Welcome to Volume 8, Issue 1 of the Australian Medical Student Journal (AMSJ). In this issue, we are proud to showcase the research and perspectives of medical students and junior doctors around Australia. We are privileged to include discussions on a wide array of topics, spanning the breadth of medicine, surgery and global health and providing snapshots into developments in these continually changing fields. We hope you will find the following articles of interest and take some inspiration on how you can also push the boundaries of medicine to improve patient care, the patient experience, and public health.
We are honoured to include the insights of doctors who are changing the face of medicine in Australia and abroad in our guest articles. Dr Stewart Condon, the current President of Médecins Sans Frontières Australia, writes of his unique journey in humanitarian and remote medicine and discusses the value in challenging yourself and expanding the possibilities of what you can achieve in your career to make a meaningful difference to those in need.
We also feature outstanding guest commentaries from clinicians with decades of research experience and leaders in their respective fields on the increasing importance of practicing evidence-based medicine, given the continuing rapid expansion of research and technology. Professor Frank Bowden provides an entertaining insight into how doctors can use EBM to navigate modern medicine and make sense of information overflow to truly determine what is best for our parents. Professor Ian Harris AM writes from a surgical perspective on how surgical practice needs to have rigorous science underpinnings, which is sometimes sadly lacking for many surgical procedures even today. Professor Rakesh Kumar invites clinicians to carefully consider their rational use of diagnostic investigations, particularly pertinent for all medical students to consider as they transit on into becoming junior doctors, accountable to not only their individual patients but also the health system at large.
The AMSJ is a national peer-reviewed journal open to all medical students across Australia and once again, we are proud to highlight ar cles covering a range of issues. Sarah Yao, in her review article, looks ahead to the rise of big data in clinical research and the challenges and rewards associated with its inevitable use in the future; issues all future clinicians and researchers should be aware of. Dr Grace Leo in an original research article conducted in her medical student years provides a scholarly discussion on the impact of acquired brain injury in childhood. Our feature articles provide a range of moving perspectives on palliative care, empathy in medicine and the challenges faced in global health, and we thank our authors for contributing their perceptive insights and personal stories that we are sure will motivate and inspire you to consider the impact we can have on our patients and on a broader level as well.
Finally, on behalf of the AMSJ team, we would like to thank all of our authors, contributors, peer reviewers and sponsors who have contributed to making this issue possible. Their e orts, dedication, tenacity and generosity in volunteering their me are truly invaluable and we are most appreciative of their support. Thank you also to those working behind the scenes – our AMSJ team consisting of volunteer medical students who work tirelessly to edit, proof-read, publish, promote and finance each issue. Lastly, thank you to you, our readers – we hope you enjoy this issue and are inspired to engage in research, discussion and collaboration, so you too can push the boundaries of medicine now and throughout your careers in the future.
The Alzheimer’s Association International Conference (AAIC) is the largest gathering of the Alzheimer’s disease (AD) research community in the world, and provides a unique forum for the discussion of ideas and dissemination of knowledge. One of the key concepts grappled by the AD research community at AAIC 2016 in Toronto, Canada, was the validity of the amyloid hypothesis.
It is generally accepted that the accumulation of b-amyloid (Ab), particularly Ab40-42, in the extracellular spaces around neurons as amyloid plaques is central to the pathogenesis of AD. This idea is expressed in the ‘amyloid cascade hypothesis’ [1,2]. It thus follows that by reducing the production of Ab or eliminating the amyloid plaques from the brain, the progression of disease could be slowed, halted, or even reversed [3]. Alzheimer’s disease is the most important cause of dementia, which affects a staggering 40 million people worldwide, a number which is predicted to double every 20 years until 2050 [4]. Therefore, achieving prevention, or even just slowing of disease progression, would have a significant impact on morbidity, mortality, and burden on healthcare systems worldwide.
Hence, significant funding has been directed by both public research institutions and private pharmaceutical corporations towards the development of drugs that target Ab. Ab is produced by two steps of enzymatic processing: first by b-secretase, and then by g-secretase [5]. The latter has been targeted by drugs collectively known as g-secretase inhibitors, most prominently avagacestat and semagacestat. Both of these drugs failed in Phase 2 and 3 trials, and notably were associated with cognitive decline, an increased risk of skin cancers, and an overall increased risk of serious adverse events [6-10]. It was suspected that the failure of g-secretase inhibitors, particularly with regards to the adverse events profile, was due to off-target inhibition of Notch, a receptor that is involved in a signalling pathway that is particularly prevalent in the skin and gastrointestinal system [9-11]. However, tarenflurbil, a g-secretase modulator that spared the active site of g-secretase and hence spared Notch, also failed to be clinically efficacious, as measured by changes in cognitive indicators such as the Mini-Mental State Examination (MMSE), Alzheimer’s Disease Assessment Scale – cognitive component (ADAS-cog), and the Clinical Dementia Rating – sum of boxes (CDR-sb) [12,13]. Hence, drug development has largely moved away from inhibition of g-secretase, and b-secretase (BACE) inhibitors are now in early development as a potential alternative.
Active and passive immunotherapeutic agents targeting Ab have also been tested, with mixed results. While bapineuzumab was successful in lowering amyloid concentrations in two Phase 3 trials, it did not cause any clinical improvement, compared to placebo, and was associated with the development of amyloid-related imaging abnormalities (ARIA) [14-17]. ARIA comprise two separate changes: vasogenic oedema and cerebral microhaemorrhages. These changes may occur due to destabilisation of amyloid in vascular walls [18,19]. While often asymptomatic, in combination with a lack of clinical efficacy this was sufficient to halt the development of bapineuzumab. Another immunotherapeutic, solanezumab, was underwhelming in its Phase 3 trial performance, but was better tolerated than bapineuzumab and showed some cognitive improvement in patients with mild AD [20-22]. Aducanumab [23], crenezumab [24], and gantenerumab [25] have all also shown promise and currently have Phase 3 trials in planning or underway. Hence, it appears that immunotherapy may be a more viable modality for the treatment of AD than inhibition of g-secretase.
It is possible that all trialled therapeutics have targeted AD too late in the disease course, when clinical features such as memory decline and functional impairments have become frankly apparent. Hence, some trials have now shifted towards targeting AD earlier in its disease course. Mild cognitive impairment (MCI), also known as prodromal AD, is the accepted early pre-AD stage in which it is now believed the greatest improvements can be made, by preventing further decline [26]. Another stage prior to this, subjective cognitive impairment (SCI), in which patients report some cognitive changes but their scores on the MMSE and other indicators are unchanged, is also being recognised and may soon be targeted by therapeutic or preventive strategies [27].
It is also possible, of course, that the current paradigm of the amyloid cascade hypothesis is wrong. Perhaps the drugs have failed to show clinical efficacy, despite reducing cerebrospinal fluid Ab levels, because Ab is not actually central to disease pathogenesis. Another player in the game is tau – a protein that accumulates intracellularly in the classical neurofibrillary tangles. It was originally thought that tau accumulation occurred later in the disease course than that of Ab and was in some way triggered by Ab, supporting the role of Ab accumulation as the primary mediator of disease progression. However, it is now being argued that tau may actually develop concurrently and independently of Ab, and hence this may prove to be a viable target for pharmaceuticals in the future. What is certain, however, is that the pathogenesis of AD is complex, and it is unlikely that engaging with a single target will be sufficient for prevention or a cure [28].
Next year, when AD researchers congregate for AAIC 2017 in London, it is likely that the amyloid cascade hypothesis will further be tested by results from clinical trials of drugs targeting Ab, particularly those of immunotherapeutic agents. Whether there is a significant paradigm shift in terms of our understanding of AD pathogenesis, or a reorientation of our efforts towards prevention over treatment, will largely depend on these results over the next decade. It is certainly important that significant progress is made in the near future, lest pharmaceutical companies that fund drug development put AD in the ‘too hard’ basket and move on to simpler challenges.
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Scheltens P, Blennow K, Breteler MMB, de Strooper B, Frisoni GB, Salloway S, et al. Alzheimer’s disease. The Lancet. 2016;388(10043):505-17.
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Penninkilampi R, Brothers HM, Eslick GD. Pharmacological agents targeting γ-secretase increase risk of cancer and cognitive decline in Alzheimer’s disease patients: a systematic review and meta-analysis. J Alzheimers Dis. 2016;53(4):1395-404.
Coric V, Salloway S, van Dyck CH, Dubois B, Andreasen N, Brody M, et al. Targeting prodromal Alzheimer disease with avagacestat: a randomized clinical trial. JAMA Neurol. 2015;72(11):1324-33.
Coric V, van Dyck CH, Salloway S, Andreasen N, Brody M, Richter RW, et al. Safety and tolerability of the gamma-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. Arch Neurol. 2012;69(11):1430-40.
Doody RS, Raman R, Farlow M, Iwatsubo T, Vellas B, Joffe S, et al. A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N Engl J Med. 2013;369(4):341-50.
Henley DB, Sundell KL, Sethuraman G, Dowsett SA, May PC. Safety profile of semagacestat, a gamma-secretase inhibitor: IDENTITY trial findings. Curr Med Res Opin. 2014;30(10):2021-32.
Proweller A, Tu L, Lepore JJ, Cheng L, Lu MM, Seykora J, et al. Impaired Notch signaling promotes de novo squamous cell carcinoma formation. Cancer Res. 2006;66(15):7438-44.
Green RC, Schneider LS, Amato DA, Beelen AP, Wilcock G, Swabb EA, et al. Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial. JAMA. 2009;302(23):2557-64.
