Category Archives: Director & Co-Directors’ Blog

Mandatory Publication and Reporting of Research Findings

Publication bias refers to a phenomenon by which research findings that are statistically significant or perceived to be interesting/desirable are more likely to be published, and vice versa.[1] The bias is a major threat to scientific integrity and can have major implications for patient welfare and resource allocation. Progress has been made over the years in raising awareness and minimising the occurrence of such bias in clinical research: pre-registration of trials has been made compulsory by editors of leading medical journals [2] and subsequently regulatory agencies. Evidence of a positive impact on the registration and reporting of findings from trials used to support drug licensing has started to emerge.[3,4] So can this issue be consigned to history now? Unfortunately the clear answer is no.

A recent systematic review showed that, despite a gradual improvement in the past two decades, the mean proportion of pre-registration among randomised controlled trials (RCTs) included in previous meta-epidemiological studies of trial registration only increased from 25% to 52% between 2005 to 2015.[5] A group of researchers led by Dr Ben Goldacre created the EU Trials Tracker (https://eu.trialstracker.net/), which utilises automation to facilitate the identification of trials that are due to report their findings but have not done so within the European Union Clinical Trials Register.[6] Their estimates show a similar picture that half of the trials that were completed have not reported their results. The findings of the Trial Tracker are presented in a league table that allows people to see which sponsors have the highest rate of unreported trials. You might suspect that pharmaceutical companies are likely to be the top offenders given the high profile cases of supressing drug trial data in the past. In fact the opposite is now true – major pharmaceutical companies are among the best compliers of trial reporting, whereas some of the universities and hospitals seem to have achieved fairly low reporting rates. While there may be practical issues and legitimate reasons behind the absence/delay in the report of findings for some of the studies, the bottom line is that making research findings available is a moral duty for researchers irrespective of funding sources, and with improved trial registration and enhanced power of data science, leaving research findings to perish and be forgotten in a file drawer/folder is neither an acceptable nor a feasible option.

With slow but steady progress in tackling publication bias in clinical research, you might wonder about health services research that is close to heart for our CLAHRC. Literature on publication bias in this field is scant, but we have been funded by the NIHR HS & DR Programme to explore the issue in the past two years and some interesting findings are emerging. Interested readers can access further details, including conference posters reporting our early findings, on our project website (warwick.ac.uk/publicationbias). We will share further results with News Blog readers in the near future, and in due course, publish them all!

— Yen-Fu Chen, Associate Professor

References:

  1. Song F, Parekh S, Hooper L, et al. Dissemination and publication of research findings: an updated review of related biases. Health Technol Assess. 2010;14(8):1-193.
  2. Laine C, De Angelis C, Delamothe T, et al. Clinical trial registration: looking back and moving aheadAnn Intern Med. 2007;147(4):275-7.
  3. Zou CX, Becker JE, Phillips AT, et al. Registration, results reporting, and publication bias of clinical trials supporting FDA approval of neuropsychiatric drugs before and after FDAAA: a retrospective cohort study. Trials. 2018;19(1):581.
  4. Phillips AT, Desai NR, Krumholz HM, Zou CX, Miller JE, Ross JS. Association of the FDA Amendment Act with trial registration, publication, and outcome reporting. Trials. 2017;18(1):333.
  5. Trinquart L, Dunn AG, Bourgeois FT. Registration of published randomized trials: a systematic review and meta-analysis. BMC Medicine. 2018;16(1):173.
  6. Goldacre B, DeVito NJ, Heneghan C, et al. Compliance with requirement to report results on the EU Clinical Trials Register: cohort study and web resource. BMJ. 2018;362:k3218.
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Happiness and Wealth: Strange Attractors

The latest Gallup data on happiness scales across the world have recently been published and summarised in an economist graphic.[1] The Gallop study is the largest to date on tracking happiness across the world. The study is based on random samples taken from 120 countries. What do the data show?

First, there is a correlation between per capita GDP and mean national happiness. Second, there are very large differences in happiness across different countries: Tanzania has a mean score of three, while in the Netherlands the mean score is over seven, on a ten-point scale. Third, the correlation between mean wealth and mean happiness is moderate, with large variation around the regression line. Fourth, the changes in happiness following an increase in GDP in a particular country are variable; in about 2/3 of cases the correlation is positive, and negative in about one-third. For example, India has become a lot less happy as it has become richer, while China, which has become much richer, has also become a little happier. Fifth, it is hard to separate the conditions leading to economic change from the economic change itself. For example, happiness has plummeted in Venezuela and Greece where wealth has declined. However, in Brazil and Vietnam happiness has declined as wealth has grown.

