C’est inSUPPORTable!

Posted on 19 September 2013 by Keith Barrington

A new publication about SUPPORT? Haven’t we heard enough?

Well no, this is fascinating, although not entirely unexpected if you think about it.

One of the 2 comparisons of the SUPPORT trial involved randomization to be either immediately intubated to receive surfactant, or to attempt to keep the baby extubated and on CPAP, unless they exceeded 50% oxygen, or just weren’t able to breathe. At the time, some centers were intubating routinely, based on older trials which showed benefit, but which did not use what we now consider best treatment in their comparison groups. Some centers were trying to keep babies on CPAP, based on prior data from the COIN trial, and on accumulating experience elsewhere. In other words this also was a comparative effectiveness comparison, both approaches were considered within acceptable medical care approaches and both were in common use.

Some centers in SUPPORT had less experience with avoidance of intubation, and starting early CPAP in the DR, so when SUPPORT was active they started to gain more experience with that approach.

This new article shows that babies who were not actually in the trial, but were born in a participating hospital while SUPPORT was being carried out, ended up being treated differently than before the trial.

LeVan JM, Wyckoff MH, Ahn C, Heyne R, Sánchez PJ, Chalak L, Jaleel MA, Burchfield PJ, Christie L, Soll R et al: Change in care among nonenrolled patients during and after a randomized trial. Pediatrics 2013.

Babies born at the Parkland hospital who were under 28 weeks were intubated in the DR 85% of the time before SUPPORT, babies who were not in  the trial were intubated 61% of the time while the trial was on-going, and after SUPPORT had ended the frequency stayed at 61%. This wasn’t a change that everyone adopted at the same time, babies in the Vermont Oxford Network, not involved in SUPPORT, over the same interval did not have much change in their intubation frequency.

This ‘spill-over’ effect is not unexpected, (it is one of the reasons that we sometimes do cluster randomized trials) but this is a very clear example.

One implication of this is that we will need to have an informed consent process for all the non-enrolled patients in clinical trials. As has been pointed out, consent for research and for clinical care have the same requirements, so we will need to inform parents that there are trials gong on in our NICU at the present time, which may change the care that their babies receive whether or not they are enrolled in the trial. Maybe also the consent forms for the trials should have a section which notes that, even if the parents refuse the trial, the performance of the trial might change how their baby gets treated anyway… so they might as well sign up to the trial! How could this happen? Surely doctors know what is optimal care, how could the fiduciary obligation of a doctor to provide optimal care to his patients, who are not in a trial, be affected by a trial being performed? (Paragraph written with tongue firmly planted in cheek: if you are not a native english speaker that means that I am not really serious).

This is still more evidence that we are already in a learning health care system, approaches to care change as a result of many factors other than published best evidence, when you have more exposure and more experience with a particular approach you may start to use it more, even if the evidence does not (or not yet) show substantial advantages. Maybe this is appropriate, maybe not, but it is a reality of modern health care.

Posted in Neonatal Research | Tagged , , | 2 Comments

Neonatal Updates #37

Posted on 18 September 2013 by Keith Barrington

Hough JL, Johnston L, Brauer S, Woodgate PF, Schibler AF: Effect of body position on ventilation distribution in ventilated preterm infants. Pediatric Critical Care Medicine 2013, 14(2):171-177. Regional ventilation was measured using computed impedance tomography. The researchers found no effect of gravity on the distribution of ventilation, consistent with their previous work in infants on CPAP or health term babies. The babies were not very sick, with mean O2 requirements of 26%, and no difference in oxygen needs when they were placed prone or supine. It is frequent in babies with sick lungs to find that their oxygen needs a reduced in prone position, perhaps gravity has an effect on the distribution of perfusion, which becomes important in improving VQ matching when the lungs are sick. There are also fewer desaturation events in prone position.

Kidokoro H, Neil JJ, Inder TE: New mr imaging assessment tool to define brain abnormalities in very preterm infants at term. American Journal of Neuroradiology 2013. One of the difficulties in assessing the literature regarding MRI imaging in the preterm infant is that everyone reports them differently, so it is difficult or impossible to compare them. What we need is some sort of standardized reporting system. Behold! Terrie Inder and her group have come up with just that. Lets hope it catches on.

