Monthly Archives: May 2012

Hopeful signs

I began blogging with $100 Dialysis – the vision.  The technical challenge is to develop cheap and perhaps novel  means to filter the blood of nitrogenous waste products.  Below is an example of three approaches, one is a more user-friendly way to use existing technology, another utilizes nanotech, and the third although not aimed at dialysis is an example of new thinking.

Peritoneal dialysis is a form of dialysis whereby the abdomen lining (called the peritoneum) within the body is used to filter the blood.  Simply, the dialysis fluid is pumped into the cavity formed by this natural filter.  Once it has absorbed some of the waste from the blood filtered through the peritoneum it is pumped back out again.  Not everyone is eligible for periotoneal dialysis, but for those who are the concept of a portable dialysis is very welcome.  Progress is definitely being made, have a look here.

Also developing wearable dialysis, but this time using an external device to remove the waste is the Dutch company Nanodialysis.   Rather than simply filter the unwanted particles through small pores they get them to adhere to a surface, a process called adsorption.  From there they get them to decompose to nitrogen, hydrogen, and carbon dioxide.  The company claims that not only will this be cheaper (yeah) and more convenient it will also increase life expectancy 10 to 15 years over standard hemodialysis! This is quite an incredible claim and as they are yet to complete animal trials is premature.  Nevertheless, it is definitely a space worth watching.

Some clever people in MIT and the National University of Singapore have demonstrated that they can remove bacteria from blood making use of a concept from normal biological process called margination in which leukocytes (white blood cells) adhere to blood vessel walls (see here).   Whilst the nitrogenous waste products are much smaller, using fluid flow technology similar to what MIT and NUS have demonstrated may be another way forward.

To PSA or not to PSA

As a male, 40 mumble years old, do I do it?  Do I get a prostate exam and PSA test?  Do I plan to keep doing tests every few years?

PSA (prostate specific antigen) is a blood test where elevated levels may indicate the presence of prostate cancer.  A powerful group, the US Preventative Services Task Force has come out against screening with PSA giving the test its lowest (D) grade.  They conclude “that many men are harmed as a result of prostate cancer screening and few, if any, benefit.”  Strong words. TV3 (misleadingly, but that’s another story!) and other media reported on this last night. The response of the Urological Society (at least its president) is to reject the report and urges men “not to be deterred” and to “discuss the PSA blood test with their GP.

This is approximately how my conversation went a couple of years ago.

GP: We’ll do a PSA test while we are at it.

ME:  Isn’t that a waste of time? Doesn’t it have a lot of false positives?

GP: Yes, but we can monitor for changes.

Hmmm…so it is not just the value of the test, but how it changes in time that is important.  A quick check on the internet I find that this is called the PSA “velocity.”  Interestingly in the evidence provided by the US Task Force I can find no mention of PSA velocity.

In the meantime, a quick check on the Canterbury Health Labs web site (see here) tells me that the test has a reference range of 0 to 4.0 ug/L (this is a concentration in plasma).  If a test is above this range a GP is likely to want to discuss it with you and may recommend a biopsy.

This is where life gets interesting.  A couple of weeks ago I talked of “False Positives” and introduced the diagram below.  A “False Positive” for myself would have been a PSA above 4.0 ug/L which didn’t turn out to be cancer.  The main issue with PSA tests is the high number of False Positives.  The Task Force suggested that in a screening regime after 3 or 4 tests (over several years) 12 to 13% of participants have a positive test.  Most, though, are False Positives.  Approximately 80% of Positive tests are False Positives!  Consider this – if screening happened in NZ and 500,000 men had a test every 5 years then after 15 to 20 years 500,000 * 0.12 *0.8 = 4800 men will have had a False Positive test.  Another 1200 a True Positive test.

Ideally every test result will lie in the dark blue (true negative) or dark red (true positive). In reality, there is always a few false positives and false negatives [A good test would have few (the narrow ellipse), a poor test would have many (broader ellipse)].

Importantly, the Urological Society put it this way “The PSA blood test does not diagnose prostate cancer. But it raises a red flag and identifies those men who need to have prostate cancer excluded through further investigation via a prostate biopsy.”

PSA does not diagnose – this is a very important point that a GP must communicate BEFORE a test is done.  I would be surprised if even 10% of men realize that PSA does not a diagnose.  So what happens to all the False Positives and True Positives?  This is what the Task Force focused on.

First they asked “Does PSA-Based Screening Decrease Prostate Cancer–Specific or All-Cause Mortality? Does PSA-Based Screening Decrease Prostate Cancer–Specific or All-Cause Mortality?

There was no clear evidence it does (contradictory studies).  In their useful “stats at a glance” publication they state “1 man in 1,000 – at most – avoids death from prostate cancer because of screening.”

If this is so, then it could be worth it (by the way – at a cost of $11.92 + GST + cost of GP visit – say $60 (low), then I estimate screening of 100,000 men a year would cost a minimum of $7.2M annually in NZ).

