process of suing thousands of doctors in an effort to regain monies paid to them by the lab to help pay back insurance companies that were defrauded. I had no idea my doctor had ordered the APOE test, and learned about it from a fax his office sent me with test results stating my APOE3/4 status. I had never heard of it and had to google it. My doctor insisted that APOE4 does not increase one's risk of Alzheimer's, but if someone is suspected of having Alzheimer's, being APOE4 confirms the diagnosis. All this occurred around 2008. My question is, how accurate was APOE testing ten years ago? Has the testing process become more accurate and how possible/probable is it that there were false positives back then? As I stated in my previous posts, I have no family history of Alzheimer's in my family. There are heart disease risk factors, such as high cholesterol and hypertension, however, no family member has ever had a heart attack. So, this APOE3/4 result was a shock to me. One more question, after ten years I still harbor much anger towards my former doctor for ordering this test without my knowledge (or his other patients'). Do I have a case to report him to the state medical board for unethical practices? If so, is there a statute of limitations? I thank you all for your assistance and inspiration.

[circular]

Hi Della, finding out one’s apoe status the way you did does come up here now and then. I forget if I’ve mentioned it to you before but it happened to me too. The lab was HDLabs. I thought a standard lipid panel was being ordered, but when I asked for copies I got an introduction to advanced cardio screening and new knowledge of my status. I knew what apoe4 was and have family history, and I remember the drive home like it was yesterday. I think maybe the fact that they’re going after the doctors to recover the kickbacks is all we need? The linked article mentions the DHHS is separately going after them. It would just be nice if they were publically outed in a list somewhere, but these days there are so many commercial conflicts in doctor practices of many types that it’s hard to single anyone out anymore for conflict of interest. Sadly it seems our world is more and more money driven. I gave the doctor’s office hell for ordering apoe without first seeking my permission and called the HDL and gave them hell too. Not that it did anything but temporarily raise my blood pressure.

You ask a lot of good questions about the statistics and I hope someone has some answers.

[Fiver]

Hi Della. It is tough to make sense of all the data, isn't it? Here is a short answer to some of your questions. Scientists have to get used to some uncertainty. There is natural variation to consider. And always some variation caused by the instruments, analyses, and human error. Researchers try to be up front about the limits of the data. To estimate the incidence of a gene allele like apoE4 researchers randomly subsample from a population they are interested in. Sometimes they use samples collected as a part of large surveys. Other times they do the collecting specifically for their study. Of course, the size of the sampling vs the size of the population determines the precision. And there's no telling if the results holds for a different population - different genders, ages, etc. An added challenge, until recently there was no way to determine for certain if some dementia was AD, or something else, without an autopsy. Now PET scans can "see" the plaques but that test is still fairly expensive. When multiple studies are combined, to get a bigger picture, it's called a meta-analysis, and the statistical tests report ranges and measure the precision as best they can. Usually, the studies weren't all done the same way and they have to make assumptions to get the data sets to "fit" into their model and provide useful data. Sorry, if I'm restating things you already know. I know those ranges can be frustrating. We all want more certainty. And sometimes when researchers say " the risk was five times higher" the risk increased from 1% to 5%, so the outcome is still unlikely.

Research reviews are a good way to get good information that has been summarized....

In the end, it's always going to be frustrating using survey data and statistical models to try and predict any one individual's risk. Insurance companies do this. But, really, they aren't worried about any one person either - they are playing the odds for the population that is all their customers.

I don't have any advice about what to do about your testing and your doctor's legal problems. Doesn't sound like the doctor had a good handle on the apoe4 story, but in 2008 we all knew a lot less. If there was a class action suit maybe you are entitled to some settlement money, but in my experience it often isn't much.

It is amazing that no one in your family has had dementia OR a heart attack. In my, non-medical doctor opinion,that seems like a really big positive for you.

[Searcher]

One issue I've found that drives me crazy is the disparity in numbers, for example, one article states APOE4 appears in 10-15% of the population, while another states it's 20-30%.

Della, estimates are based on samples. If you repeated the sampling exercise, you'd get a different estimate. The lower and upper bounds of the estimate indicate what would happen if you kept repeating the sampling. Only 5 times in 100 samples would you find an estimate outside the range. If you actually repeated the sampling and showed otherwise, then the bounds of the estimate would change.

So a good way to think of your example above might be "at least 10% of the population is likely to have APOE4" or "no more than 30% of the population is likely to have APOE4".

Take the interpretation which goes against whatever case you want to argue. If your view survives that, it becomes more persuasive.

As an aside, legal battles are a good way to invite stress, even in the unlikely event that somebody makes a substantial financial gain or gives the other party a black eye. Stress is a good way to invite neurodegeneration. It's all down to what really matters to you.

[Della66]

I thank you for your replies; I will say that these statistics have my head spinning. Circular, I also was tested by HDL and my experience was very similar to yours. Like you, I gave my doctor hell and demanded that the test results be taken out of my file, which fell on deaf ears. I'd just like to stress that I am not looking to get any monetary gain out of this. I do not want to seek legal action against my doctor, I was just speculating if his actions are reportable to the state medical board for unethical practices. I wouldn't want him to do this again to his patients. I was actually dealing well with my status for the past 9 years (after getting over the initial shock), but now that I'm 66, my anxiety has returned with a vengeance. I am currently seeing a therapist and hope she will be able to help me find peace with my feelings regarding my status and the manner in which I learned about it. Thank you all again.

