“False positive” data from the European screening trial and other matters

The “game” of retrospectively analyzing every possible piece of data from the European Randomized Screening Study for Prostate Cancer (ERSPC) has been under way for a while now … and we can expect this game to produce lots and lots of controversial information and media coverage. But much of the data from these subset analyses will need to be treated with great caution.

Let’s look at just two current examples.

A new analysis of data from the Finnish section of the trial (where the men received a PSA test once every 4 years) has claimed that for every eight Finnish men who met the criteria for a biopsy, one man had a “false positive” result. But if you read even the abstract of the actual paper, you wonder whether this is really what the authors meant to state.

Writing in the British Journal of Cancer, Kilpeläinen et al. note that Finland was the largest recruiter of patients for the ERSPC. (Finland actually enrolled 80,379 of the total of 162,243 men in the ERSPC, nearly half of the total enrollment.) The Finnish men who were recruited had a PSA test every 4 years and (to date) have been followed for an average of 9.2 years, including three rounds of PSA tests. Patients were referred for a biopsy if they had a PSA of 4.0 ng/ml or higher or a PSA of 3.0 to 3.9 ng/ml and “a positive auxilliary test” (a digital rectal examination until 1998 and calculation of the ratio of the free PSA value to the total PSA value — with a value of ≤0.16 — starting in 1999, according to the original report of the results of the trial in the New England Journal of Medicine).

The researchers defined a false positive result as “a positive screening result without cancer in [biopsy cores taken] within 1 year from the screening test.” But why on Earth would one define this as a “false positive” result? It is well understood that PSA levels rise for all sorts of reasons. It is perhaps shocking that as many as 7 men in 8 out of all those biopsied in Finland in this trial would have had a positive biopsy result! It is the biopsy that defines a diagnosis of cancer, not the PSA test. The PSA test only indicates the possibility of the cancer!

Unsurprisingly, the Finnish researchers go on to state that more than half of the men who had a negative biopsy for prostate cancer after a finding of an elevated PSA level in their first or second round of screening had another negative biopsy result after an elevated PSA at a subsequent round of screening. Is it possible they just had BPH, or prostatitis? That would be a shock!

So let us be clear … There is nothing wrong with this paper except that the term “false positive” has been used to describe the biopsy results where “negative” might have been a more appropriate term. This could be no more than a language issue resulting from Finnish epidemiologists writing a paper for an English language journal (although it is mildly surprising that someone at the British Journal of Cancer didn’t notice this!)

Perhaps the two more important things that we learn from this paper are as follows:

  • The prevalence of undiagnosed prostate cancer in Finland at the time the trial was conducted was very high (if 7/8 men with a PSA level meeting the study criteria went on to have a positive biopsy).
  • That the men who had a negative biopsy after an elevated PSA at their first or second round of screening were 1.5 to 2.0 times more likely to not participate in subsequent rounds of screening compared with men with a normal screening result.

But the second of these two facts suggests a further possibility … which is that these men really were being told that they had had a false negative biopsy result in the prior screening round, as opposed to just being told that their biopsy result showed no signal for cancer at that time. If that was what was happening, then the expectations of the Finnish researchers would seem to have been sadly out of synch with the entire premise behind using the PSA test to screen for prostate cancer!

There are data “missing” from the report of the PLCO trial in the New England Journal of Medicine. It would have been nice to know what percentages of men enrolled in the screening arm of this trial, and who had a PSA meeting the criteria for a biopsy, actually went on to have a positive and negative biopsy results. Unfortunately the study report does not provide these data, but we suspect it was significantly less than 7/8 or nearly 88 percent

Another paper (by Roobol et al.) has just been published in the European Journal of Urology.

Roobol and her colleagues have re-analyzed data from 1,850 men who were initially screened (for a PSA level of ≥3.0 ng/ml) and biopsied in the Rotterdam section of the ESPRC. They then used these data to calculate the probabilities that individual patients would have a positive biopsy [P(biop+)] and the probabilities that they would have an indolent cancer [P(ind)] if prostate cancer was, in fact, detected at biopsy. In fact, 541/1,850 men in the first round of screening and in 225/1,201 men in the second round had positive biopsies in the Rotterdam section of the ESPRC (and it is worth contrasting that with the 7/8 men in the Finnish section who were getting positive biopsies!).