It is the next questions of the Task Force that are revealing.  The looked at the harms of screening.  The harms of those with Positive test (True or False) and then the harm to those finally diagnosed with prostate cancer.  Again the summary is revealing:

Most prostate cancers found by PSA screening are slow growing, not life threatening, and will not cause a man any harm during his lifetime. However, there is currently no way to determine which cancers are likely to threaten a man’s health and which will not. As a result, almost all men with PSA-detected prostate cancer opt to receive treatment. In addition to the frequent complications of biopsy that lead to a cancer diagnosis, there can be serious harms from treatment of screen-detected prostate cancer.

For every 1,000 men who are screened with the PSA test:

  • 30 to 40 men will develop erectile dysfunction or urinary incontinence due to treatment
  • 2 men will experience a serious cardiovascular event, such as a heart attack, due to treatment
  • 1 man will develop a serious blood clot in his leg or lungs due to treatment 

For every 3,000 men who are screened with the PSA test:

  • 1 man will die due to complications from surgical treatment

And they did not attempt to assess social or psychological harm!  Imagine the conversation at home:

Man: Hi honey, I’m home.  I got a positive PSA test today.

Woman:  That’s nice dear.  Did you get an appointment for a biopsy.

Man:  Yes, in 3 months time.

Woman: Great.  Shall we go out for dinner?

Somehow, I don’t think it would be like that, except perhaps the waiting time for a next appointment.

So where does this leave us.  My opinion, for what it is worth, is that:

  1. A PSA screening program should not take place in New Zealand.
  2. GPs should use PSA tests only where there are other risk factors
  3. Prior to any other procedure, repeat tests of positives should be done under strict conditions. Particularly the diet of the person involved should be changed to minimize the risk of false positives (there is still debate about the role of diet in false positives – so some research should be done at the same time: “Does changing diet change PSA levels in the short term?”).  Men – you can ask for this!
  4. GPs should explain that:
  •            a positive test does not mean cancer (most probably already do explain this, but it worth emphasizing),
  •            there are risks with biopsies, and
  •            there are great risks with treatment (prostectomy or radiation normally).

I qualify this with what appears to me to be a lack of assessment of the benefit of “changes in PSA” levels.  The sort of question which comes to mind is “How accurate is the diagnosis of a 2 ug/L or 100% increase (say) in PSA over 5 years?”

I wonder, would you have a PSA test?

The costs and inequalities of diabetes

So it might not end after all

Just like scientists the world over, the Mayan’s evidently disagreed about when the world would end.  Check out the new calendar found predicting lunar eclipses many thousands of years in the future.

A long time in Mayan years

Central American Laborers Cut Down By Mystery Kidney Disease

A fascinating story which, amongst other things, highlights the need for widely available and inexpensive dialysis.

Benjamin Witte's Web Site

The northwestern Nicaraguan town of La Isla has lost so many of its residents in recent years that locals have unofficially renamed it “La Isla de las Viudas,” or island of widows. The victims, mostly men, all die from the same cause – kidney failure. They have something else in common too: they all worked in the nearby sugar cane fields.

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A positive STD

The doc said it was an STD.  I laughed.  Why?

The answer my friends lies in the numbers.

Of course the doctor wanted me to have an awkward conversation and prescribed some anti-bs.  I, on the other hand, was very confident, so took a different line – “Do the test again,” I said.

And the rest is history…

Any blood or urine test has a reference range – that is a range of concentrations  at which it is negative and above (or below) at which it is positive (some tests are just shown as a “+” or a “-“ as in home pregnancy kits rather than a number).  It is up to the doctor when they receive a positive test result how they interpret them.  They may chose to believe the test has diagnosed a disease, they may choose to do more tests in order to “confirm a diagnosis”, or they may choose to think that the results are erroneous.  I really don’t know how often they choose any course.  What I do know, is that every school child should be taught about false positives and false negatives.

A false positive is simply a test which says that you do have the disease when you don’t. 

A false negative is simply a test which says that you do not have the disease when you do.

What we want is a test with as few false positives and false negatives as possible (the “narrow” ellipse in the diagram).  In reality, tests vary a lot.

Ideally every test result will lie in the dark blue (true negative) or dark red (true positive). In reality, there is always a few false positives and false negatives [A good test would have few (the narrow ellipse), a poor test would have many (broader ellipse)].

How often do false negatives and false positives occur?  I don’t know the exact number, but the answer is “frequently.”  The more tests done, the more false negatives and false positives there are.  For a test like chlamydia which is ordered by doctors even when it is not asked for by patients (grrrr!) my guess is that it is very frequent.  Consider this – if the boffins who developed the test for chlamydia decide on the threshold for positivity (eg the concentration above which the test is called “positive”) such that the test correctly identifies as having the disease 99% of those that have it (ie only 1% of the “positives” are False positives) then for every 100 people diagnosed with the disease, 1 does not have it.  If it identifies correctly 99% of those who do not have the disease as not having the disease then 1 out of every 100 people who are told they do not have the disease actually have it.