Wilcock GK, Black SE, Hendrix SB, Zavitz KH, Swabb EA, Laughlin MA. Efficacy and safety of tarenflurbil in mild to moderate Alzheimer’s disease: a randomised phase II trial. Lancet Neurol. 2008;7(6):483-93.
Blennow K, Zetterberg H, Rinne JO, Salloway S, Wei J, Black R, et al. Effect of immunotherapy with bapineuzumab on cerebrospinal fluid biomarker levels in patients with mild to moderate Alzheimer disease. Arch Neurol. 2012;69(8):1002-10.
Liu E, Schmidt ME, Margolin R, Sperling R, Koeppe R, Mason NS, et al. Amyloid-beta 11C-PiB-PET imaging results from 2 randomized bapineuzumab phase 3 AD trials. Neurology. 2015;85(5):692-700.
Salloway S, Sperling R, Fox NC, Blennow K, Klunk W, Raskind M, et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med. 2014;370(4):322-33.
Salloway S, Sperling R, Gilman S, Fox NC, Blennow K, Raskind M, et al. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology. 2009;73(24):2061-70.
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Sperling R, Salloway S, Brooks DJ, Tampieri D, Barakos J, Fox NC, et al. Amyloid-related imaging abnormalities in patients with Alzheimer’s disease treated with bapineuzumab: a retrospective analysis. Lancet Neurol. 2012;11(3):241-9.
Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med. 2014;370(4):311-21.
Farlow M, Arnold SE, van Dyck CH, Aisen PS, Snider BJ, Porsteinsson AP, et al. Safety and biomarker effects of solanezumab in patients with Alzheimer’s disease. Alzheimers Dement. 2012;8(4):261-71.
Siemers ER, Sundell KL, Carlson C, Case M, Sethuraman G, Liu-Seifert H, et al. Phase 3 solanezumab trials: secondary outcomes in mild Alzheimer’s disease patients. Alzheimers Dement. 2016;12(2):110-20.
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I have been interested in humanitarian work since high school. I was always looking for a career that allowed me to help people, using the combination of science and communication. Medicine seemed to fit perfectly.
By the end of my medical degree I was thinking about how I could start working in the humanitarian sector. I liked the idea of taking my skills around the world, to places like South Sudan or Pakistan. We had a field worker come and talk to our Medsoc at a symposium around “travelling with your degree”. This inspired me and showed me that I didn’t have to take a standard path in becoming a specialist or a GP, living and working in Australia for the rest of my life. Alternate possibilities were out there.
It was at this time I also started orienting my work towards building skills that would be useful overseas. Paediatrics stood out for me – being able to treat sick or injured kids in third world contexts was always going to stand me in good stead. I worked my PGY3 as a paediatric resident at Sydney Children’s Hospital at Randwick, and then half the year at Wollongong Hospital in general paediatrics. Having my diploma of paediatrics gave me a sense of confidence.
Working out bush
The next step was to get experience in remote medicine. I had lived in Sydney for all of my study years, and aside from a couple of years in the Illawarra, I’d remained city-based as I started to work. I needed to get out, and an opportunity to work in the centre of Australia came at almost the perfect time. I headed out to the Northern Territory for six months to work in the Yuendumu community, with the Warlpiri people.
Dr Stewart Condon attending an MSF refugee camp awareness raising campaign in Martin Place Sydney. Copyright: MSF
Many Australians who work with MSF have experience working remotely, particularly with the Indigenous communities in Australia. Working within these remote communities is a challenge, for so many reasons. It’s about resources, distance but perhaps most importantly a different concept of health and disease.
These circumstances exposed me to the idea that you cannot have access to everything that you need all the time, and at times it is necessary to trust your clinical gut to make a decision. You learn to be able to look at a patient and decide whether they need an urgent test today, in which case you can organise an immediate evacuation to hospital, or whether it’s something you can keep an eye on. Working in the bush gave me the confidence to be able to do that, as well as the ability to work unsupported – an essential skill in remote areas.
Working remotely also opened my eyes to those patients who live in truly difficult circumstances and don’t get the care they need. I knew about other organisations that did similar work to MSF but I was attracted to MSF because it worked right on the frontlines of international humanitarian crises, treating those patients that weren’t being reached.
It was this experience in the Northern Territory that really prepared me for my first field assignment with MSF in Bentiu, in what is now South Sudan. It was 2004 and there were only three medical doctors at our project- two were international staff, including myself, and one Sudanese doctor. We had very basic medical resources, no access to tests and some very sick patients who you had to take care of, quite often on your own. It was here I was able to challenge myself and recognise I had been taught what I needed to know – how to examine and treat a patient, and how to make a diagnosis. In modern medicine we often rely on a full battery of blood tests, x-rays, scans and specialist opinion. But from my experience in the Northern Territory I knew I could make a clinical judgement, and that not having the tests did not necessarily mean that patient care was compromised.
Dr Stewart Condon on his first field assignment with MSF in Bentiu, (now South Sudan) 2004. Copyright: MSF
My time in South Sudan gave me a taste for this humanitarian side of medicine, but it was really my second assignment in Aceh, Indonesia following the devastating tsunami in 2004, that opened my eyes up to the humanitarian issues around the patients we were seeing every day. It was in Aceh that I began to recognise that it was not just about the patients that we were seeing nor the medical care, it was just as much about humanitarian need. It was at that point I realised I was interested in becoming a Coordinator, rather than solely a doctor. During my next assignments in Pakistan, Sri Lanka and Bangladesh I took on roles as Project Coordinator and Country Medical Coordinator. In these roles I was able to work together with other humanitarian organisations, as well as government authorities. It gave me a sense of other parts of MSF that I could give value to, beyond medicine.
MSF, Amman Hospital – 2016. This man is a 23 years old Syrian. he used to study law in Damascus. He was among the first revolutionaries in Deraa, in the ASL brigade. This is the third time he is wounded, a bomb took his leg away.
Amman hospital reconstructive surgery project is meant for the wounded of Jordan’s surrounding countries that undergo war, armed conflict or violence. The reconstructive surgery hospital offers integrated care and sophisticated surgical operations, physiotherapy and psychological support. All patients admitted are considered being “impossible to treat” in their original country, because of either access problems or technical complexity. Since the opening of the structure, MSF has been taking care of 3 600 patients. photographer: Chris Huby
Examination in the laboratory of the hospital of Souleymanieh, October 2008.In the medical bacteriological laboratory teams prepare culture media and reagents in order to carry out the bacteriological analysis. photographer: Jean Baptiste Ronat
Attacks on hospitals
I have been President of MSF Australia for nearly three years and on the board since 2011. The most important part about being President is my responsibility to our field workers and patients. One of the most alarming trends we have faced in the last couple of years is the attacks on hospitals and medical facilities. In Afghanistan, South Sudan, Yemen and Syria we have seen our hospitals repeatedly attacked. Unfortunately, these are not isolated events and the normalisation of such attacks is intolerable. For us attacking hospitals and medical workers is a non-negotiable red line. International humanitarian law protects medical facilities, the people working in them, and the people receiving treatment.
Another challenge, more medical but no less critical, is antimicrobial resistance. Drug-resistant infections are a looming challenge for our humanitarian work. We see them in the war-wounded people we treat in Jordan, in newborns in Niger, and in our burns unit in Iraq.
Kunduz Hospital After the Attack: The remains of a bed frame in a room on eastern wing of the main Outpatient Department building. Burnt-out corridors, collapsed roofs, twisted metal and ash, is all that remains of many building at the MSF Trauma Centre in Kunduz, northern Afghanistan, following the 03 October US airstrike on the facility which killed more than 20 MSF staff members and patients. photographer: Andrew Quilty
Our medical staff are increasingly seeing people with infections that can only be treated with the last lines of antibiotics. When I was in Pakistan in 2006, post-earthquake, we recognised quite early on many patients were not improving after treatment. Some of these patients were already on very heavy antibiotics because in this particular community they had been given antibiotics for anything and everything. As a result, many had resistant bacteria on their skin which would then go into their bones, giving them bone infections. We were having to use heavy antibiotics (e.g. meropenem) that we are only now really starting to use in a similar way in hospitals in Australia.
Central laboratory of Koutiala hospital. End of 2013, MSF initiated the restructuring and renovation of the central laboratory of Koutiala hospital, where MSF manages the pediatric unit. MSF has added a department of bacteriology, operational since March 2014, to improve the diagnoses made in the laboratory and meet the requirements of quality of medical care at the hospital. Through the department of bacteriology, MSF is now able to diagnose all bacterial diseases which are affected children. photographer: Aurelie BaumelHaydan Hospital. Haydan Hospital, March 2016, after 5 months of air strikes. Constant bombing , blocking of aid, non-observed truces … In six months , the Yemeni conflict has claimed thousands of lives, including many hundreds of children, and reports of more than 1.5 million displaced. photographer: Atsuhiko Ochiai
There are many global challenges caused by antimicrobial resistance. Countries must do much more to better use existing antibiotics by strengthening health systems, human resources and laboratory capacity. There also needs to be improved access to existing medical tools, including reduced prices for existing vaccines to prevent infections, as well as research and development of new products that are patient-focused, affordable and appropriately available to all who need them. MSF is participating in global efforts to control drug-resistant infections by increasing our capacity to diagnose infections, improve the use of antibiotics, prevent the transmission of infections in hospitals and monitor rates of resistance, as well as supporting efforts to develop new, affordable diagnostic tools and treatments.