Now Roobol and her colleagues were trying to develop strategies that would potentially reduce the number of unnecessary biopsies while still detecting most of the clinically important cases of prostate cancer.

What Roobol et al. did, therefore, was to say, “Well what would have happened if we apply an additional [P(biop+)] of 12.5 percent to these 1,850 men?” which would have meant that, using the algorithm they had constucted, 613/1,850 men would not have been biopsied at all. In that case you get the following results:

  • The positive predictive value of a biopsy in the first screening round would increase from 29 percent (541/1,850) to 38 percent (468/1,237).
  • At repeat screening, the positive predictive value of a biopsy would again increase — from 19 percent (225/1,201) to 25 percent (188/760).
  • 14 percent of prostate cancer cases (110/776) would not have been diagnosed.
  • Of these 110 cases, 70 percent could be considered potentially indolent in the initial screening round and 81 percent in the repeat screening rounds.
  • None of the “deadly” cases would have been missed.

According to Roobol and her colleagues, if a PSA cut-off of ≥ 4.0 ng/ml had been used (instead of the cut-off of ≥ 3.0 ng/ml that was actually used in the Rotterdam section), similar numbers of biopsies cases could have been saved but considerably higher numbers of missed diagnoses would have resulted.

Roobol et al. conclude that their individualized screening algorithm, which is based on the patient’s actual PSA level together with other, available prebiopsy information, can significantly reduce the number of unnecessary biopsies currently being carried out. They further note that very few important cases of prostate cancer (i.e., cases for which diagnosis at a subsequent screening visit might be too late for treatment with curative intent) would be missed.

The abstract of the paper by Roobol and her colleagues does not give the details of how they calculated the [P(biop+)] and [P(ind)] values that underlie this analysis, but the idea that one could use such a model to avoid unnecessary biopsies in men at minimal risk for clinically sign ificant prostate cancer is, at least, enticing.

8 Responses

  1. And just how many angels can dance on the head of a pin? Oh! And what IS the Meaning of Life — apart from 42?

  2. Mike, YOUR conclusions make no logical sense, and rather than recognizing there might be something wrong with your interpretation of the results (how could YOU possibly be wrong?) you go on a tirade about how the Finns have obviously erred in their use of the screening term, “false positive”.

    The problem that you deplore, I BELIEVE, is actually created by your assignment of the use of the term “false positive” to the Biopsy results, in isolation from the PSA screening results, rather than in concert with them, as is intended. Let me explain how I interpret those same results as stated in the Abstract of the Kilpeläinen TP, et al Study (the link to which you thoughtfully provided).

    The European Randomized Study of Screening for Prostate Cancer was initiated in the early 1990s to evaluate the effect of screening with prostate-specific–antigen (PSA) testing on death rates from prostate cancer. Clearly understanding this original “purpose” statement is key to the proper interpretation of the data contained in this current Paper.

    YOU STATE: “The researchers defined a false positive result as “a positive screening result without cancer in [biopsy cores taken] within 1 year from the screening test.” But why on Earth would one define this as a “false positive” result?

    MY RESPONSE: Because the “false positive result” refers to a positive SCREENING PSA, which means an elevated screening PSA test above the Study threshold, which is defined as, “a PSA of 4.0 ng/ml or higher or a PSA of 3.0 to 3.9 ng/ml and “a positive auxiliary test” (a digital rectal examination until 1998 and calculation of the ratio of the free PSA value to the total PSA value — with a value of ≤0.16 — starting in 1999, according to the original report of the results of the trial in the New England Journal of Medicine)”.