[circular]

Hi Della, I wondered after my last post whether at the time there were any professional guidelines in place for doctors about ordering a patient's SNPs and needing permission first. I suspect there weren't at that time, especially since I don't think there are even now, but I could be wrong. A genetic counselor may know, and you may consider consultation with a genetic counselor as well to help with digesting the risks. One thing I suspect they would very likely emphasize is your lack of family history of Alzhimer's. There are so many genes that can modify our APOE 4 risk (uncertain as even that risk is as you show!) and your family may well also carry a significant modifier or a number of modifiers of less significance on their own, but sufficient combined significance, although this is all still being studied. Many will still argue that patients should not be testing their APOE status since age is still the #1 risk factor, and family history itself sends a very strong signal. Very good though that when you felt the need to have a therapist to help your process you took charge and got one on board, and regardless of one's APOE status, living a healthy lifestyle is a boon to our even more important epigenetic dynamics.

[slacker]

Thanks Tom and Searcher for your clear and elegant explanation of this subject of uncertainty.

[Harrison]

Hi Della66,

I can address some of your questions about the statistics. First, I will crib from a post I made a few months ago:
The allele frequency for APOE4 is 13-15% in most Western countries depending on the population (ranging from 21.5% in Finland to 8.3% in Italy). Allele frequency means what percentage of the APOE alleles in a population are APOE4. Remember that everybody carries two APOE alleles. It does not mean what percentage of the people in a population have an APOE4 allele (or two). That requires some calculations and assumptions, but the bottom line is that approximately 25% of a population have at least one APOE4 allele when the frequency is 13%.

As far as the percentage of Alzheimer's diseases cases that are ApoE4+, that has been a matter of controversy for a few reasons, but primarily because Alzheimer's disease used to be only a post-mortem diagnosis with plaques and tangles. With amyloid imaging, things have changed. However, if you take all cases of dementia regardless of causes and then ask how many ApoE4 carriers there are, you will get a wildly different number (say 40%) than if you ask how many amyloid positive Alzheimer's causes are there. In studies with amyloid imaging, the rate of Alzheimer's cases with at least one copy of apoE4 has been pretty consistently around 60%.

What I think you really want to know is what percentage of ApoE4 carriers will develop Alzheimer's disease. This is where the epidemiologists used Odds ratios and Hazard Ratios because they really can't say who will develop Alzheimer's. There are several studies that try to determine lifetime incidence of mild cognitive impairment or Alzheimer's due to apoE4. Here is a recent one: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5360223/. Here is the statement they put out to people who may want to participate in their drug study:

The Generation Study elected to disclose the following “lifetime” risks of MCI or dementia to its potential participants: 30%–55% for individuals with APOE-e4/e4; 20%–25% for individuals with APOE-e3/e4 and -e2/e4 (with a note that risk might be lower for those with APOE-e2/e4); and 10%–15% for individuals with APOE-e3/e3, -e3/e2, and -e2/e2 (with a note that risk might be lower for those with APOE-e2/e3 and -e2/e2). These values are consistent with our findings, but use round numbers for intelligibility, and broader ranges to reflect statistical and other sources of uncertainty.

[Searcher]

after ten years I still harbor much anger towards my former doctor for ordering this test without my knowledge (or his other patients'). Do I have a case to report him to the state medical board for unethical practices? If so, is there a statute of limitations?

Della, your anger is understandable. Your response can be self-sabotaging or self-enhancing.

If your anger will be defused by reporting him, then perhaps you can do it for your own peace of mind. The statute of limitations is only relevant if you are bent on him suffering in some way. The important thing might be to ask what is good for you and your own wellbeing, rather than what is bad for him. There's no guarantee that reporting him will defuse your anger.

If your habits and knowledge about health have been improved in any way as a result of his misconduct, then there's at least a tiny bit of benefit to you to help soothe your understandable outrage.

[Della66]

after ten years I still harbor much anger towards my former doctor for ordering this test without my knowledge (or his other patients'). Do I have a case to report him to the state medical board for unethical practices? If so, is there a statute of limitations?

Della, your anger is understandable. Your response can be self-sabotaging or self-enhancing.
If your anger will be defused by reporting him, then perhaps you can do it for your own peace of mind. The statute of limitations is only relevant if you are bent on him suffering in some way. The important thing might be to ask what is good for you and your own wellbeing, rather than what is bad for him. There's no guarantee that reporting him will defuse your anger.
If your habits and knowledge about health have been improved in any way as a result of his misconduct, then there's at least a tiny bit of benefit to you to help soothe your understandable outrage.

I do know myself, and I do know that I will do nothing more than post my feelings on this very helpful message board as it helps to vent to those who understand. Hopefully, the therapist can assist me in diffusing my anger and live with my status with less anxiety. Regarding your last sentence, there was one benefit from the testing and that is the fact that my husband tested 3/3, which gave us some peace of mind regarding his future health because his Mother had Alzheimer's (we do realize that being 3/3 does not exempt him from Alzheimer's). I thank you all for your kindness and concern.