Rita Faria’s journal round-up for 2nd September 2019

Every Monday our authors provide a round-up of some of the most recently published peer reviewed articles from the field. We don’t cover everything, or even what’s most important – just a few papers that have interested the author. Visit our Resources page for links to more journals or follow the HealthEconBot. If you’d like to write one of our weekly journal round-ups, get in touch.

RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ [PubMed] Published 28th August 2019

RCTs are the gold standard primary study to estimate the effect of treatments but are often far from perfect. The question is the extent to which their flaws make a difference to the results. Well, RoB 2 is your new best friend to help answer this question.

Developed by a star-studded team, the RoB 2 is the update to the original risk of bias tool by the Cochrane Collaboration. Bias is assessed by outcome, rather than for the whole RCT. For me, this makes sense.  For example, the primary outcome may be well reported, yet the secondary outcome, which may be the outcome of interest for a cost-effectiveness model, much less so.

Bias is considered in terms of 5 domains, with the overall risk of bias usually corresponding to the worst risk of bias in any of the domains. This overall risk of bias is then reflected in the evidence synthesis, with, for example, a stratified meta-analysis.

The paper is a great read! Jonathan Sterne and colleagues explain the reasons for the update and the process that was followed. Clearly, there was quite a lot of thought given to the types of bias and to develop questions to help reviewers assess it. The only downside is that it may require more time to apply, given that it needs to be done by outcome. Still, I think that’s a price worth paying for more reliable results. Looking forward to seeing it in use!

Characteristics and methods of incorporating randomised and nonrandomised evidence in network meta-analyses: a scoping review. Journal of Clinical Epidemiology [PubMed] Published 3rd May 2019

In keeping with the evidence synthesis theme, this paper by Kathryn Zhang and colleagues reviews how the applied literature has been combining randomised and non-randomised evidence. The headline findings are that combining these two types of study designs is rare and, when it does happen, naïve pooling is the most common method.

I imagine that the limited use of non-randomised evidence is due to its risk of bias. After all, it is difficult to ensure that the measure of association from a non-randomised study is an estimate of a causal effect. Hence, it is worrying that the majority of network meta-analyses that did combine non-randomised studies did so with naïve pooling.

This scoping review may kick start some discussions in the evidence synthesis world. When should we combine randomised and non-randomised evidence? How best to do so? And how to make sure that the right methods are used in practice? As a cost-effectiveness modeller, with limited knowledge of evidence synthesis, I’ve grappled with these questions myself. Do get in touch if you have any thoughts.

A cost-effectiveness analysis of shortened direct-acting antiviral treatment in genotype 1 noncirrhotic treatment-naive patients with chronic hepatitis C virus. Value in Health [PubMed] Published 17th May 2019

Rarely we see a cost-effectiveness paper where the proposed intervention is less costly and less effective, that is, in the controversial southwest quadrant. This exceptional paper by Christopher Fawsitt and colleagues is a welcome exception!

Christopher and colleagues looked at the cost-effectiveness of shorter treatment durations for chronic hepatitis C. Compared with the standard duration, the shorter treatment is not as effective, hence results in fewer QALYs. But it is much cheaper to treat patients over a shorter duration and re-treat those patients who were not cured, rather than treat everyone with the standard duration. Hence, for the base-case and for most scenarios, the shorter treatment is cost-effective.

I’m sure that labelling a less effective and less costly option as cost-effective may have been controversial in some quarters. Some may argue that it is unethical to offer a worse treatment than the standard even if it saves a lot of money. In my view, it is no different from funding better and more costlier treatments, given that the savings will be borne by other patients who will necessarily have access to fewer resources.

The paper is beautifully written and is another example of an outstanding cost-effectiveness analysis with important implications for policy and practice. The extensive sensitivity analysis should provide reassurance to the sceptics. And the discussion is clever in arguing for the value of a shorter duration in resource-constrained settings and for hard to reach populations. A must read!

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Rita Faria’s journal round-up for 24th September 2018

Every Monday our authors provide a round-up of some of the most recently published peer reviewed articles from the field. We don’t cover everything, or even what’s most important – just a few papers that have interested the author. Visit our Resources page for links to more journals or follow the HealthEconBot. If you’d like to write one of our weekly journal round-ups, get in touch.