Filippa M, Devouche E, Arioni C, Imberty M, Gratier M: Live maternal speech and singing have beneficial effects on hospitalized preterm infants. Acta Paediatrica 2013, 102(10):1017-1020. Cool: Sick preterm babies have fewer apneas and hypoxic events when their mothers sing to them or talk to them.

Serce O, Benzer D, Gursoy T, Karatekin G, Ovali F: Efficacy of saccharomyces boulardii on necrotizing enterocolitis or sepsis in very low birth weight infants: A randomised controlled trial. Early Human Development 2013 Just over 200 VLBW babies were randomized to a probiotic fungus or control. No benefits were shown, either in reduction of NEC or in sepsis or mortality.

Ruano R, da Silva MM, Campos JA, et al: Fetal pulmonary response after fetoscopic tracheal occlusion for severe isolated congenital diaphragmatic hernia. Obstetrics & Gynecology 2012, 119(1):93-101 It is starting to look like this might actually work. The group in Sao Paolo are now reporting some outcomes from two small randomized trials, with a total of  just over 70 patients randomized. Fetuses had very severe pulmonary hypoplasia, with an observed to expected Lung/Head ratio below 25% and the liver herniated. Only 5% of the controls survived, and over 50% of the intervention group. The particular technique used requires a fetoscopic laryngoscopy, with occlusion of the trachea by balloon, followed, usually by an EXIT procedure, although they have sometimes done a second fetoscopy to remove the balloon. The report of the second trial is free access and has neat pictures. The same group has also done some earlier procedures also with some success. With this approach the gestational age at delivery was pretty close to term on average at 35 + weeks, which is also better than previous reports. If other centers can replicate this success, then we are on our way.

Posted in Neonatal Research | Leave a comment

What are the responsibilities of clinical researchers?

Posted on 18 September 2013 by Keith Barrington

One of the presentations at the OHRP hearings of the HHS was by George Annas, a JD who has an MPH (for those outside of north america that means he is a lawyer, but with a masters in public health). He is an influential figure who made the following statement (or something very like it) ‘physicians have a fiduciary obligation to their patients to provide optimal care; researchers have no such obligation.’ He was very emphatic.

He is also wrong.

In neonatology at least, the big majority of trials are performed by physicians who are also researchers. There are a few trials led by epidemiologist/trialists, but even in those trials the local investigators are almost always neonatologists. So what are our ethical responsibilities as clinicians who are also researchers? I think they still include the obligation to provide optimal care, an obligation that has to take into account, as it does in daily clinical practice, the fact that we often do not know what is the optimal treatment. Thus in the NICU, in identical situations, I might choose one treatment one day, and another treatment on the other. That can be consistent with all of my fiduciary obligations, whether I do that because the fellow has made a good argument for one treatment rather than another, and I can’t find any evidence to counter their argument, or because the parents prefer one treatment rather than another, and both are acceptable alternatives, or because it didn’t go well last time, or the phase of the moon has changed…

Professor Annas doesn’t really address that problem in his presentation, but it is addressed in the question session. He doesn’t, however, answer the question when it is posed, he talks about how important people feel it is to be able to choose their own physician. But even if preterm babies chose me as their physician (that really isn’t how it works, by the way) I still often don’t know what is best to do! Annas states that he doesn’t believe that physicians don’t know anything, and that every treatment decision is not a flip of the coin. But nobody said that. Many treatment decisions are evidence based, and many are proven to be better than alternative options. So if a preterm baby with HMD needs to be intubated and still has significant needs for oxygen, we know very well that they should get surfactant. If a full-term baby with hypoxic respiratory failure has an OI that is greater than 25 they should get inhaled NO; whoever they choose to be their doctor, the choice of treatment should be the same. That also has nothing to do with the ethics of uncertainty. Also, in many health care systems you don’t get to choose your doctor, or at least you rarely have an unrestricted choice. In the USA you don’t get an unrestricted choice either, and a baby in an NICU (and his family) really has little or no choice of doctor. That doesn’t change that fiduciary obligation.