    It would have been more clearly stated, IN MY OPINION, if the definition was worded as follows: “A FALSE POSITIVE reflects a positive (PSA) screening result, without cancer (BEING SUBSEQUENTLY DETECTED) in a (FOLLOW-UP BIOPSY, OBTAINED) within 1 year from the screening test.” However, if you examine, and apply, the percentages cited in the abstract, the conclusions you proffer are not statistically feasible.
    There are other clues, including the statement, “ False-positive men (PSA’s) constitute a special group THAT RECEIVES THE UNNECESSARY INTERVENTIONS (THE BIOPSIES), but may harbour missed cancers. New strategies are needed for risk stratification in PC screening to minimise the proportion of FP men”.

    I hope by highlighting in CAPITALS and adding (ADDITIONAL CLARIFICATIONS) that I have made this complicated attempt at correcting some erroneous interpretations of the poorly worded Abstract, able to be understood. If not I will be happy to respond to any direct questions. No, this does not qualify as a typo! – John@newPCa.org (aka) az4peaks

  3. Dear John:

    As you will see, I have posted your “comments” exactly as you provided (since I happen to believe, up to a point, in freedom of speech).

    Please note that I understood precisely that the researchers were using the term “false positive” to apply to the PSA result. Perhaps you would care to explain to me (and perhaps others, but I may well be the only person who “doesn’t get it”) how one can have a “false positive” or a “false negative” outcome for something that you don’t know beforehand is capable of being true or false? There may well be something wrong with my interpretation of this study — but it was not because of how I interpreted the terms they used. On that (apparently to your surprise) we absolutely agree.

    Perhaps it would have been better, in the seventh paragraph above, if — instead of the sentence, ‘There is nothing wrong with this paper except that the term “false positive” has been used to describe the biopsy results where “negative” might have been a more appropriate term” — I had written:

    ‘There is nothing wrong with this paper except that the term “false positive” has been used to describe a negative biopsy result in a patient whose PSA met the study criteria requiring a biopsy. How can meeting a specific PSA level be a “false positive” (or a false negative for that matter) if what one is trying to do is to determine whether, if a man is biopsied after his PSA reaches that level, is indeed a valid mechanism for screening at all?’

    The key point that I was trying to make (which I apparently failed to communicate successfully to you) is that the Finns’ definition of a “false positive” is inherently meaningless. It is neither “false” nor “positive,” because it was an inevitable consequence of the criteria they used to identify the need for a biopsy in the first place. The whole thing is a circular argument. And the fact that the same term is used with the same meaning in the report on the PLCO study in the New England Journal does not (in my apparent ignorance) make the terminology justifiable.

    Then again — to Terry’s point above — exactly how many angels would you like to fit onto the head of a pin?

  4. “The researchers defined a false positive result as ‘a positive screening result without cancer in [biopsy cores taken] within 1 year from the screening test.'”

    I see the point the Mike is making considering up to 62% of negative biopsies from moderately elevated PSAs are wrong, depending on who you talk to. And using the term “positive” PSA screening is extremely ambiguous in the first place. While labs will generally list a “normal” range of 0.0 to 4.0 in their assay analysis reports, a seasoned physician will consider anything above these ranges (or a sharp rise not exceeding a normal range) as only a possibility of prostate problems and not a positive marker for cancer. I think the researchers should have used the term “False Assumption” if they think any pre-diagnosis moderately high PSA measurement should be considered as a possible cancer indicator first. This as opposed to other causes of elevated PSA. And when you consider saying “false positive” as they applied it could also mean that the needles missed the cancerous cells, it renders this study kinda useless in my opinion.

    I only need one angel on that pin if he has the ability to make Yorkshire Pudding. Because God knows that might be the only way I may ever get to try the stuff … (inside joke of unknown origins)

  5. When we read journal articles, we need to understand the words they use. False positive and false negative are standard terms that are used to evaluate screening tests.

    From the NCI website:

    False-positive tests: False-positive test results (also called false positives) occur when the PSA level is elevated but no cancer is actually present. False positives may lead to additional medical procedures that have potential risks and significant financial costs and can create anxiety for the patient and his family. Most men with an elevated PSA test result turn out not to have cancer; only 25 to 35 percent of men who have a biopsy due to an elevated PSA level actually have prostate cancer.