Northern Yemen, Oct15-Feb16. A man clears debris revealing the Médecins Sans Frontières logo 29 October 2015 painted on the roof of MSF’s hospital in Haydan, Yemen after an airstrike on the facility. photographer: Rawan Shaif
Ask yourself “why medicine?”
For those who are looking ahead to their future in medicine and are interested in working in the humanitarian sector my advice is very simple, get out and challenge yourself. Remove yourself from the big city hospitals and work remotely. You will not typically be provided this opportunity without asking. Ask your hospital for a rotation to a regional centre or request something a bit different. Take a leap and show up.
You need to be interested in things that are not strictly just medical. I am sure that you already are, of course! Working at MSF we look at so many issues outside of the first emergency response. It can be anything from access rights to medications, the humanitarian needs of a particular context, the effects of war on communities or what happens to women after a natural disaster. This information influences how we treat a patient and what kind of patients we see.
And most importantly make sure you’re asking yourself the really important questions. Why are you studying medicine? What type of patients do you want to be treating in ten to fifteen years? Why do you think you will get a buzz out of being a doctor? Understanding your ‘why’ will help you understand how to get there and what your career will look like in the future.
Working in the humanitarian field can be dynamic and volatile. If you don’t mind that lifestyle partnered with medicine, then it’s the perfect job for you.
Professor Frank Bowden
Source: h p://unihouse.anu.edu.au
Professor Frank Bowden Source: http://unihouse.anu.edu.au
Medicine, to paraphrase LP Hartley, is a foreign country – they say things differently there [1]. When I started out, most of the anatomy, physiology, biochemistry and microbiology was, well, Greek to me. My undergraduate years were as much language lab as pathology lab but by the time I completed my final exams after 6 years of full immersion I was speaking Medicine in my dreams.
Then, in the 1990s, I met a tribe known as ‘Clinical Epidemiologists’ who spoke a medical dialect I had not previously encountered. Their words were familiar but the meanings were hard to exactly translate. I knew, for example, the common definition of ‘sensitive’ and ‘specific’, (indeed my wife said that at times I had too much of the latter and not enough of the former), but these strangers had something else in mind when they used the words. Some phrases seemed to be self-evident – what else could ‘positive predictive value’ be apart from the ‘predictive value of being positive’? And what on earth was a ‘meta-analysis’ or a ‘likelihood ratio’?
The Lancet, that bastion of all that is right and good in the medical world, wrote an editorial in 1995 expressing the view that the emerging EBM speakers were OK as long as they stayed ‘in their place’ [2]. Since then, two generations of medical students have learnt their trade in clinical environments that have only reluctantly and incompletely adopted EBM as the lingua franca. Some young doctors have entered the workforce truly bilingual but most have EBM as a second language. The paucity of native speakers in hospitals and general practices means that many doctors never have enough time to adequately practice their conversation skills. Some have forgotten even the most basic vocabulary.
Critics – and they are many [3] – argue that evidence based medicine focuses on groups and averages; that it is only about research and academia; that it is an excuse for cost-saving and external control and that it is not really about individual patients. But from the outset David Sackett, the father of EBM, defined his newborn as ‘the conscientious, explicit and judicious use of current best evidence in making decisions about the care of the individual patient’ [4]. Take each of the words in that sentence seriously and I believe that it would be hard to find a better way to live a medical life.
Like most doctors I struggle to stay up to date even in my area of specialty. (If they change the name of one more bacterium or fungus I will scream!) Yet it is hard to convey to people younger than 30 how precious information was in the time before the interweb. It is not surprising then, that after we graduated, virtually the only source of education about new treatments and diagnostics came from the people who made and sold them. We read clever advertisements in journals and we listened, over fine food and wine, to well-dressed experts talking about new advances. There was no Cochrane database, anything that was in Harrison’s textbook was unquestionably correct and Up to Date was something that we wanted to be, not log on to. Today we carry more information in our mobile phone than was ever imagined by Douglas Adams or Isaac Asimov.
But some things don’t change: I have observed that doctors, as a species, hate bureaucracy, administration and any form of external control, yet we are naively open to the influence of experts that look or sound like us. If a colleague we like says something, we are inclined to believe them. Even if we don’t like them, we tend to be more Mulder than Scully. If you think I’m exaggerating, consider the exponential rise of PSA testing in the 1990s [5], the explosion of thyroid cancer diagnoses in the last decade [6], the sunburst of unnecessary vitamin D measurement [7], the overuse and subsequent loss of every new antibiotic released in the last 50 years [8], the epidemic of unnecessary radiological investigations and the steely push for wider access to the unproven benefits of robotic surgery [8-10] – to name just a few examples. On the other hand, independent sources, such as the Australian Choosing Wisely program [11], almost exclusively recommend that we do fewer investigations and treat fewer people, rather than more.
If good medical practice is the offspring of a metaphorical marriage between expert, independent professionals and autonomous, informed patients, we have to acknowledge the risk that a third party presents to the relationship. My patients have the right to know where I get my facts and who is influencing my decision making.
So, how can doctors make sense of modern practice in a world that is overflowing with information, short on knowledge, long on potential for conflict of interest and sadly wanting for wisdom? Just teach them more evidence based medicine? That it were so easy… Sorting out the treatments that really do make a difference to our health and well being is much harder than it seems. If you want doctors who are able to tease out the complex arguments about the pros and cons of prostate or breast cancer screening [12], who can make an independent judgement about the role of early thrombolysis in stroke [13], who can convey the difference between absolute risk and relative risk in a way that is understandable to the lay person, then EBM instruction has to be integrated into all levels of medical training.
I hate to admit this but I used to watch my students’ eyes glaze over when I tried to teach them certain things in evidence based medicine. For example, and this will make the EBM purists cringe, it is very difficult to get undergraduate medical students excited about critical appraisal of research studies. It’s not that it isn’t important – understanding the fine details of clinical research methods is essential for doctors who are going to be creators of knowledge – it’s just that the vast majority of us are consumers, not makers. The well informed consumer needs to know how to safely and effectively use the product they have, more than they need to know how to manufacture it. I worry that many medical students never learn the importance of EBM (and its parent – epidemiology) if the early focus of teaching is on the laborious dissection of the mechanisms of evidence-making rather than on a more general exploration of what evidence is and how it can be applied in the real world.
Medical facts change rapidly but the principles of EBM stay remarkably stable. The range of treatments that existed when I was a medical student was nothing like that which is available today and we can only guess at the progress that will occur over the next 30 years. Nevertheless, the design of the studies needed to prove the efficacy and safety of those new treatments will be almost identical to those of today and we will still use the tools of EBM to interpret the results.
Perhaps only a small group of doctors – the creators – need to be truly fluent in EBM. But the rest of us – the users – need to make the effort to learn the basics of the language of evidence. Those who don’t may find that they have been left out of the conversation altogether.
It’s often said that surgery is more art than science. Rubbish. Too much emphasis is placed on surgeons’ technical skills and not enough on the decisions behind them.
Any good surgeon can operate, better surgeons know when to operate and the best surgeons know when not to. Knowing when to operate and when to hold off relies on weighing up relative probabilities of success and failure between alternatives.
Good decision makers (and therefore good surgeons) base such decisions on quality evidence, and this is where science comes in. The evidence we seek is evidence of the true effectiveness of an intervention, and it is the scientific method that provides us with the most accurate and reliable estimate of the truth. Faced with alternatives, surgeons can sometimes make the wrong choice by being unscientific.
Surgeons often decide to do certain procedures because it’s what’s usually done, because it’s what they were taught, because it sounds logical, or because it fits with their own observations. If the surgeon’s perception of effectiveness and the evidence from scientific studies align, there is little problem. It’s when the two conflict that there’s a problem: either the surgeon’s opinion or the evidence is wrong. Worse, sometimes there is no good quality evidence and we are left with the surgeon’s opinion.
There is abundant evidence that surgeons overestimate the effectiveness of surgery, and considerable evidence of seemingly effective operations (based on observational evidence) turning out to be ineffective on proper scientific testing.
So what evidence should we rely on? Put simply, when you are trying to determine true effectiveness, the best method is the one that is least wrong, i.e., the method that has the least error. The scientific method is constructed to reduce error – we rarely know the truth, but we can increase the likelihood of our estimates containing the truth and we can make those estimates more precise by reducing error. In other words, we can never be certain but we can reduce uncertainty.
There are two types of error: random error and systematic error. Random error is easy to understand. If you toss a coin ten times, you may get seven heads, but that doesn’t mean the coin is unbalanced. Toss it 100 times and if you get 100 heads then you have reduced random error (the play of chance in generating such a result) and it is now very likely (and we are more certain) that the coin is unbalanced.
Systematic error (bias) is when we consistently get the wrong answer because we are doing the experiment wrong. There are many causes of bias in science and many go unrecognised, like confirmation bias, selective outcome reporting bias, selective analysis bias, measurement bias, and confounding. Systematic error is poorly understood and a major reason for the difference between the true and the apparent effectiveness of many surgical procedures.
The best way to test the effectiveness of surgery and overcome bias (particularly when the outcome is subjective, such as with pain) is to compare it with a sham or placebo procedure and to keep the patients and those who measure the effectiveness ‘blinded’ to which treatment was given. Yet such studies, common in the drug world, are rare in surgery.
In a study that summarised the research that has compared surgery to sham or placebo procedures, it was shown that the surgery in most such studies was no better than pretending to do the procedure [1]. And in the studies where surgery was better than placebo, the difference was generally small.