Of course, happiness is only half of the story. Life satisfaction and happiness are different constructs and are only loosely correlated.

Aggregation at the country level cannot tell us about variation and its possible causes at a local level. We are currently studying happiness and satisfaction across slums in four countries. The preliminary results are very interesting. Our hypothesis is that health, wealth and satisfaction vary more widely among slum dwellers than among other groups. We speculate that while urbanisation has always been the route out of poverty, it nevertheless creates winners and losers. We speculate further that the balance of winners and losers can be influenced by relatively small shifts in public policy. Watch this space!

— Richard Lilford, CLAHRC WM Director

Reference:

  1. The Economist. Economic growth does not guarantee rising happiness. The Economist. 21 March 2019.

Step Wedge Cluster Designs: Research or Implementation

Our CLAHRC group is arguably pre-eminent internationally on the step-wedge cluster design. As a research design it has its strengths and weaknesses. The statistical strengths of this design relate to high precision (thanks to the fact that all clusters act as intervention and control) and the ability (given sufficient sample size) to track intervention effect sizes over time. The weakness of the classical step wedge design lies in the need to make a statistical adjustment for any secular trend – something that is not necessary in a “standard” parallel cluster trial.[1] Of course, the design can also have ethical and logistic advantages.[2] It is on the latter, logistic, advantages of the design that this article is focussed. In a nutshell, I argue that the step wedge design is best thought of as both a research and as a practical management or implementation tool.

The argument starts with two widely accepted principles:

  1. It is frequently necessary to roll out a service intervention in sequence over a geographical area or service – it cannot be implemented simultaneously in every part of the service for logistic and cost reasons.
  2. It is important to evaluate an intervention as it is implemented, notwithstanding a favourable result in preceding studies. This is because service results are not fixed, but vary by context. For example, women’s groups are usually successful in improving maternity care,[3] but not always and not everywhere.[4]

So if the intervention has to be rolled out over time, and if an evaluation is intrinsic to implementation, then a lottery is a fair way to determine the order of implementation. In other words, we end up with a step wedge cluster trial.

But this will add expense and make adoption less likely, do I hear you say? To be clear – I am not asking that a step wedge cluster implementation evaluation should replicate a typical grant-funded study with collection of end-points bespoke for study purposes. In fact, I am not arguing for collection of any more data than would be collected absent the step-wedge implementation evaluation. If, absent the step wedge, only process information would have been collected, then given the step wedge only process information need be collected. If, absent a step-wedge only routine data would be collected, then given a step wedge only routine data need be collected. Implementors must decide what information collection they need or can justify. I am simply saying that the value of this information will be enhanced if it is part of a step-wedge implementation evaluation. The words ‘study’ and ‘research’ can get in the way – for a start, simply using the word ‘research’ creates a set of specific ethical and procedural requirements that may be difficult to meet given service time tables.[5] Currently there is a massive gap between research and routine data collection and practice. Let’s not let the ideal be the enemy of the goal.

— Richard Lilford, CLAHRC WM Director

References:

  1. Hemming K, Haines TP, Chilton PJ, Girling AJ, Lilford RJ. The stepped wedge cluster randomised trial: rationale, design, analysis, and reporting. BMJ. 2015; 350: h391.
  2. Brown CA & Lilford RJ. The stepped wedge trial design: a systematic review. BMC Med Res Methodol. 2006; 6: 54.
  3. Prost A, Colbourn T, Seward N, et al. Women’s groups practising participatory learning and action to improve maternal and newborn health in resource-limited settings: systematic review and meta-analysis. Lancet. 2013; 381(9879): 1736-46.
  4. Mbuagbaw L, Medley N, Darzi AJ, Richardson M, Habiba Garga K, Ongolo-Zogo P. Health system and community level interventions for improving antenatal care coverage and health outcomes. Cochrane Database Syst Rev. 2015; 12: CD010994.
  5. Watson S, Lilford RJ, Dixon-Woods M, et al. Revising ethical guidance for the evaluation of programmes and interventions not initiated by researchers. [Submitted].