Annas talks about the case of the law suit brought in the 80’s by someone who became blind as a result of high O2 levels when he was randomized (with no consent process at all in those days) to the high arm in one of the O2 trials in the 50’s. He describes this atrocious ophthalmologist who repeatedly examined the eyes of the baby every week, watching him going blind and doing nothing about it. He describes this as if it were a case of some ‘Nazi-like’ (my characterization, not his) medical experimentation, and comments that he could only have acted like that if he saw himself as a researcher, and not a physician. But in reality, he could have acted like that while being both, for what was the doctor supposed to do? There was no proof that higher O2 was the cause of RoP, many people doubted it, and there were cases of RoP in both the high oxygen and the low oxygen arms of the trials. Turning down the oxygen would not necessarily have had any effect on the progression of the eye disease (indeed the, much later, STOP-ROP trial showed that it does not). Another baby in the same NICU who was receiving the, then standard, treatment with very high oxygen and also getting repeated eye exams would have been receiving exactly the same care as the baby in the trial, despite being in a ‘fiduciary relationship’ with their physician! And, furthermore, there was no effective treatment; Cryotherapy was not available then, there was nothing anyone could do except watch the retina deteriorating.  Professor Annas has his retrospectoscope on high power, which has created substantial distortion: he seems to think that all the babies in the high oxygen arm of the trial went blind, that switching to low oxygen would have saved the baby’s eyesight, that the doctors knew this and that they were just doing the trial to have a nice publication in order to get famous.

So while I agree that I have a fiduciary obligation to provide optimal treatment, I also have a moral obligation to know what the optimal treatment is, and to know when more than one treatment is equally ‘optimal’, by which I mean equally supported by the current evidence.  I also, simultaneously, have a moral obligation as a researcher to keep trying to find out what the best treatments may be.

I also think that a non-physician investigator, for example Pr Annas, if he decided to do a clinical research project, also has a moral obligation to ensure that the patients in his study are receiving optimal treatment. No-one in a trial is simply a guinea-pig. No-one as a trial subject loses their rights as a person to receive good care. Comparative effectiveness research is a waste of time and money, and is indeed unethical, if we already know that one arm of the trial is optimal therapy and the other is not.

Posted in Neonatal Research | Tagged , , , | Leave a comment

“There is no foot too small that it cannot leave an imprint on this world”

Posted on 16 September 2013 by Keith Barrington

This link will take you to a very touching tribute written by a 16 year old to his little sister. It is a very personal essay, about his love for the girl who died at 6 weeks of age, but I have permission to link to it.

I love the phrase that they will put on her gravestone, which I have quoted as the title for this post.

I remember another child, a little one born with a muscle disease. We were never able to get him off respiratory support, every time we tried to stop his CPAP he would deteriorate, and eventually after 6 months in the NICU, he died.

My ‘traditional’, medical response was that the life had been of no value, the baby had never gone home, and never ‘contributed’. But, after his death the mother was so grateful that she had been able to spend time, cuddling and kissing her son, she thanked us for giving him those 6 months, those months when she could care for him, and love him. Six months that have no value when looked at from one direction, but are priceless from another.

That mother taught me a lot; she taught me that the value of a life is not measured in minutes, hours or days. It is not even measured in QALYs! Quality Adjusted Life Years are used in many calculations of such things as the cost-effectiveness of new medical interventions. A life of profound disability and short duration may have very few QALYs, but still have a big impact in this world.

Posted in Advocating for impaired children | Tagged | 1 Comment

Predicting outcomes, but not before birth

Posted on 13 September 2013 by Keith Barrington

One very important article that I failed to blog about last year when it came out is this one (Ambalavanan N, Carlo WA, Tyson JE, Langer JC, Walsh MC, Parikh NA, Das A, Van Meurs KP, Shankaran S, Stoll BJ et al: Outcome trajectories in extremely preterm infants. Pediatrics 2012.) It refers to an outcome prediction tool that can be applied after birth, that takes into account many different prognostic factors.