It’s not always necessary to compare surgery to a sham – sometimes comparing it to non-surgical treatment is sufficient. This is particularly the case for objective outcomes (survival, recurrence of disease, anatomic corrections) where blinding is less important. But you still have to compare it to something – to merely report the results of an operation with no comparator provides no reference for effectiveness beyond some historical control (of different patients, with possibly different conditions, from another place and another time). Journals are littered with case reports showing that most people got better after receiving treatment X but such reports tell us nothing about what would have happened to the patients if they did not receive treatment X, or received some other treatment. These types of non-comparative studies continue to sustain many quack therapies as well as common medical and surgical therapies, just as they sustained the apparent effectiveness of bloodletting for thousands of years.
However, even when comparative studies are done, they are not always acted upon. In a study looking at the evidence base for orthopaedic surgical procedures, it was found that only about half of all orthopaedic procedures had been subjected to tests comparing them to not operating [2]. And for those procedures that had been compared to not operating, about half were shown to be no better than not operating, yet the operations were still being done. The other surgical specialties are unlikely to be much better.
So there are two problems in surgery: an evidence gap in which there’s a lack of high quality evidence to support current practice, and an evidence-practice gap where there’s high quality evidence that a procedure doesn’t work, yet it’s still performed.
Part of the problem is that operations are often introduced before there’s good quality evidence of their effectiveness in the real world. The studies comparing them to non-operative treatment or placebo often come much later – if at all.
Surgical procedures should not be introduced or funded until there’s high quality evidence showing their effectiveness, and it should be unethical to introduce a new technique without studying its effectiveness. Instead, the opposite is argued: that high quality comparative studies (placebo controlled trials) are unethical.
Often, procedures that surgeons consider to be obviously effective are later shown to be ineffective. In the US in the 1980s, a new procedure that removed some lung tissue was touted for emphysema. Animal studies and (non-comparative) results on humans were encouraging. So the procedure became commonplace. A comparative trial was called for but proponents argued that this would deprive many people of the benefits of the procedure, the effectiveness of which was obvious.
Medicare in the US decided only to fund the surgery if patients participated in a trial comparing it to non-surgical treatment. The trial was done and the surgery was found wanting. This cost Medicare some money, but much less than paying for the procedure for decades until someone else studied it. This type of solution should be considered in Australia – only introduce new procedures if they are being evaluated as part of a trial.
The current practice of surgery is not based on quality science. If you got a physicist from NASA to look at the quality of science supporting current surgical practice they would faint. But it is getting better. It is getting better because of advancements in our understanding, because of the spread of evidence based medicine (in teaching and in journal requirements, for example), and because surgeons are understanding science better. The trials are getting better, but the incorporation of the results of those trials into practice is slow and often meets resistance because of suspicions that stem from a lack of understanding of science and the biases that drive current practice.
Billions are spent worldwide on surgical procedures that may not be effective because in many areas of surgery we still rely on surgical opinions based on biased observations and tradition. It is time for surgery to be a real science and to rely on the kind of evidence on which other scientific endeavours rely; the kind of evidence that we demand of other medical specialties and of non-medical practitioners. It’s not too hard. It’s not unethical. It’s right, and it’s time.
References
[1] Wartolowska K, Judge A, Hopewell S, Collins GS, Dean BJF, Rombach I, et al. Use of placebo controls in the evaluation of surgery: systematic review. BMJ. 2014;348:3253.
[2] Lim HC, Adie S, Naylor JM, Harris IA. Randomised trial support for orthopaedic surgical procedures. PLoS One. 2014;9(6):96745.
Every senior medical student and young doctor want to be able to keep up with the latest advances in medicine. However, the output of published literature keeps rising, so that we are all in danger of drowning in data. It’s difficult enough to keep up with the latest in clinical practice, let alone in basic research.
To at least some extent, evidence-based medicine can help, because it offers approaches that help to turn the data into knowledge which can actually be applied. Notably, these include systematic reviews and meta-analyses, which yield evidence-based practice guidelines that can inform clinical decision-making. Of course, one must remember that guidelines are only generalisations. Achieving the best outcomes for any given patient requires a combination of:
skilled clinical observation
appropriate investigations
application of knowledge and expertise gained by experience
the best scientific evidence from the literature.
In this article, I will focus on the appropriate use of investigations. This is an important issue with respect to the care of individual patients, because unnecessary and inappropriate investigations may have adverse effects, while false-positive results may prompt further needless investigation. It is also important with respect to utilisation of resources, particularly in Australia where costs to the health care system are substantially borne by the taxpayer. Over the past decade, the use of laboratory tests has seen a modest annual increase of approximately 3% to 6% [1]. At the same time, requests for diagnostic imaging investigations have increased at approximately 9% per year, so that these services now account for approximately 15% of all Medicare outlays [2].
When looking at evidence-based medicine in the context of the rational use of investigations, it is easy to get lost in the arithmetic of predictive values, probabilities and likelihood ratios. An alternative simpler approach is to rely on the maxim “Only request a laboratory test if the result will change the management of the patient” [3]. This may be an oversimplification in that among other things, investigations are relevant to establishing a diagnosis, excluding differential diagnoses, assessing prognosis and guiding management. Nevertheless, focusing on investigations that matter is sound advice, which is unfortunately all too often ignored.
The quality of the evidence around overuse of diagnostic investigations is relatively low. In hospital settings, however, it has long been recognised that as many as two-thirds of requests for some common Pathology tests may be avoidable, in that they fail to contribute to diagnosis or management [4]. Senior medical students and junior medical officers need to be especially aware of this, because most hospital Pathology test requests are submitted by junior doctors. Among factors that contribute to the uncritical overuse of investigations by JMOs are inexperience, lack of awareness of the evidence base for using a particular investigation and lack of awareness of the cost of the test. Other significant factors are the desire to anticipate the expectations of one’s supervisor and the fear of missing something important. Perhaps the supervisors of PGY1/2 trainees themselves need to drive cultural change and better model the appropriate use of diagnostic investigations!
Some strategies targeted at the test-requesting behaviour JMOs appear to be effective in at least some settings, for example restricting the range of tests that junior doctors may request in emergency departments [5,6]. More generally, management systems with budgetary controls, as well as online systems with decision support, have been promoted [7]. Importantly, education also has a valuable role to play [8].
With funding support from the Commonwealth Department of Health, my colleagues and I developed an open-access website to educate JMOs about the rational use of diagnostic investigations. As a user, you interact with simulated cases and can request investigations as you attempt to establish a diagnosis, while being presented with a running tally of the costs of the tests sought. At the end of each case, you receive feedback via comparison with what an expert would have done. Try it by self-registering, without cost, at http://investigate.med.unsw.edu.au/. The largest collection of cases is targeted to JMOs, but are also likely to be of interest to senior medical students. In addition, there are cases for trainee GPs, plus a few specifically created for advanced trainees in Respiratory Medicine. However, all cases are accessible to all users.
We have evidence that this educational approach can work: in a trial at a large Sydney hospital, we demonstrated that in the period immediately following active engagement of the cohort of junior doctors with this website, there were significant hospital-wide cost savings and an encouraging reduction in the number of blood samples collected from patients [9]. Unfortunately, in agreement with other studies of educational interventions, these changes in test-requesting behaviour were not sustained over the following months. However, there is additional evidence that routine requests for diagnostic investigations can be reduced if junior doctors are provided with cost data at the time of submitting a request [10]. We think a good case can be made for integrating this information into online systems in hospitals, to provide reinforcement.
Meanwhile, I encourage you to have a look at one of the few collections of guidelines about the use of investigations, available on the Australian Choosing Wisely website at http://www.choosingwisely.org.au/resources/clinicians?displayby=MedicalTest. These guidelines are supported by a number of specialist medical colleges, notably including the Royal College of Pathologists of Australasia and the Royal Australian and New Zealand College of Radiologists. Also well worth reading is a thoughtful reflection on the “big picture” of overuse and the Choosing Wisely initiative, published late last year and targeted specifically to medical students and trainee doctors [11].
References
National Coalition of Public Pathology. Encouraging quality pathology ordering in Australia’s public hospitals – Final Report, 2012 http://www.ncopp.org.au/site/quality_use.php (last accessed January 2017).
Hawkins RC. The Evidence Based Medicine approach to diagnostic testing: practicalities and limitations. Clin Biochem Rev. 2005; 26:7-18.
Hammett RJ, Harris RD. Halting the growth in diagnostic testing. Med J Aust 2002; 177:124-125.
Stuart PJ, Crooks S, Porton M. An interventional program for diagnostic testing in the emergency department. Med J Aust 2002; 177:131-4.
Chu KH, Wagholikar AS, Greenslade JH, O’Dwyer JA, Brown AF. Sustained reductions in emergency department laboratory test orders: impact of a simple intervention. Postgrad Med J 2013; 89:566-71.
Janssens PMW. Managing the demand for laboratory testing: Options and opportunities. Clin Chim Acta 2010; 411:1596-602
Corson AH, Fan VS, White T, Sullivan SD, Asakura K, Myint M, Dale CR. A multifaceted hospitalist quality improvement intervention: Decreased frequency of common labs. J Hosp Med. 2015; 10:390-5.
Ritchie A, Jureidini E, Kumar RK. Educating young doctors to reduce requests for laboratory investigations: opportunities and challenges. Med Sci Educ 2014; 24:161-3.
Feldman LS, Shihab HM, Thiemann D, Yeh HC, Ardolino M, Mandell S, Brotman DJ. Impact of providing fee data on laboratory test ordering: a controlled clinical trial. JAMA Intern Med 2013; 173:903-8.