Methodological issues in assessing the economic value of next-generation sequencing tests: many challenges and not enough solutions. Value in Health [PubMed] Published 8th August 2018

This month’s issue of Value in Health includes a themed section on assessing the value of next-generation sequencing. Next-generation sequencing is sometimes hailed as the holy grail in medicine. The promise is that our individual genome can indicate how at-risk we are for many diseases. The question is whether the information obtained by these tests is worth their costs and potentially harmful consequences on well-being and health-related quality of life. This largely remains unexplored, so I expect seeing more economic evaluations of next-generation sequencing in the future.

This paper has caught my eye given an ongoing project on cascade testing protocols for familial hypercholesterolaemia. Next-generation sequencing can be used to identify the genetic cause of familial hypercholesterolaemia, thereby identifying patients suitable to have their relatives tested for the disease. I read this paper with the hope of finding inspiration for our economic evaluation.

This thought-provoking paper discusses the challenges in conducting economic evaluations of next-generation sequencing, such as complex model structure, inclusion of upstream and downstream costs, identifying comparators, identifying costs and outcomes that are related to the test, measuring costs and outcomes, evidence synthesis, data availability and quality.

I agree with the authors that these are important challenges, and it was useful to see them explained in a systematic way. Another valuable feature of this paper is the summary of applied studies which have encountered these challenges and their approaches to overcome them. It’s encouraging to read about how other studies have dealt with complex decision problems!

I’d argue that the challenges are applicable to economic evaluations of many other interventions. For example, identifying the relevant comparators can be a challenge in the evaluations of treatments: in an evaluation of hepatitis C drugs, we compared 633 treatment sequences in 14 subgroups. I view the challenges as the issues to think about when planning an economic evaluation of any intervention: what the comparators are, the scope of the evaluation, the model conceptualisation, data sources and their statistical analysis. Therefore, I’d recommend this paper as an addition to your library about the conceptualisation of economic evaluations.

Compliance with requirement to report results on the EU Clinical Trials Register: cohort study and web resource. BMJ [PubMed] Published 12th September 2018

You may be puzzled at the choice of the latest Ben Goldacre and colleagues’ paper, as it does not include an economic component. This study investigates compliance with the European Commission’s requirements that all trials on the EU Clinical Trials Register post results to the registry within 12 months of completion. At first sight, the economic implications may not be obvious, but they do exist and are quite important.

Clinical trials are a large investment of resources, not only financial but also in the health of patients who accept to take part in an experiment that may impact their health adversely. Therefore, clinical trials can have a huge sunk cost in both money and health. The payoff only realises if the trial is reported. If the trial is not reported, the benefits from the investment cannot be realised. In sum, an unreported trial is clearly a cost-ineffective use of resources.

The solution is simple: ensure that trial results are reported. This way we can all benefit from the information collected by the trial. The issue is, as Goldacre and colleagues have revealed, compliance is far from perfect.

Remarkably, around half of the 7,274 studies are due to publish results. The worst offenders are non-commercial sponsors, where only 11% of trials had their results reported (compared with 68% of trials by a commercial sponsor).

The authors provide a web tool to look up unreported trials by institution. I looked up my very own University of York. It was reassuring to know that my institution has no trials due to report results. Nonetheless, many others are less compliant.

This is an exciting study on the world of clinical trials. I’d suggest that a possible next step would be to estimate the health lost and costs from failing to report trial results.

Network meta-analysis of diagnostic test accuracy studies identifies and ranks the optimal diagnostic tests and thresholds for health care policy and decision-making. Journal of Clinical Epidemiology [PubMed] Published 13th March 2018

Diagnostic tests are an emerging area of methodological development. This timely paper by Rhiannon Owen and colleagues addresses the important topic of evidence synthesis of diagnostic test accuracy studies.

Diagnostic test studies cannot be meta-analysed with the standard techniques used for treatment effectiveness. This is because there are two quantities of interest (sensitivity and specificity), which are correlated, and vary depending on the test threshold (that is, the value at which we say the test result is positive or negative).

Owen and colleagues propose a new approach to synthesising diagnostic test accuracy studies using network meta-analysis methodology. This innovative method allows for comparing multiple tests, evaluated at various test threshold values.