The Mortality Gradient

A young man was admitted to a hospital in North KwaZulu-Natal (a province of South Africa) with a stab wound in the upper left quadrant of the abdomen and a falling blood pressure. Only a skeleton staff was on duty, thanks to a public sector strike taking place at the time. Further, only one member of the team was medically qualified, and she was assisted by two medical students on their elective periods. The doctor anaesthetised and intubated the patient, scrubbed, and then started to open the abdomen. A number of things then happened in rapid succession: the blood was found to have turned a blue colour, the oximetry alarm sounded, and the heart stopped. The doctor opened the chest to give internal cardiac compression but to no avail. On opening the chest the problem was identified. Firstly, the knife had penetrated the diaphragm to enter the left lung; a frequent finding with stab wounds to the upper left abdomen. Secondly, the left main bronchus (windpipe) had been intubated. The result was that only the left lung had been ventilated and air had been forced under pressure into the cavity around the lung. This air, forced into the plural space under pressure, had compressed the chest contents, causing the patient’s oxygen levels to plummet.

Mortality rates from surgery for a given condition are roughly twice as high in low- and middle-income countries (LMICs) as in high-income countries. Why is this?

A very large number of recent studies [1-4] have replicated Aneel Bhangu’s classic study in the British Journal of Surgery,[5] confirming the mortality gradient. That the gradient exists is not in real doubt but its causes are. Possible, non exclusive, causes are:

  1. The patient arrives in worse condition in LMICs than in high-income countries because they are in worse shape generally, and/or there were large delays in reaching the health care system.
  2. Care is worse before surgery, including longer delays within the health care system, and/or post operative care was suboptimal.
  3. Intraoperative care was worse, either in terms of anaesthesia (as in the above example – intubation of the left bronchus is a classic error requiring special vigilance in cases where there is a risk that the integrity of the lung has been compromised), and/or surgery itself.

A fashion has broken out to compare death rates for given conditions across high- and low-income countries, and then ascribe observed differences in outcome to differences in healthcare provision, expressed in terms of lives (or even DALYs) lost. Such an approach can work well at the specific level when two conditions are met:

  1. A specific condition is examined and this condition has a poor natural history, but an extremely good prognosis given appropriate medical care. Perinatal haemorrhage and eclampsia are good examples.
  2. The way in which healthcare can remedy the situation is well defined. Treatment of ruptured spleen or meningitis are good examples.

Absent conditions fulfilling the above criteria, comparisons between high- and low-income countries should motivate serious investigation for causes. Until the cause of the difference is determined, advocacy based only on differences between high- and low-income countries is without intellectual or moral value. Decisions should be based on the best use of restricted resources and simply pointing out north-south differences in outcomes adds no value to determining priorities within LMICs. It is wasteful to advocate resource allocation under scarcity until the payback among different competing causes has been examined. The correct use of measuring differences in outcome over countries should not be to advocate for resources for action. These differences in outcome should motivate a sober search for these causes, and then for cost-effective short- and long-term solutions.

To that end I am leading a cross NIHR initiative into one particular candidate area – access to hospital when care is sought. I also lead the access theme for the NIHR Global Health Research Unit on Global Surgery. One of our tasks is to model the cost-effectiveness of various solutions to overcome the second barrier to access identified above. Our work is hampered by poor data (poor because it is hard to collect) on effects of delay on outcome. Strangely enough, snakebites is the one area where rather good data exist, so we are starting our work in this, otherwise rather narrow, topic. We also plan to study survival rates in UK by measuring distances from local hospitals in conditions such as leaking aortic aneurysms and heart attack.

In the meantime Dr Bruce Biccard of Cape Town, who leads the hospital care work stream in Global Surgery, is turning his attention from differences in outcome to the causes and remedies.

— Richard Lilford, CLAHRC WM Director

References:

  1. Abbott TEF, Fowler AJ, Dobbs TD, Harrison EM, Gillies MA, Pearse RM. Frequency of surgical treatment and related hospital procedures in the UK: a national ecological study using hospital episode statistics. Br J Anaesthesia. 2017; 119(2): 249-57.
  2. Anderson GA, Ilcisin L, Abesiga L, et al. Surgical volume and postoperative mortality rate at a referral hospital in Western Uganda: Measuring the Lancet Commission on Global Surgery indicators in low-resource settings. Surgery. 2017; 161(6): 1710-9.
  3. GlobalSurg Collaborative. Management and Outcomes Following Surgery for Gastrointestinal Typhoid: An International, Prospective, Multicentre Cohort Study. World J Surg. 2018; 42(10): 3179-88.
  4. Biccard BM, Madiba TE, Kluyts H-L. Perioperative patient outcomes in the African Surgical Outcomes Study: a 7-day prospective observational cohort study. Lancet. 2018; 391: 1589-98.
  5. GlobalSurg Collaborative. Mortality of emergency abdominal surgery in high-, middle- and low-income countries. Br J Surg. 2016; 103(8): 971-88.

Traditional Healers

We have written before about the role of traditional healers in mental health.[1][2] Our ideas are gradually crystallising around a potential programme of research. What do we need to know?