I think this is on the right lines. Prediction of outcomes before birth is so limited, so uncertain and so imprecise, except at the very extremes, that its value is limited. The only thing we can say with much certainty before birth is that if the baby survives their quality of life will be highly acceptable to them and their families, nearly 100% of the time.

So can we predict after birth, as time goes on, how a baby will turn out?

That is what this publication was all about. They took the data from the NRN of the NICHD (if you haven’t been into neonatology for long, that is the neonatal research network of the NIH institute for children) and constructed predictive models at 4 critical times. In the delivery Room, at 7 days, at 28 days of age and at 36 weeks post-menstrual age.  Those times were presumably chosen based on the structure of the NRN database.

At each time, by entering a number of different clinical factors you can calculate the probability that the baby will die, based on the relative impact of those individual factors, in previous babies in the database, on survival. Also a calculation of ‘neurodevelopmental impairment’, NDI, can be made and a combined likelihood of survival without ‘NDI’.

I think as far as predicting death is concerned, if the calculation gives a very high likelihood of death, then that might be an appropriate indication that it is time to mention the prognosis to the parents.

As for ‘NDI’, well I am going to get on my hobby-horse one more time (I am sure it won’t be the last):

A Bayley mental development index (MDI) at 18 to 22 months corrected age below 70 is not an impairment, and I wish the NRN would stop using this term. Most of the babies classified as ‘NDI’ are so classified because of a poor Bayley result. The majority of ex-preterm infants with a Bayley 2 are not cognitively impaired in the long term, as determined by IQ testing at early school age. The proportion of those with a Bayley (version 2) MDI <70 who are cognitively impaired, when tested later, varies between 20 and 33%. I think keeping parents informed about prognosis, and having on-going discussions with them is vitally important; but I really don’t know how to use the information about ‘NDI’, I think it would be a huge mistake to tell a parent that there is X risk of neurodevelopmental impairment, when much of that risk is due to developmental delay which will likely substantially improve with time.

There is an on-line calculator that you can use, but beware of the calculation of NDI, not only for the reasons I have given above, but also because it varies a lot in other populations. A publication from the Melbourne group in 2012 compared their results to what the previous NICHD calculator, (designed to be applied around birth and therefore only including sex, birth weight, steroids, multiple birth and gestation) came up with. The Melbourne groups results for mortality were similar but for developmental delay their figures were substantially lower. That may be in part because of the use of 24 month Bayleys by the Melbourne group, rather than 18 month score from the NICHD. The Melbourne group have already shown that there is an improvement in scores between 18 and 24 months (of around 4 points on average). As a result the 24 month scores are a bit more predictive of long term outcomes than the 18 month scores, but if you look at the graphs in that paper, you can see that they still are not very good as predictions. But most importantly, different populations, with different backgrounds may have differing long term outcomes, either because Australian babies are just much tougher, or for a whole host of other reasons.

Also to illustrate my point, in the Melbourne paper, at 24 months there were 4 babies who had ‘severe delay’ (which is an appropriate terminology) that is, a Bayley 2 MDI score below 50. Only one of these infants was severely impaired on IQ testing at 8 years. Even very, very low Bayley scores, and even at 24 months, are very poorly predictive of long-term impairments. We should be extremely careful about using outcome data based on early developmental testing for counseling or decision making.

I think we need confirmation and expansion of this kind of prognostic information, from other networks if possible, to refine the prognoses, especially for mortality, and if at all possible, for really important truly long term outcomes.

Posted in Neonatal Research | Tagged , | 1 Comment

HHS hearings, now available on-line

Posted on 12 September 2013 by Keith Barrington

As John Lantos pointed out in a comment response to a previous post on this issue, the public hearings of the HHS which was set up to address consent issues in research comparing standards of care are now available on line. The HHS has created a Youtube playlist that you can access here.