Lakhani A, Lass E, Silverstein WK, Born KB, Levinson W, Wong BM. Choosing Wisely for medical education: six things medical students and trainees should question. Acad Med 2016; 91:1374-8.
Universal healthcare is a privilege and a right that we must protect to ensure the healthy future of Australia. As medical students and doctors, we are more than simply practitioners of medicine. We hold more responsibility than solely the management of disease. A key responsibility of our profession is advocacy for the health of our patients, the health of our nation, and the protection of our public health system.
The recent election has highlighted the fragility of our public health funding, and the willingness of both sides of politics to use Medicare and public healthcare as a political tool to serve their own agenda. This short-term and selfish thinking has the potential to abolish equal and fair access to healthcare; this is something that is, and should continue to be, a universal right for every Australian. The opportunity to live a long and healthy life should not be decided by our wealth. As it stands, the health gap between those from upper and lower socioeconomic backgrounds is significant [1]. The ramifications of freezing or removing funding to Medicare and public healthcare will be widespread. The current policy of a “freeze” on Medicare will increase out-of-pocket costs to all patients, impacting patients from lower socioeconomic backgrounds significantly. The effect of this freeze will be two-fold, with the added effect of increased practice costs in areas where patients cannot afford to pay out-of-pocket fees [2]. In turn, this will impact practice viability, and in lower socioeconomic areas, some practices may be forced to close, leaving vulnerable groups with limited access to healthcare [2].
The result of increased out-of-pocket fees will be an increasingly privatised healthcare system, and one does not need to look far to see the detrimental effect of such a system. In America, the healthcare system screams of inequality. It is a system where doctors are often placed in tremendously difficult situations, and are often left with no option but to turn away patients who are unable to afford healthcare [3]. America has a per capita healthcare expenditure that far exceeds that of other developed nations, however, public spending only covers 34% of residents in the United States, compared to every resident in Australia and the UK [4]. What is most damning about these statistics is that despite exorbitant healthcare expenditure, predominantly at a cost to patients or their insurers, the life expectancy American citizens languishes at 31st in the world, well below that of Australia, which is ranked fifth [5]. But that is not where the inequality stops. The privatised, self-funded system in America also stakes claim to the highest infant mortality rate amongst all developed nations, and a higher prevalence of chronic disease than that in developed nations with a universal public healthcare system [4]. If we are to preserve the health of Australians, we must take on the responsibility to advocate for healthcare as a universal right for all Australians.
In the lead up to, and in the days following the recent election, the Australian Medical Association (AMA) and the Royal Australian College of General Practitioners (RACGP) have been highly outspoken regarding their concerns about the inequality of funding cuts to Medicare. This advocacy, along with campaign material centred on Medicare, led to a strong response from the Australian public at the election, making it evident that Australians value free universal healthcare. However, this has not led to a response from parliament about the freeze on Medicare funding. Without a change in this policy, 57% of GPs have said they will increase out-of-pocket expenses, and 30% have said they will stop bulk billing [2]. This will directly affect patient access to healthcare, and has the potential to have a detrimental impact on Australian health outcomes, similar to health outcomes seen in America. As medical students and doctors, we are on the frontline of these changes, and it is our responsibility to protect our universal healthcare system. It is an issue that needs all of our support.
As a highly educated and privileged group, we need to ensure that governments understand the ramifications of cutting funding to Medicare and public healthcare. Universal healthcare needs to remain a priority in Australia and a right for all Australians, young and old. The health of our nation reflects the spirit of our nation, and it is the role of all medical professionals to advocate for equality in healthcare. Our advocacy need not make headlines in newspapers or fill prime-time television slots. Through simple conversation we can raise awareness about the importance of universal healthcare. It is our role to ensure that Medicare and public healthcare remains a priority, not just for the next election cycle, but for the long-term, so that future generations of Australians can enjoy long, prosperous, and healthy lives, just like the Australians of today.
Conflicts of interest
None declared.
References
[1] World Health Organisation. Health Impact Assessment: The determinants of health [Internet]. World Health Organisation; 2016. Available from: http://www.who.int/hia/evidence/doh/en/index1.html.
[2] RACGP. Antifreeze campaign – fact sheet for GPs and practices [Internet]. RACGP; 2015. Available from: http://www.racgp.org.au/download/Documents/News/Antifreeze-information-sheet-GPs-and-practices.pdf.
[3] Weiner S. I can’t afford that!: Dilemmas in the care of the uninsured and underinsured. J Gen Intern Med. 2001 Jun;16(6):412–8.
[4] Squires D, Anderson C. U.S. health care from a global perspective: spending, use of services, prices, and health in 13 countries. The Commonwealth Fund; 2015.
[5] World Health Organisation. Life expectancy 2015 [Internet]. World Health Organisation; 2015. Available from: http://www.who.int/gho/mortality_burden_disease/life_tables/situation_trends/en/.
I feel like a dying breed. A dinosaur, if you will. At the outset of my studies I knew this and I still think about it occasionally, still wonder if I made the right decision at the naïve age of 17.
I’m talking of course about my name. Specifically, what’s going to appear after it in just a few years’ time — MBBS. That cultural UK tradition drawn from the fusion of Physicians (Bachelors of Medicine) and Surgeons (Bachelors of Surgery), who at some point decided it was all the same stuff, and that MBBS was more attractive than BM, BS.
In Australia, and in my university, we’re seeing a relatively new kid on the block — the Doctor of Medicine (typically MD). The roots of this seem to come from across the pond, where at some stage Americans decided to silently disagree once again with the conventions of England. In fact, I am the last cohort of MBBS in my university – many of the students below my year boast their superior would-be qualification, and I’ve heard it time and again from universities that already have it. But is MD a new degree, or just a new name? Is this really a new breed of Doc that will one day uniformly scoff at me, a dinosaur from the age of MBBS?
I set about this question in a number of ways. There are the facts and figures, the institutional requirements that fall under the Australian Qualifications Framework (AQF) and the Australian Medical Council. And then there are the perceptions — much more difficult to grasp, but no less important for a degree so public as medicine, where your qualifications guide your job opportunities, your patient trust, and ultimately the ability to help people.
So to the facts. The AQF guides the ability of universities and other tertiary providers to name programs. This is a 10-step ladder, available in an interactive website provided by the AQF [1]. It runs from Level 1 – a Certificate 1, through to Level 10 – a PhD. In Australia, universities are self-accrediting higher education providers, and are overseen by the Tertiary Education Quality and Standards Agency, a Commonwealth Government department. Although I can’t admit to knowing the exact process of application and oversight, the simple fact remains: In Australia, your primary medical degree can be Level 7, Level 8 or Level 9.
Level 7 is a Bachelor degree – there are several broad expectations of someone having attained this level of degree, which is summarised on the AQF website as the following:
“Graduates at this level will have broad and coherent knowledge and skills for professional work and/or further learning” [1].
That seems pretty good to me. Medicine is a profession that I want work in, and I’m very open to further learning – such as a specialty or a research higher degree.
Level 8 is a Bachelor degree with Honours, something provided by many of the universities that still offer MBBS. Although it must be noted that at some universities, Honours is given only to those who undergo extensive research on top of their studies, while at other universities, the requirements seem far less stringent. Level 9 qualification is where MD comes in — according to the AQF levels it is a single Masters degree. The summary of graduates of this level is:
“Graduates at this level will have specialised knowledge and skills for research, and/or professional practice and/or further learning” [1].
This doesn’t seem to mean much to me as a medical student. Surely “specialised knowledge” is gained in postgraduate vocational training, as per the system of Australian Specialist Medical Colleges, in turn overseen by the Confederation of Postgraduate Medical Councils and the AMC [2]? And in terms of research, does that mean I can’t complete useful medical research, with my measly BSc/MBBS?
Maybe the Australian Medical Council could straighten things out for me, and tell me how much I’m worth. The AMC is ultimately responsible for the training of all medical students and doctors in Australia, as dictated by the Medical Board of Australia [3]. This is a huge responsibility – and with medicine changing more and more rapidly over the past 50 years, it’s impressive that they could keep up!
In fact, there is no difference in the AMC accreditation level of university medical graduates. Quite the opposite – the AMC regards all medical students as having had a comparable experience in medical school to make them safe enough for an Australian internship. For the University of Melbourne, the first university to offer the MD in Australia, there was a re-accreditation process with the AMC before the degree could be offered [4]. Likewise, the University of Western Australia overhauled their program, entirely changing the number of years of medical school [5]. But every other medical school in Australia that has switched or is considering switching has not required extensive re-accreditation beyond the normal requirements that exist year-to-year [6][7].
On the ground, what is this meaning for students? Are students becoming better doctors and better scholars, or are they not? My personal feeling is the latter. I have peer-tutored at my university for the year below me, and they do not seem to be a new breed at all. Like me, they wish they started cramming a week earlier with each coming semester. Like me, they whinge when the School makes small program changes that they don’t agree with, or schedules lectures that they think are useless. Like me, they attend Evidence-Based Medicine with a somewhat silent resentment, not because it’s not important but because it’s not exciting.
The School has made some changes; I suppose to be in line with AQF standards. All MD students at my university now write a research protocol – as I understand it, a report on how they might do some research. It’s not revolutionary, it’s not PhD-worthy, and in fact, it’s a lot less than the research required to get an Honours in my current program.