    False-negative tests: False-negative test results (also called false negatives) occur when the PSA level is in the normal range even though prostate cancer is actually present. Most prostate cancers are slow-growing and may exist for decades before they are large enough to cause symptoms. Subsequent PSA tests may indicate a problem before the disease progresses significantly.

    The only way to evaluate whether cancer is present is by doing a biopsy and that is also imperfect with prostate cancer.

    The objective of any screening test is to have a perfect correlation to actually having cancer. Documenting the number of false positives and false negative tests is an important part of validating the test.

    I guess I am a little confused why the standard terms need to be changed. The words are understood by the research community and maybe we need to learn to speak their language and understand what they mean.

  6. Hi Kathy, – Of course you are exactly right and that was my point, but you have expressed it much more effectively. Thank you! Medical Studies and Papers are written, published and intended for those within the profession of Medicine.

    We lay persons need to recognize that if we wish to participate in, or even understand and/or comment on the conclusions involved, it is incumbent on us to learn the language of those in whose world we have entered.

    To complain that their professionally understood, long standing terminology is not understandable to those for whom it was not intended, and further, to draw rediculous conclusions to try and support that position is, in my opinion, not only unwarranted, but constitutes poor journalism. – John@newPca.org (aka) az4peaks

  7. Dear Kathy (and John):

    The use of the terms “false positive” and “false negative” have a long and honorable history in medical and scientific literature. However, that usage has always been premised on the concept that there was a high probability that the test in question would give an accurate result under normal circumstances. So, as an example, when you have every known symptom of pneumonia, and the lab tests a blood or sputum specimen to see if they can isolate Ps. pneumoniae, and it comes back negative, but you respond to a drug given specifically to treat pneumonia, it is likely that the lab result was a false negative because these tests are now pretty accurate.

    In contrast, the cardiology community decided some years ago that we should all try to keep our total cholesterol levels below 200 mg/dl. They further state that if your choleterol level is 240 ng/ml or higher, you have twice the normal risk for heart disease. However, it is a number, and people die with heart disease and cholesterol levels way under 200, while others live out their lives with cholsterol levels significantly higher thas 240. I have never heard anyone suggest that a cholesterol level of a certain amount might be a “false positive” or a “false negative” marker for heart disease under such circumstances, even though cholesterol levels are probably a better risk indicator for clinically significant heart disease than the PSA test is for prostate cancer.

    Similarly, a man’s PSA level is a number. The vast majority of men over 60 with an elevated PSA level (whatever that is) do not have cancer. They have BPH or some other clinical condition. This is why Dr. Stamey said, several years ago, that (in his, reasonably well informed, opinion) the PSA test was no longer a good tool for finding prostate cancer at all. We have (to date) failed to demonstrate that there is any really meaningful correlation between a specific PSA level and either risk for or mortality from prostate cancer. The fact that someone at the NCI has given a definition does not mean that we all have to suddenly fall in line with the poor use of either English or scientific language — especially when normal use of such inappropriate terminology is liable to confuse patients. Indeed, one of the primary roles of an advocate in the fields of science and medicine is to persuade the scientific and medical community to “speak plainly” whenever possible.

    I am in Tony’s camp on this one. Terms like “false positive” and “false negative” should retain their historic meanings. We need a better term to define positive and negative results in the analysis of the capacity of unproven tests to predict a specific outcome. And I absolutely reject the idea that we all have to just “roll over” when a few people in the scientific and medical community start to apply an inappropriate terminology to a specific situation. To quote Winston Churchill, that is a concept “up with which I will not put.”


  8. I am confused about this discussion that seems to be one of the word used by a group where the group knows what the word means (see Baker et al. and this other article).

    It seems like our time could be better spent working with researchers for better designed clinical trials that are set up to better accrue patients or to work with them to represent the needs of the patients in their research rather than getting into a debate of semantics. If we want to do something putting consents in plain English would do more good for the men rather than changing the language they use when communicating with each other.

    This phrase is used with all cancers so if we want to change the terms then we need to work with individuals in other cancer groups.

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