I think Michael Carome and Alice Dreger must be on the same drugs, at least they seem to be involved in a ‘folie-à-deux’. Carome repeats the same nonsense about the standard of care for 24 to 25 weekers, he claims that the standard of care for such infants was to intubate them all and give them all life-saving surfactant. He seems to be completely impervious to the truth; if he had bothered actually talking to one of us, he could easily have found out that the majority of forward looking NICUs were already trying to keep babies from being intubated, and that the COIN trial had already shown that that was a very reasonable idea. So don’t watch his presentation unless you have got your BP under control.

There are however, some excellent presentations, some from individuals in neonatology, some for other physicians, some from other ethicists.

Posted in Neonatal Research | Leave a comment

Neonatal Updates #36

Posted on 12 September 2013 by Keith Barrington

Shaw RJ, St John N, Lilo EA, Jo B, Benitz W, Stevenson DK, Horwitz SM: Prevention of traumatic stress in mothers with preterm infants: A randomized controlled trial. Pediatrics 2013. This looks really interesting, an RCT of a clinical psychologist led intervention to help mothers (what about the dads?!) cope with the stress of NICU and prevent depression. And it worked. There were fewer symptoms of trauma and less depression 4 to 5 weeks after birth for those parents who received the 6 sessions. Now I must admit that I don’t know what they actually did, it is described as ‘psychoeducation, cognitive restructuring, progressive muscle relaxation, and development of their trauma narrative. The intervention also incorporated material targeting infant redefinition’ (I only understand the relaxation bit). It was also apparently ‘highly manualized’ which I think just means all the stuff they were supposed to do was written down, in a manual. But, whatever they did, it worked in the short term, and if the benefits are prolonged then we all will have to get manualized.

Ganapathy V, Hay J, Kim J, Lee M, Rechtman D: Long term healthcare costs of infants who survived neonatal necrotizing enterocolitis: A retrospective longitudinal study among infants enrolled in texas medicaid. BMC Pediatrics 2013, 13(1):127. Two of the authors of this study are from Prolacta, but I must say, after being rude about one of their other studies, this looks quite reliable. Up to a year of age survivors of medical NEC have higher health care costs than controls and surgical NEC cases much more. Surgical cases continue to have higher costs out to 36 months.

Belsches TC, Tilly AE, Miller TR, Kambeyanda RH, Leadford A, Manasyan A, Chomba E, Ramani M, Ambalavanan N, Carlo WA: Randomized trial of plastic bags to prevent term neonatal hypothermia in a resource-poor setting. Pediatrics 2013. Full term babies in Zambia were put in plastic bags (don’t worry, just up to the armpits), in the first 10 minutes of life. They were less likely to be hypothermic at one hour, but that reduction was from 73% to 60%, so more needs to be done. Just in case you weren’t already aware, Dr Wally Carlo is one of my heroes, I don’t think he ever sleeps, but I am sure he doesn’t have time to write a blog!

McCarthy LK, Molloy EJ, Twomey AR, Murphy JFA, O’Donnell CPF: A randomized trial of exothermic mattresses for preterm newborns in polyethylene bags. Pediatrics 2013. If you aren’t in the field you may not realize that we already put preterm babies in plastic bags. For the same reason, to keep them warm. This trial from Dublin, which tends to be cooler than Zambia, but has the advantage of electricity, showed that you can keep preterm babies warm with plastic bags (and radiant heaters and incubators), and adding a special heat generating mattress doesn’t help, in fact it tends to overheat the little ones.

Posted in Neonatal Research | Leave a comment

Pluto, not just a planet anymore.

Posted on 11 September 2013 by Keith Barrington

Or should that be, not even a planet…

One other thing I wanted to mention about the PLUTO trial is the entry criterion. The main entry criterion was the presence of clear lower urinary tract obstruction in a male fetus, if ‘the clinician was uncertain as to the optimum management.’

Now I understand the reason for that, but in fact, as I have been mentioning in many of my previous posts about SUPPORT’ it is implicit in the ethical principles guiding all trials. If the clinician is certain as to the optimum management, and one arm of the trial requires withholding that optimal management, then it would be morally indefensible to enroll a patient in that trial. The problem with using that as the main entry criterion, without other severity of illness criteria, is that it then become very difficult to extrapolate the results to other populations.