But more than all the facts and figures, I do care about the perceptions. I do wonder if a patient one day will take a look at my name-tag and ask me what an MBBS is, and why they’re not being seen by a real doctor. I wonder if the applications office at RACP or RACS will one day look at my name and think less of me. I wonder if I should have chosen to be the last of the MBBS cohort at my university, or done an extra year of science and slipped into the first MD class. These are worries that can’t easily be put to rest – especially when my juniors already think themselves superior in some way. As though somehow, their research protocol made them able to pick the diagnosis when I would have missed it.
Many students at my university are from overseas, and eventually become fully registered doctors in countries like the US. There, MBBS means nothing, and MD sits in a strange qualifications level that we don’t have in Australia. In many states of America, you can, for a nominal fee, apply to legally change from MBBS to MD after your name, and many of my colleagues will do so [8]. This may be a potential solution to my worries down the track, should they ever really arise.
I decided at the end of the day, that MD is much more about business than health. It was attractive for the University of Melbourne to pioneer a new name, and now each new medical school that “gets the MD” can call themselves on par once again. Unfortunately, the restrictions for Domestic Full-Fee Places in universities do not apply to postgraduate courses such as Masters, which legitimately poses a financial threat to new students, and added strain to the internship crisis [4]. For now, I’m content in the hope that most people don’t care what’s in a name. A medical degree by any other name would doctor just as well. And after all, the Australian National University now provides their students an MChD and nobody seems to complain [9]!
Acknowledgements
The Australian Medical Students’ Association (AMSA) for inviting me to present policy related to this topic.
Conflict of interest declaration
None
References
[1] Australian Qualifications Framework [Internet]. Canberra ACT: Australian Government Department of Education and Training; 2015. AQF Levels; 2013 [cited 2016 Jul 24]. Available from: http://www.aqf.edu.au/aqf/in-detail/aqf-levels/
[2] Confederation of Postgraduate Medical Education Councils [Internet]. Melbourne VIC: Confederation of Postgraduate Medical Education Councils; 2008. Postgraduate Medical Councils; 2008 [cited 2016 Jul 24]. Available from: http://www.cpmec.org.au/Page/about-cpmec-postgraduate-medical-councils
[3] Australian Medical Council Limited [Internet]. Kingston ACT: Australian Medical Council; 2016. About the AMC; 2016 [cited 2016 Jul 24]. Available from: http://www.amc.org.au/about
[4] Roberts-Thomson RL, Kirchner SD, Wong CX. MD: the new MB BS? Med J Aust [Internet]. 2010 Dec [cited 2016 Jul 24];193(11/12):660-661. Available from: https://www.mja.com.au/system/files/issues/193_11_061210/rob11006_fm.pdf
[5] Australian Medical Council [Internet]. Canberra ACT: Medical school accreditation program and status report; 2015 [cited 2016 Jul 24]. Available from: http://www.amc.org.au/accreditation/primary-medical-education/schools/status
[6] Australian Medical Council [Internet]. Canberra ACT: Changes to Primary Qualifications for Admission to Practise Medicine in Australia: Implications for AMC Accreditation; 2012 [updated October 2012; cited 2016 Jul 24]. Available from: http://www.amc.org.au/joomla-fil
[7] University of Queensland [Internet]. Brisbane QLD: Doctor of Medicine (MD); 2016 [cited 2016 Jul 24]. Available from: https://www.uq.edu.au/study/program.html?acad_prog=5578
[8] New York State Education Department Office of the Professions [Internet]. New York NY: New York State Education Department; 2009. Conferral of M.D. Degree; 2009 [updated Dec 15 2009; cited 2016 Jul 24]. Available from: http://www.op.nysed.gov/prof/med/med-mdconferral.htm
[9] Australian Government Department of Industry, Innovation, Climate Change,
Science, Research and Tertiary Education. 2014-16 Mission-based Compact Between The Commonwealth of Australia and The Australian National University. Canberra ACT; 2014 [cited 2016 Jul 24]. 23. Available from: http://docs.education.gov.au/system/files/doc/other/anu_2014-16_compact_final.docx
Background: Medicine is an ever evolving field of knowledge, new practice, and research. There are various clinical research methodologies; the clinical researcher may actively collect patient information, or retrospectively obtain patient data from traditional datasets, such as hard-copy patient records. In more recent years, clinical research has seen the emergence of ‘big data’.
Big data are large electronic databases characterized by the four V’s-volume, variety, veracity and velocity. The rise of big data suggests that there are advantages to its use. One advantage of big data is easy accessibility, which allows information to be obtained and analysed in a short period of time. However, there are shortcomings of using big data in clinical research, mainly with regards to sampling bias and validity. Nonetheless, big data are here to stay in today’s digitised age of medicine, and the researcher must consider the appropriate contexts for the use of big data in clinical research.
Aim: The aim of this paper was to define ‘big data’ in medicine and examine its use in clinical research.
Methods: A literature review was conducted on Ovid MEDLINE to identify relevant literature. The PRISMA statement was used to screen and select articles that would be reviewed for the paper.
Conclusion: The future of big data is promising, with the allure of low-cost, immediate, and comprehensive data, but it is important that clinical researchers understand how to utilise these well for research and knowledge translation.
Introduction
The future of medical practice is shaped by the outcomes of today’s clinical research trials. Medicine is an increasingly data-intensive field reliant on clinical research [1]. For decades, the clinical research industry has conducted large amounts of research by either actively collecting patient data or retrieving it from hard-copy patient records [2]. However, recent years have seen the emergence of ‘big data’ as the key source of data for clinical trials and observational clinical research alike [3,4]. Big data algorithms in medicine broadly refer to the aggregation of individual medical datasets into large, electronic databases that are readily available for data analysis in clinical research [3,5]. The rise of big data in clinical research suggests that there are obvious advantages of its use. However, there are also challenges in optimising its use in clinical research due to the risk of bias [6]. The aim of this paper was to define ‘big data’ in medicine and examine its use in clinical research.
Methods
This literature review examined recent literature that focused on the use of big data in clinical research. This included researching its validity, reliability, advantages, and disadvantages. Recent literature was defined as articles published from 2005 until 2016.
A literature search was performed on Ovid MEDLINE using the following query:
(“validity” OR “reliability” OR “advantages” OR “disadvantages”)
AND
(“administrative data” OR “database” OR “big data” OR “electronic health records” OR “electronic medical record” OR “clinical database”)
AND
(“clinical research” OR “healthcare”)
The PRISMA statement was used when selecting articles for this review (Figure 1). A total of 164 publications were identified through the database searches. One additional record was identified through the bibliography of one of the articles retrieved from the database search. The abstracts of these articles were manually reviewed for relevance to the topic, excluding 119 articles. Full-text screening excluded a further 23 articles due to inappropriate topic focus and repetition. This paper subsequently focused on reviewing 23 articles. These articles were primarily original research articles and systematic reviews.
Figure 1. PRIMSA ow diagram demonstra ng search strategy.
What is big data?
Defining big data in a medical context
Big data in medicine is characterised by the four V’s – volume, variety, veracity, and velocity [7]:
Volume refers to the large amounts of patient information being collected over time and stored, as suggested by the term ‘big data’. Various elements incorporated into big data include patient demographics, history, investigations, diagnoses, and length of stay [8]. Big data are available in the form of registries and patient databases. Registries gather disease- or population-specific information, while patient databases document patient information throughout the course of an illness [8].
Variety of data can be broadly discussed as structured or unstructured data. Structured data is information that is easily stored, searched, retrieved, edited, and analysed digitally, as in keying in patient ID numbers into electronic medical records to access patient information [7]. In contrast, unstructured data include traditional print records, electronic free text, radiographic films, or survey data collected from patients [9].
Veracity concerns the true representativeness of the data. It refers to the goal of achieving validity and credibility in the data set [7].
Velocity represents the rate at which data is recorded and generated to allow timely retrieval for analysis and decision-making [7].
Advantages of using big data
Accessibility and availability
Big data are readily available [10]. Patient records, such as admission history, investigations, diagnostic results, and medications, are all electronically documented on hospital databases. As these hospital databases are installed on staff computers in the hospital, health professionals working in these hospitals are able to easily access this data for review or, increasingly, for clinical research. The integration of multi-pathway patient records1 in big data provides a convenient, comprehensive pool of information available to researchers [11]. This integration facilitates retrospective cohort studies and therefore aids researchers to identify patterns in disease progression and compare the effectiveness of treatments [11].
Cost- and time-efficiency
Given the convenience of data collection using electronic patient registers, the process of obtaining information needed for clinical research is shortened, in comparison to the more time-consuming alternative of manually collecting patient data [12]. Big data are useful in minimising logistical impediments in prospective and retrospective, longitudinal, population-based studies [13,14]. Researchers who require large sample sizes can also easily extract information from the available pool of data in these databases, potentially increasing the study power of their research [13]. The added benefit of being able to use computerised techniques to analyse unstructured data within big data also means that finer data acquisition can be performed, compared to data acquired by laborious, manual extraction from traditional datasets [14]. In addition, this information is available at a low cost, if not free, to clinical research staff, bypassing potential additional costs that might be incurred through manual data collection [15].
Challenges of Big Data
Kaplan et al. [16] suggests that several biases can arise when analysing big data, including, but not limited to, sampling bias and lack of scope in the information recorded. Secondly, the validity of big data is highly dependent on the context in which it is being used [17]. Lastly, minor data security issues may arise from the utilisation of big data.
