Sunday, January 19, 2014

This 15-Year Old Did Not Transform Medicine

I recently came across this news article about Jack Andraka, a 15-year-old boy from Maryland who invented a test to detect pancreatic cancer in its early stages. Naturally this is HUGE. For those who are not familiar, pancreatic cancer is one of the worst cancers one could get. Due to its lack of symptoms (as it's seated deep inside the abdomen), it's usually diagnosed at a very late stage, and the majority of people do not survive for longer than one year.

This simple, fast and cheap blood test Jack Andraka invented promises to change all that altogether, creating an unprecedented revolution in medicine by causing the greatest improvement in cancer medicine we have ever seen. This test costs just 3 cents, nearly 100% accurate, and won him the grand prize in the prestigious Intel International Science and Engineering Fair. The test uses nanotechnology to detect mesothelin, a type of protein which is found in the blood when one has pancreatic cancer. His wish is that this test will become widely available on the shelves of the supermarket, and everyone could just pick it up and do this test during their free time, and no one will die from late stage pancreatic cancer any more.

It's very nice, except that it does not work.

First of all, I would like to congratulate this bright young man for achieving so much at such a young age, and has dipped his feet into the world of scientific research and made a name for himself. To have your name on a "cancer sensor inventor" as a 15-year-old boy is simply amazing.

However, unfortunately that's where the achievement ends.

As a medical doctor I feel compelled to debunk the hype: This invention will unfortunately NOT save lives, and in fact I suspect if it were to be introduced as a 5-cent dipstick available in your local supermarket (which WILL NOT happen as you will see below), it may actually end up doing more harm than good to people's health.

It may be a difficult concept to explain but I hope you bear with me as I go through the reasoning.

I would begin by how making diagnosis works. It is often mistakenly thought that diagnosing a disease in the modern era is as easy as finding the correct protein in the blood, and BAM you have this disease. It's almost like if you find a fingerprint then BAM there has to be matching, unique person behind that fingerprint. However, the majority of medical diagnoses are simply not made this way.

I would use the pregnancy test as an example. We all know that urine or blood pregnancy tests are pretty accurate these days - it detects a hormone called βHCG which is secreted during pregnancy. So, if you find βHCG in urine or blood, then you are pregnant, right? WRONG. While the vast majority of high βHCG is due to pregnancy, sometimes it could also be due to sinister causes called gestational trophoblastic diseases which are a type of tumour in the genital organs. But in practice, if you missed your period and you are tested positive, then you would be told "you are pregnant" unless the doctor has deep suspicion that something amiss is going on.

This is because
  1. There are FAR MORE pregnant people than people with this tumour 
  2. The fact that you missed your period makes pregnancy even more likely.
βHCG is useful because:
  1. When it's level is very close to zero, then you can't be pregnant (It has good negative predictive value
  2. In pregnant people the level is ALWAYS elevated. (It is sensitive)
  3. When it's elevated, 99% of the time it's gonna be due to pregnancy (the other 1% being the gestational trophoblastic disease) (It is highly specific)
  4. When it's used, it enables good outcome (you know you are pregnant hence you commence antenatal care etc)
While these 4 conditions, especially the last, may seem trivial, they are THE criteria that any diagnostic test have to meet prior to being practical. If someone comes along and develop a 5-cent new pregnancy test, they will either have to meet these criteria, or being dumped despite being only 5 cents.

That's for diagnostic test. Moving on to screening test. Wouldn't it be nice if we find a test for early stages of various cancers, so that all we need to do is to wake up everyday and dip a few drops of blood, and we would know that we have (or not have) cancer? Yes it would be nice, but unfortunately medicine is hard and nothing like this exists, and no, Jack Andraka's dipstick is not the elusive magic test.

I would use PSA as an example. PSA (Prostate-Specific Antigen), as the name suggests, is a protein quite specific to the prostate, and is elevated in prostatic cancer. We used to do PSA screening quite commonly to detect early prostate cancer (but it's no longer recommended but that's a long story on its own). The problem with PSA, as with many other types of cancer blood tests, are that they are not specific and often not sensitive enough. In PSA's case, there are many other conditions which also increase its level (namely large prostate, severe infection etc). And last but not least, because prostate cancer is such a slow growing tumour, it's been found that even after using PSA and detecting some earlier cases, the mortality rate (chance of dying) is THE SAME whether or not you test everyone for  PSA. Hence population-wide prostate cancer screening is no longer recommended.

Moving on to mesothelin and pancreatic cancer. 

For the scholarly minded, this is THE article that shows why mesothelin is useless as a pancreatic cancer screening marker: 

Jack Andraka is right in pointing out that mesothelin is almost always present in patients with pancreatic cancer. However, mesothelin is ALSO present in ovarian and pleural cancer, AND in normal healthy people. The range of mesothelin level amongst pancreatic cancer sufferers overlaps greatly with the level amongst normal population. Even though Jack claims this to be 100% sensitive, it only means that it will detect a particular level of mesothelin 100% of the time. It still does not meet these criteria:

1. Does mesothelin differentiate between different cancers? No as it's also present in ovarian and pleural cancer. 

2. Does mesothelin differentiate between disease and health? No, when you are "positive" for mesothelin you may very well be healthy. 

In other words, if you bought this test and is tested positive, you could either have pancreatic cancer, other pancreatic conditions, ovarian cancer, pleural cancer, or have nothing at all. Not that useful isn't it? 

At this juncture, some people might claim, even if some healthy people mistakenly test positive in this test, they could always just do more tests and find out that they don't have disease - isn't that better than the alternative, having pancreatic cancer and not knowing it? The answer is NO. As pancreatic cancer is such a rare disease, you will have far less disease detection rate (true positive) than false positives. The thousands and thousands of people who had false positive results will now have to go through more tests (CT scans, biopsies etc), and all these tests actually do harm if you are healthy (CT increases your risk of cancer, biopsies are invasive procedures and put you at risk of infection and bleeding). So in the end, having such a test, despite costing only 3 cents, will end up putting a lot more healthy people at risk of complications of over-investigation than saving a few lives from its actual detections. 

To sum it up: Yes this man has a bright future, but he's not a cancer saviour, and we still have a long road ahead in our battle with cancer. He is not the genius kid who managed to discover something that millions of scientists in thousands of universities have overlooked in decades of cancer research. Unfortunately there has been a huge media circus surrounding his invention, most of which were more focused on perpetuating the "prodigy cancer saviour" feel-good story without getting an established scientist to put things into context. The whole media circus has planted a distorted perception on cancer research, and could end up instilling distrust amongst public in proper scientists and researchers. In the comment section of the aforementioned news article, the top comment is about how such an invention (like the many dozens of "cancer cures" invented each month) will never see the light of the day because pharmaceutical companies need to keep making money from cancer treatment drugs rather than saving people's life with cheap, easy and effective inventions like this. It insults the efforts of millions of scientists in labs everywhere, who toil away in their often frustrating and mundane efforts day in day out, without the benefit of being glorified in the media as a cancer saviour.

When something sounds too good to be true, often it's because it is too good to be true.

Footnote: This article by Forbes Science is one of the rare media articles which summarised the hype surrounding Jack Andraka instead of joining the media circus of how we have found the young saviour which will save millions of lives, before he even published a single journal article on the invention.

Footnote 2: Another article with a LOT more details about doubts on Jack Andraka's invention and personal motives, though it is a lot more sensational and may sound more personal.