It really reminds me of the INNOVO trial. For that trial of rescue inhaled NO therapy in the preterm infant the main entry criterion was that ‘Infants of <34 weeks’ gestation, aged <28 days, and with severe respiratory failure requiring ventilatory support (and having had surfactant when appropriate) were eligible for trial entry if the responsible clinician was uncertain about whether an infant might benefit from iNO.’

That is ethically entirely defensible, but, I don’t know the varieties of opinion among neonatologists in the UK, and who they might feel would definitely benefit, or definitely not benefit from iNO. I do know that they randomized a desperately sick group of babies: the average OI at baseline was 32, which for a premie is really, really bad; and the mortality was about 60% (it wasn’t affected by NO by the way), proving that an OI of 32 in a premie is really, really, bad.

So the quality of the trial was very high, but how do we determine the external applicability? I now know that a premie in my NICU who is very sick and for whom an average neonatologist in the UK would not be sure about whether iNO was indicated, would probably not benefit from iNO. I actually have lots of other data about rescue iNO in the preterm, but if this was the main source of data I would find it very hard to know how to apply these results.

Now perhaps you could say that I don’t know much about the non-enrolled subjects in other trials either, which is true, and is a good reason for trying to collect as much data as we are allowed to on non-enrolled eligible subjects; but that will be tough to do unless we have objective eligibility criteria, to know who could qualify to be a subject, and what happened to them if they were not enrolled. That is one of the great benefits of the CONSORT approach, and why we should insist of having all of the CONSORT flow diagram data in reports of RCTs.

I also don’t know, in the specific instance of the INNOVO trial, how a caregiver could possibly have been certain, before doing the trial, whether or not a baby would benefit from iNO. Before INNOVO there was little data, mostly from very small trials, and absolutely no certainty at all about the role of iNO in rescue treatment of sick preterm babies. That is why I think it is preferable in such a circumstance to say, ‘we do not know if any preterm baby with an OI over 15 despite surfactant benefits from iNO, they will therefore all be eligible for randomization’ but with the understanding that if there is some specific circumstance which makes iNO either clearly indicated or clearly contra-indicated, under such a circumstance it is inappropriate to randomize the baby, and we should seek consent to collect data.

Incidentally the PLUTO group are collecting a lot of information about interventions and outcomes of other mothers/fetal pairs with the diagnosis in the participating centers, which will help to make it clear how representative the PLUTO results are in comparison with non- randomized patients.

Posted in Neonatal Research | Tagged , , , | Leave a comment

Who was Bayes, and what did he know about medical research?

Posted on 11 September 2013 by Keith Barrington

I don’t have much detail to answer the first question: he was an 18th century English mathematician who wrote something about probability, that was published after he died. That publication described something called Bayes’ theorem which is a way of incorporating the prior probability of something happening with the evaluation of new data to arrive at an updated probability. (I think) (someone tell me if I am way off base….)

So if you can calculate the probability of something, then you take into account any new information that you find, and recalculate a new probability. In some ways this is how we operate all the time in daily life, but Bayes thought of new ways of doing the calculations.

Anyway, I have heard about incorporating Bayesian probability into clinical trial design for a while, but I don’t recall having seen many examples. The idea being that the usual way of doing a trial is to assume that the two arms of the trial have an equal probability of being preferable (which is sort of like the null hypothesis) then do the trial with a specified sample size, avoid looking at the data until the end of the trial (if possible, but with safeguards built-in, just in case) and then do a test of significance and declare that one arm of the trial was better, hence the benefit of treatment B is proven. A Bayesian trial explicitly incorporates prior probability into the design, encourages adaptive trial designs with flexible sample sizes, encourages repeated looks at the data as they are accumulating, and at the end produces a new posterior probability that treatment B is better than treatment A.

Which all sounds interesting, and I know there are examples of it actually being done, but I wasn’t aware of any perinatal trials.