Sampling bias and lack of scope
Sampling bias of big data can be discussed in terms of its standardisation and completeness. Completeness of data encompasses both its comprehensiveness and whether it is a good representation of the population of interest [17]. Clinical research often requires data collection from a large sample size of patients. As every patient will have different investigations, diagnoses, and treatment plans, every patient will have varying types and amounts of clinical documentation and to differing degrees of detail. There will, therefore, be difficulty in standardising a method for data collection across an array of available patient information to ensure completeness of the data. It is crucial to ensure that the data is complete, otherwise the research results could be subject to information bias [8]. Typically, the ideal method to achieve this is to conduct prospective data collection, minimising omissions [8]. However, as big data is retrospective, it is often difficult to agree upon a decision regarding inclusion of the data or methods to retrieve missing data when medical records are not available [8]. In those situations, the clinical researcher will be required to design algorithms to clean and correct the available data, however it is difficult to design an objective method to validate certain choices made in this process of data collection.
In addition, the coding of information is very much skewed towards documenting and following up the primary diagnoses [17]. As such, secondary diagnoses are often missed or poorly recorded, resulting in a lack of well-documented secondary patient information, such as co-morbidities.
Validity of big data
Joppe defines validity in quantitative research as a criterion that determines whether a research truly measures what it was initially intended to measure [18]. The validity of big data varies between different clinical specialties and the circumstances in which the data is being used [17].
Occasionally, big data may contain incomplete data sets, or even incorrect data, due to errors in transcription or abstraction [8]. There have been instances when data is misclassified during the recording of data during the data coding process [17]. These may occur when a patient undergoes a procedure that treats more than one condition, or in recording a patient’s hospital admission based on presenting complaint [17]. These systematic errors are hence potentially misrepresentative of the data [17]. A literature review by Talbert and Lou Sole [8] in 2013 found that there has been substantial research suggesting that administrative databases, a subset of big data, have only moderate sensitivities and specificities for correct data coding and may underreport procedures [8].
The increasing trend of activity-based funding of hospitals in some countries, such as the United States and Australia, may also influence the information recorded in big data at discharge [19]. Activity-based funding is a policy intervention targeted at restructuring incentives across healthcare systems through a fixed funding allocation for each episode of care administered to each patient, regardless of their duration of stay and resources used [19]. Obvious benefits include reduced hospital costs and shorter hospital stays, however, hospitals may misuse the system to increase revenue by up-coding diagnoses, or focusing on profitable patients and procedures [19]. As a result, the diagnoses and procedures included in the discharge coding within big data may misrepresent the actual situation in the hospital.
It is crucial to note that electronic medical records adapted for clinical research serve the purpose of a clinical care record and are not designed for research [20]. Electronic inpatient databases document the clinician’s case notes, which often focus on treating the patient’s current illness and respond to the individual clinician’s concerns. These may not always correspond with the aims of future clinical researchers. As such, the available information on the patient may not necessarily be as comprehensive as required by the clinical researcher [12].
Analysis of inaccurate data may cause incorrect conclusions to be drawn. In situations where researchers simply use whatever big data are provided to them, the validity of the clinical research is compromised as the data collected and analysed may not truly reflect the research aims.
Data security
Griebel et al. [1] suggest that users who lack experience in using big data and third party users could potentially pose a threat to data confidentiality. Such circumstances may occur when healthcare providers work with commercial corporations and outsource the information to a commercial cloud [1]. However, mitigation strategies, such as the implementation of high-security data authentication protocols to limit access, can be put in place to ensure data security [1]. Examples of high-security data authentication protocols include advanced firewalls to prevent access by unauthorized users and setting up a digital certificate, which requires the user to identify himself or herself [5]. There are also newer techniques, such as obfuscation, where patient data is stored in an encrypted form and decryption is only allowed through authorised privacy manager software [5].
Choosing appropriate contexts to utilise big data in clinical research
Big data are beneficial to clinical research in providing the following information:
Patient demographics and risk factor profile for disease
Big data are highly applicable in the field of patient profile analytics [2]. Big data can be used to identify relationships between patient demographics and disease or treatment outcomes. By routine monitoring and documentation of patient flow and outcomes, big data allow the incidence and prevalence of diseases, as well as the overall outcome amongst selected patient groups, to be estimated [17]. Furthermore, big data are ideal for developing predictive analytic models based on risk factor profile. As big data capture patient demographics, they help the clinical researcher pinpoint patient risk factors specific to certain diseases, draw links with disease progression and hence, has the potential to be used in developing prediction models [17]. Moreover, risk factors can also be prognostic, and highlight the possibility of a future health outcome [17]. When advanced analytics are applied to these patient profiles and patients at risk of developing specific diseases are identified, there is the opportunity to intervene and provide preventive care to the selected group of patients [2].
Patient treatment outcome
Additionally, by combining both structured and unstructured data across multiple disciplines—medical and surgical clinical data, financial and operational data, and genomic data—to match treatments with outcomes, big data can also predict treatment effectiveness for patients [2]. Collectively, these suggest that big data can be useful in calculating the risks and benefits for various outcomes of both a disease and treatment in different patient groups, hence enabling the clinician to provide more efficient and cost-effective care [2,15].
The future of big data
Improvements in big data organisation and an increasing familiarity with using big data will allow clinical researchers to better utilise the data to their advantage. For instance, researchers are progressively able to model inclusion criteria to obtain relevant data [21]. Up and coming technological infrastructure can be expected to springboard the potential of big data in medicine. For example, cloud computing allows big data to be bigger, better and faster. Cloud computing has the potential to provide researchers with multi-scale data integration tools that will help highlight relationships between discrete data entities [22,23]. Cloud computing will also enable researchers to customise personal networks and virtual servers to increase data security of the electronic resources being used [1].
Beyond clinical practice, there is also potential for big data in other healthcare areas [2]. Big data have the potential to integrate population clinical data sets with genomics data, facilitating pharmaceutical development [2]. There is also a role for big data to play in public health surveillance. Big data can aid in analysing and tracking disease patterns, which is of utmost importance in delivering effective and efficient healthcare responses during disease outbreaks [2].
Conclusion
Big data are a useful and efficient source for obtaining patient information. It offers immediate access to large amounts of patient data with high convenience, low cost and easy accessibility. However, big data may be a poor source for immediate causal inference in data analysis as it lacks randomisation. Yet, there is much potential for big data in clinical research and clinical researchers must improve their utilisation of big data in knowledge translation and data analysis. Appropriate handling of big data through well-designed algorithms and data analysis must be done to overcome its limitations. Nonetheless, with its allure of low-cost, immediate, and comprehensive data, the rise of big data is promising. It is here to stay.
Conflicts of interest
None declared.
Acknowledgements
The author of this paper would like to thank Dr Nora Mutalima (Research Co-ordinator Orthopaedic Services, Dandenong Hospital and Adjunct Research Fellow, Monash University) for her critical review and support.
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Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide contributing to approximately 600,000 deaths each year with this number on the rise in the developing world. The aetiology of HCC has been well characterised, including chronic hepatitis B and C infection as well as alcoholic cirrhosis. Current screening programs for patients at high risk of developing HCC, including ultrasound and alpha-fetoprotein analysis, are neither sufficiently sensitive nor specific to detect early HCC. This reduces the likelihood of detecting HCC when curative treatment is effective. One genetic marker which has been shown to be associated with HCC carcinogenesis is the p16 INK4a/ARF locus. If further research confirms this mutation as a common step in early hepatocarcinogenesis then this maker could be utilised to screen for early HCC lesions in at risk populations. Further research in this area could facilitate the early diagnosis of HCC, improving the efficacy of treatment.
Introduction
Liver cancer is the sixth most common cancer worldwide and the second largest cause of cancer mortality [1]. It has several subtypes including hepatocellular carcinoma (HCC), bile duct cancer, hepatoblastoma, and various other liver sarcomas and carcinomas [2]. Of those subtypes, HCC is the most common, comprising about 78% of all liver cancers [1,2]. HCC is unequally distributed globally with over 80% of cases occurring in either Sub-Saharan Africa or Eastern Asia; predominantly in China [3,4]. When considering Western countries, there is strong evidence from the United States that the incidence of HCC is rising, with nine cancer registries reporting via the National Cancer Institute that there has been a 41% rise in mortality from primary liver cell cancer and a 70% rise overall in incidence between 1980 and 1995 [5].
A similar rise in HCC incidence and death rates in Australia have also been identified; possibly linked to the increased prevalence of Hepatitis B and Hepatitis C infection in Australia [6,7]. Moreover, there is evidence that HCC incidence rates in Australia may be up to two-fold higher than the rates reported by cancer registries such as the Victorian Cancer Registry [8]. A higher rate of HCC has also been reported in Aboriginal and Torres Strait Islander populations; estimated at 2% and 8% in urban and rural areas, respectively, compared with less than 1% for the total Australian population [9].
The aetiology of HCC is well documented in the literature with high rates linked to both hepatitis B and hepatitis C exposure [9]. Other significant causes that may cause patients to present include alcoholic liver disease, non-alcoholic steatohepatitis as well as hereditary conditions such as haemochromatosis, alpha-1 antitrypsin deficiency, and autoimmune disorders (Figure 1) [10,11]. These conditions result in significant parenchymal loss, increased fibrogenesis and inflammatory signalling resulting in cirrhosis; a condition associated with 70-90% of all detectable HCC cases [10,11].
Figure 1. Aetiology of hepatocellular carcinoma
The natural history of HCC growth begins as small asymptomatic nodules which can often take years to develop depending on the aetiological exposure [5]. Small HCCs at detection have relatively long tumour doubling times with tumours of less than five centimetres associated with a survival of 81-100% at one year, and 17-21% at three years without therapy, which suggests that early diagnosis may allow for a greater intervention window [5].