If, on any given day, 1000 people in New Zealand have the test.  For a moment, let us assume that of those 1000 people, 100 actually have chlamydia.  With the numbers above it means 1 person will be told they have chlamydia when they don’t and 9 will be told that they don’t when they do!

Telling someone they have a disease when they don’t matters most if the treatment for the disease is dangerous and/or expensive, or the psychological or social consequences for the individual are serious (eg divorce!).

Telling someone they don’t have a disease when they do matters most if the failing to treat could lead to more serous healthy problems and/or costs for the person or their community (as with an STD).

All these factors have to be weighed up when deciding on test thresholds and on whether a test should be made available in the first place.  It is why, for example, we don’t routinely screen for prostrate cancer – the test has too high a likelihood of false positives.

Recently in the media there was concern over screening for breast cancer in Southland.  Some women had received negative readings of mammograms, yet later were found to have breast cancer.  Was this because of poor reading of mammograms?  The answer appears to be “No”, the “False negatives” were at the rate expected (See

For the record – the second test was negative.

Cheesecake files: Keeping a promise 1

I believe in open access and the right of the public to know what I am doing.  Putting my money where my mouth is, is another story.  When I started this blog in January I promised myself to write something every time an article of mine appeared in print. That’s happened three times already this year and I’ve yet to fulfill that promise…so this is the first of several posts (promise).

Ideally all my research would be freely available online as soon as it has been through the peer review process.  Unfortunately, that costs a lot of money which few research budgets can meet (in the journals I publish it typically costs an extra US$3000 above and beyond normal page charges of around $70 per page and $500 per colour figure).  Nevertheless, this year I have managed to make two articles “Open Access” and another is on the way.   The one I have chosen today is my first book chapter in the field of Acute Kidney Injury.  I received an invite to contribute to a book  and responded positively for a change – for a reasonable cost (US$1000) it was an opportunity to produce a longer treatise on an important area of my work and to make it freely available to anyone and everyone.

 Pickering JW, Endre ZH. The Metamorphosis of Acute Renal Failure to Acute Kidney Injury [Internet]. In: Sahay M, editor. Basic Nephrology and Acute Kidney Injury. Rijeka: InTech; 2012. p. 125–49.

Freely downloadable from:

The story begins with a lament as to the repeated failure of clinical trials to discover any effective therapy for Acute Kidney Injury (AKI).  We then discuss the history of how the thinking has changed from Acute Renal Failure – the idea that the kidney filtration function is suddenly reduced – to Acute Kidney Injury – the idea that the kidney tissue is injured which often results in a reduction in function.  For the mathematically minded there is a section on how to determine the function of the kidney on the basis of the concentrations of a marker (plasma creatinine) in the blood.  Those who prefer words to symbols, though, can skip this.  We discuss the current definitions of Acute Kidney Injury (still based on function!  – That is soon to change…watch this space), then I introduce three things important to clinical trials.

  1. Although AKI is associated with higher mortality rates it is financially ruinous to run a trial with mortality as an outcome because of the very high numbers of patients needed.  For that reason, a surrogate for kidney function is used.  Often this has been a definition of Acute Kidney Injury that is categorical – ie the plasma creatinine concentration increases by more than 50% you have AKI, if it doesn’t, you don’t.  A trial will then compare the proportions of patients in the placebo and treatment groups with AKI.  A couple of years ago I published an article in which I demonstrated that such a categorical trial outcome was not the best idea – better was to use a continuous measure of the change of creatinine that takes into account the duration as well as the extent of that change (I called this the RAVC). I explain this in the chapter.
  2. When we use plasma creatinine to judge kidney function, we need to know what the concentration was prior to someone ending up in intensive care (ie we are interested in the change from a baseline).  About half of patients have a suitable measurement on record.  What do we do about the other half?  I present a way of dealing with the problem from a clinical trial perspective.  Previously I had shown that the first recommendations given to solve this problem were no better than using a random number generator.  There are some more clinically relevant (and less mathematical!) ways of determining baseline creatinine.
  3. Finally I deal, a little (for this is an ongoing saga) with how to use the new injury biomarkers (often little enzymes measured in the urine – see “I am a pee scientist”).  Ideally, we would initiate therapy (or placebo) on the basis of measured injury even before we were able to detect a change in function.  My colleague (Prof Zoltan Endre) was the first to attempt a randomized control trial based on just such a measurement.  I was brought in to manage the numbers and since then have managed to show that it isn’t quite as easy as we hoped…hence the ongoing saga

I hope that wasn’t too boring.  I think the chapter is pretty accessible to most, and what’s more anyone can download it.  If you do do that, let me me know just if it was understandable at all.

Addendum: One of the nice things about Open Access is that people from all over the world get access to your article – according to  one person from the Dominican Republic, 2 from Macedonia, 8 from Poland, and 9 from New Zealand have downloaded this book chapter…cool.