I cannot comment on the method itself as evidence synthesis is not my area of expertise. My interest comes from my experience in the economic evaluation of diagnostic tests, where we often wish to combine evidence from various studies.

With this in mind, I recommend having a look at the NIHR Complex Reviews Support Unit website for more handy tools and the latest research on methods for evidence synthesis. For example, the CRSU has a web tool for meta-analysis of diagnostic tests and a web tool to conduct network meta-analysis for those of us who are not evidence synthesis experts. Providing web tools is a brilliant way of helping analysts using these methods so, hopefully, we’ll see greater use of evidence synthesis in the future.

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Hawking is right, Jeremy Hunt does egregiously cherry pick the evidence

I’m beginning to think Jeremy Hunt doesn’t actually care what the evidence says on the weekend effect. Last week, renowned physicist Stephen Hawking criticized Hunt for ‘cherry picking’ evidence with regard to the ‘weekend effect’: that patients admitted at the weekend are observed to be more likely than their counterparts admitted on a weekday to die. Hunt responded by doubling down on his claims:

Some people have questioned Hawking’s credentials to speak on the topic beyond being a user of the NHS. But it has taken a respected public figure to speak out to elicit a response from the Secretary of State for Health, and that should be welcomed. It remains the case though that a multitude of experts do continue to be ignored. Even the oft-quoted Freemantle paper is partially ignored where it notes of the ‘excess’ weekend deaths, “to assume that [these deaths] are avoidable would be rash and misleading.”

We produced a simple tool to demonstrate how weekend effect studies might estimate an increased risk of mortality associated with weekend admissions even in the case of no difference in care quality. However, the causal model underlying these arguments is not always obvious. So here it is:

A simple model of the effect of the weekend on patient health outcomes. The dashed line represents unobserved effects

So what do we know about the weekend effect?

1. The weekend effect exists. A multitude of studies have observed that patients admitted at the weekend are more likely to die than those admitted on a weekday. This amounts to having shown that $E(Y|W,S) \neq E(Y|W',S)$. As our causal model demonstrates, being admitted is correlated with health and, importantly, the day of the week. So, this is not the same as saying that risk of adverse clinical outcomes differs by day of the week if you take into account propensity for admission, we can’t say $E(Y|W) \neq E(Y|W')$. Nor does this evidence imply care quality differs at the weekend, $E(Q|W) \neq E(Q|W')$. In fact, the evidence only implies differences in care quality if the propensity to be admitted is independent of (unobserved) health status, i.e. $Pr(S|U,X) = Pr(S|X)$ (or if health outcomes are uncorrelated with health status, which is definitely not the case!).
2. Admissions are different at the weekend. Fewer patients are admitted at the weekend and those that are admitted are on average more severely unwell. Evidence suggests that the better patient severity is controlled for, the smaller the estimated weekend effect. Weekend effect estimates also diminish in models that account for the selection mechanism.
3. There is some evidence that care quality may be worse at the weekend (at least in the United States). So $E(Q|W) \neq E(Q|W')$. Although this has not been established in the UK (we’re currently investigating it!)
4. Staffing levels, particularly specialist to patient ratios, are different at the weekend, $E(X|W) \neq E(X|W')$.
5. There is little evidence to suggest how staffing levels and care quality are related. While the relationship seems evident prima facie, its extent is not well understood, for example, we might expect a diminishing return to increased staffing levels.
6. There is a reasonable amount of evidence on the impact of care quality (preventable errors and adverse events) on patient health outcomes.

But what are we actually interested in from a policy perspective? Do we actually care that it is the weekend per se? I would say no, we care that there is potentially a lapse in care quality. So, it’s a two part question: (i) how does care quality (and hence avoidable patient harm) differ at the weekend $E(Q|W) - E(Q|W') = ?$; and (ii) what effect does this have on patient outcomes $E(Y|Q)=?$. The first question answers to what extent policy may affect change and the second gives us a way of valuing that change and yet the vast majority of studies in the area address neither. Despite there being a number of publicly funded research projects looking at these questions right now, it’s the studies that are not useful for policy that keep being quoted by those with the power to make change.

Hawking is right, Jeremy Hunt has egregiously cherry picked and misrepresented the evidence, as has been pointed out again and again and again and again and … One begins to wonder if there isn’t some motive other than ensuring long run efficiency and equity in the health service.

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