These features make HCC an insidious and difficult disease to clinically detect and investigate. Patients who develop HCC are usually asymptomatic, mostly displaying symptoms related to their chronic liver disease which can become modified with disease progression [6,12]. Examples of this include signs of decompensation such as ascites, encephalopathy, jaundice, and variceal bleeding [12]. Advanced lesions also can present more conspicuously causing obstructive symptoms such as jaundice, diarrhoea, weight loss, and fatigue [13]. These signs are a result of local tumour invasion and growth inside the liver. However, systemic signs can also occur as a result of metastases which can develop in the lung, portal vein, periportal nodes, bone or brain [13]. As a result of these features, HCC is typically diagnosed late in its course with a median survival following diagnosis of 6 to 20 months, and a five-year survival ranging from 12% in those outside major cities and 17% within major cities in Australia. [13,14].
Screening and detection of HCC
Accordingly, screening programs for HCC in at risk groups, those with chronic liver disease or chronic hepatitis infection, is recommended with specialist review forming part of a 6-12 monthly management plan [15]. These programs involve using alpha-fetoprotein (AFP) and ultrasound to screen for the presence of cancer lesions.
AFP is a widely studied screening test marker for HCC with a level above 400 ng/mL regarded as diagnostic [5]. However, two thirds of HCCs less than 4 cm have AFP levels less than 200 ng/mL and up to 20% of HCCs do not produce AFP even when they are very large [5]. Moreover, there is evidence that fluctuating levels of AFP in patients with cirrhosis might reflect flares of HBV or HIV infection or liver disease exacerbation rather than HCC development [16]. Some studies investigating the clinical utility of AFP have suggested it lacks the sensitivity to be useful, with one study suggesting it rarely assisted in a diagnosis [5,17,18]. As a result of this, it has been suggested that AFP testing alone should only be used if ultrasound is unavailable, with the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver recommending it not be used at all [16,18,20]. This therefore limits the use of AFP as a reliable test to screen for HCC in at risk groups. Due to these limitations, other serum markers which include plasma microRNAs such as miR-122 and miR-192, des-gamma-carboxy prothrombin, AFP isoforms and glypican-3 are currently being investigated and evaluated for future use [19,20].
Another modality that is used in HCC screening is ultrasound. Ultrasound can detect large HCCs with high sensitivity and specificity; however, it is less able to reliably identify smaller lesions, which are required if more effective therapy is to be offered [6,19,20]. Ultrasound has been shown to detect 85-95% of lesions 3-5 cm in diameter, but can only achieve a 60-80% sensitivity of 1 cm lesions [5]. A large meta-analysis investigating this in 2009 found similar results demonstrating that surveillance with ultrasound showed a limited sensitivity (64%) for early HCC detection [19]. Combined use of AFP and ultrasound has been shown to increase detection rates, but had a raised combined false positive rate of 7.5% compared to AFP and ultrasound alone at 5.0% and 2.9% respectively [18]. Despite the limitations of these tests, the Royal Australian College of General Practitioners guidelines suggest that patients with chronic liver disease or chronic hepatitis infection should be considered for 6-12 monthly AFP and ultrasound screening [15]. The Asian Pacific Association for the Study of the Liver also recommends surveillance for HCC with both AFP and ultrasound every 6 months [21].
The importance of early HCC detection cannot be understated. The natural history of early tumours is poorly known as most are treated upon diagnosis; however, surgical resection, tranplantation and ablation offer high rates of complete responses and a potential cure in all patients with early HCC [22]. Advanced course HCC has a survival of less than six months without treatment with prognostic factors for survival including anatomical extension of the tumour, performance status and functional hepatic reserve based on the Child-Pugh Score [22-24]. It is from this that researchers are currently investigating superior screening techniques which can identify tumours earlier and with greater sensitivity and specificty to enable earlier intervention and better treatment outcomes.
Cancer biology as the pathway for a HCC screening test
One approach that is currently being investigated in the medical literature focusses on the biology of HCC hepatocarcinogenesis to develop a sensitive early screening test that can guide and detect treatment before the cancer can extend and spread. Mature hepatocytes have an average lifespan of between 200-400 days and rarely proliferate unless stimulated by acute injury [25]. The observation of normally quiescent hepatocytes and cholangiocytes proliferating after partial hepatectomy has highlighted the significant regenerative ability of the liver after acute insult [26]. If this regenerative capacity is compromised, the liver has liver progenitor cells (LPCs) which can expand and regenerate the chronically damaged liver [27,28]. LPCs can propagate and differentiate into two types of liver epithelial cells; hepatocytes and cholangiocytes [27]. These cells have been defined as stem cells because they are clonogenic, with a high growth potential and are able to be induced to differentiate into both types of liver cells and have shown capability in repopulating the liver on transplantation [27-30].
The proliferation and differentiation of LPCs into hepatocytes render them a target population for hepatocarcinogenesis [30]. LPCs have been traced to hepatocytes and are markedly elevated in chronic liver disease [28]. Recent laboratory experimentation has shown a link between induced liver damage in mice and the development of HCC, suggesting a tenable link between LPCs and HCC development [31,32]. LPCs have also been documented in chronic human liver pathologies, such as chronic hepatitis C, which is highly associated with hepatocarcinogenesis [29,33-35]. Analysis of premalignant lesions in HCC have also identified the presence of LPCs, with up to 50% of developed HCCs being shown to express markers of progenitor cells including CK7, CK19, OV6 [35-38] These findings have also been found in further studies on both human and mouse liver cells [38,39]. These results suggest a significant link exists between LPCs and HCC carcinogenesis.
From a molecular analysis of HCC progression, it has been shown that hepatocarcinogenesis is a multistep process that is heterogeneous and not well understood [40]. Progressive genetic alterations have been shown to cause a spectrum of cellular changes starting from cell hyperplasia, proliferation to dysplasia and eventually cancer [28,40]. This model is widely accepted and has been applied to many types of cancer, including HCC [28]. Multiple studies have demonstrated that two tumour suppressor pathways are important in controlling cell proliferation including the retinoblastoma protein pathway and the p53 pathway [28,41]. Most human tumours have genetic mutations, deletions, deregulated methylation or alterations in microRNA signalling in their Retinoblastoma and p53 pathways; making these genes likely candidates in the transformation of non-tumourigenic LPCs to tumourigenic LPCs [42-44].
Future HCC screening with the marker p16 INK4a/ARF
One gene involved in the p53 tumour suppressor pathway which may play a crucial role in hepatocarcinogenesis is the INK4a/ARF locus. Studies have identified variable rates of inactivation of the p16 INK4a/ARF gene in HCC with inactivation ranging in the literature from 35-82% of HCCs depending on the aetiology [45-50]. Studies on HCC mouse models have highlighted the important role of INK4a/ARF in tumourigenesis with concomitant loss of p53 and INK4a/ARF accelerating tumourigenesis and the progression to metastatic lung lesions [51-53]. Furthermore, tumours lacking both p53 and INK4a/ARF demonstrated strong migration and invasion capabilities. This was not demonstrated when p53 itself was inactive; suggesting that INK4a/ARF inactivation may be a critical step in HCC development (Figure 2) [52,53]. Significant evidence suggests that INK4a/ARF are important tumour suppressors encoded at 9p21 [9,46,52-54]. Kaneto et al. suggested that the methylation of the INK4a/ARF locus promoter is an early event in hepatocarcinogenesis, making this gene an ideal candidate for further study in the pursuit for an accurate diagnostic tool for HCC [46].
Figure 2. Stages of hepatocellular carcinoma development
The nature of how genes are inactivated in tumourigenesis is biologically complex. The INK4a/ARF gene can be affected by many different forms of inactivation notably mutations, homozygous deletions or gene methylation [54]. Tannapefel et al. showed that of 71 carcinomas examined, 59% showed aberrant methylation of the INK4a gene [54]. Another recent review suggested that as many as 40-70% of HCCs demonstrate an INK4a methylation resulting in the downregulation of protein expression [55]. The pathogenesis of the ARF gene in HCC was not as clear, with studies finding ARF gene methylations in non-cancerous liver tissue as well as low rates of ARF methylation in human HCC samples [54,55]. Despite this, evidence of promotor methylation has arisen from investigations into the cause of INK4a/ARF inactivation in other tumours such as human cutaneous squamous cell carcinoma and colorectal carcinomas [56,57]. These studies provide evidence that the methylation of the INK4a/ARF gene may be an important step in the hepatocarcinogenesis of HCC and therefore could be an effective clinical marker for the identification of HCC development in at risk patients.
Conclusion
While it is clear from this review that further research needs to be conducted to better understand the role of the INK4a/ARF gene locus in HCC development, the potential for a clincial application remains a potent driver for further research in this area of molecular medicine. While the current screening methods using AFP and ultrasound are considered to be clincially useful in detecting HCC, there exists a space for more accurate modalities to detect early HCC lesions. If future research shows that the INK4a/ARF gene is a common early mutation in HCC hepatocarcinogenesis, then future tests may be developed which can sample high probability sites in the liver or the blood to investigate for DNA which contains this mutation. This could potentially improve the prognosis of patients with HCC development and allow early directed treatment with the possibility of cure.
Acknowledgements
Thank you to Professor George Yeoh for his assistance in proofreading this article and providing support and advice.
Conflicts of interest
None declared.
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