Here though is a trial of antenatal intervention for urinary tract obstruction called the PLUTO trial. It was a multicenter RCT with a planned sample size of 150 women and their fetuses. After several years they were only able to randomize 31 mothers, so they had to stop the trial, as they probably ran out of both money and patience. Now as far as I can tell the trial team did not put anything about Bayesian analysis into the registration documents, nor the published protocol, but, given that the sample size was so small and the results therefore rather negative, they proceeded with an analysis using Bayes’ methods. They used some estimates of what they thought, before the trial, was the probability that antenatal shunting would be the better treatment, and then calculated the new probability that shunting is better by adding in the new data.

So what did they find in the trial? Seven of the 16 babies randomized to be shunted survived to one year of age; and 3 of the 15 randomized to be treated conservatively, with evaluation and treatment after birth, survived.

That shows what a bad condition this is, the fetuses were eligible in cases of visualisation of an enlarged bladder and dilated proximal urethra, bilateral or unilateral hydronephrosis, and cystic parenchymal renal disease, if the obstetrician was unsure of the best clinical management.

The CONSORT diagram below shows you how horrendously complicated it is to do and then analyze a trial like this.

pluto

So of the 16 allocated to shunting, 3 were not shunted, and 1 changed their mind and decided to terminate the pregnancy, and there were 3 treatment related pregnancy losses. Some of those allocated to conservative treatment got shunted anyway, and some others terminated. So how do you decide whether shunting was better or not? I know the ‘correct answer’ is an ITT analysis, you just calculate according to the numbers randomized into each group. But I think there is a good case to be made here for, at least, taking out of the analysis the non-procedure related terminations, which gives you 7/15 vs 3/13 survivors to 2 years. I think an analysis by procedure actually performed is interesting also, but you always have to be very careful, as you don’t know why the protocol violations occurred, it may because of clinical factors that might also influence prognosis. Anyway the ‘as-treated’ analysis shows 8/14 survivors who were shunted vs 2/14 conservative.

This is suggestive that maybe the shunting really did help, but it is clearly still a maybe.

The reasons for going into so much detail of this trial (apart from the fact that it is a trial that we really needed, and it is a great shame that they were unable to get a bigger sample) is that the authors then incorporate a Bayesian analysis, they determine a prior probability that shunting would be better, then add in the new results, and then calculate a new probability that shunting really improves survival. They calculate the prior probability as being 0.79 that shunting is preferable, and with the new trial data they state that the posterior probability is now 0.86.

So this is a Bayesian analysis of results a trial that was planned as a more conventional trial to determine superiority. My major problem with the analysis in this trial is that the prior probability is based on asking ‘experts’ what they thought. I think that even prior probabilities should be based on some sort of data, now having said that the prior observational data were actually more positive than the experts’ opinions, which just shows you how careful you have to be about observational data, it can be seriously biased.

Trials actually planned using Bayesian methods are also interesting. I know little about this, so I was pleased to find this document, it is a document reproducing what was taught to participants in a workshop on clinical research methods. It is a great introduction to what clinical research is all about, and there is quite a long and detailed section about Bayesian trial design.

I have been wondering about trials like the future lactoferrin trials, for example, if we try to calculate the likelihood that lactoferrin will prove to be very potent at preventing nosocomial infections (for which we actually have some hard data), and incorporate that into trial design, perhaps we can reduce the required sample size for future trials, and get an answer sooner.

By the way all the articles about Bayes use the same image, which probably isn’t him!

Posted in Neonatal Research | Tagged , | Leave a comment

10 Things Having A Preemie Has Taught Me About Life

Posted on 9 September 2013 by Keith Barrington

One of the ‘parent of premie’ blogs that I read is ‘Cheering on Charlie’ from a parent of a 26 weeker who is now a beautiful little girl of about 16 months (just about 1 yr old corrected!).

I really appreciated one of her recent posts, so I thought I would send out a link:

10 Things Having A Preemie Has Taught Me About Life.

Her honesty and insights are refreshing.

Posted in Neonatal Research | Leave a comment