First, there is an enigma to solve. Our recent multi-country study showed that a very small proportion of people in low- and middle-income countries (LMICs) consult traditional healers.[3] Emerging results from our slum health project are corroborating this finding. Yet we are not believed and ‘social acceptability’ bias is offered as the explanation for our findings. We think this is unlikely because the people collecting information have little or no cultural distance from their interviewees. So we have an alternative hypothesis. We speculate that ‘health needs’ are described differently in different societies (and in the same society at different times). Whereas ‘mental health’ issues are conceptualised as ‘health needs’ in high-income countries, in many LMICs they are conceptualised differently – existential angst, worries over ancestral anger, or some such. We propose a study based on in-depth interviews with allopathic and non-allopathic practitioners, and members of the public to explore this idea.

Second, traditional healers may have a valuable role to play. First, the care they deliver is likely to meet the cultural expectations of their clients. Second, there is a well-documented gap in provision of allopathic services that traditional healers might fill. However, different mental illnesses require different approaches. Services therefore need to be integrated so that people with severe mental illness can be channelled to medical services where they can be prescribed chemotherapy, at least to induce remission. We would therefore propose pilot studios of educational (in both directions) interventions between allopathic mental health practitioners and traditional healers. Such experiments are not, of course, novel – a point to which we return. So we think that a survey of willingness of traditional healers to work with allopathic providers is important. This would build on previous work on this topic, and would also take views of clients into account. Arguably this study needs a broader base of interviewers than the first study proposed above.

Lastly, as argued previously in this News Blog,[1] there may be a lethal flaw in all of the above ideas. The two types of practitioner come from completely different epistemic traditions. Previous attempts to integrate services have risked allopathic practitioners becoming implicit in what would be regarded as unethical, even cruel, procedures.[4] However, we do not think this obstacle, real as it is, should be too hastily judged as insuperable. So again we propose in-depth discussions between practitioners of different types, patient groups, and policy-makers. These could be a precursor of pilot studies, perhaps better informed than previous attempts.

Before any of the above can happen, we propose a thorough literature review and informal discussions with people who have attempted something similar to this before.

— Richard Lilford, CLAHRC WM Director

References:

  1. Lilford RJ. Traditional Healers and Mental Health. NIHR CLAHRC West Midlands News Blog. 12 January 2018.
  2. Lilford RJ, Chilton PJ, Oyebode O. So It Is Not True What They Say – Traditional Healers are Not as Widely Used After All. NIHR CLAHRC West Midlands News Blog. 31 October 2014.
  3. Oyebode O, Kandala N-B, Chilton PJ, Lilford RJ. Use of traditional medicine in middle-income countries: a WHO-SAGE study. Health Policy Plann. 2016; 31(8): 984-91.
  4. Lilford RJ. Modern Chemotherapy for Severe Mental Disorders in a Prayer Camp. NIHR CLAHRC West Midlands News Blog. 9 February 2018.

Engaging with Engagement

Engagement is easy. We are in a fortunate position in CLAHRC West Midlands that there is seemingly a long queue of people keen to talk to us about interesting and exciting health and social care projects. However, there is little point in engagement for engagement’s sake: our resources are too scarce to invest in projects or relationships with little or no return, and so meaningful engagement is much harder.

In putting together our application for hosting an Applied Research Collaboration we were faced with our perennial challenge of who to engage with and how. To do so we began to map our networks (see figure) and quickly realised even the number of NHS organisations (71) was too broad for us to work across in depth, never mind the wide range of academic, social care, voluntary sector and industry partners in the wider landscape beyond.

Our approach has been to work with partners who are keen to work with us; we make no apology for being a coalition of the willing. However, we have worked purposefully to ensure reach across all sectors, actively seeking out collaborators with whom we have had more limited interactions with, but who we know can help deliver the reach we require for research and implementation. For instance, we have one of the best performing and most forward thinking ambulance services in the country, with paramedics working at the very interface between physical and mental health, social care and emergency medicine. Given that we know some of these problems are best addressed upstream, the ambulance service gives us the opportunity to head closer to where the river rises than ever before.

119 GB - Figure 1

[1] Based in 2013/14 figures from RAWM
[2] Department of Business Enterprise Innovation and Skills, Business Population Estimates

In addition to this, we seek to use overarching bodies to help reach across spaces which are too diffuse and fragmented to allow us to access (such as the voluntary, charitable and third sectors). Even using these we will have to be selective from the 21 which exist when we seek to engage with voluntary groups (for example around priority setting, Public and Community Involvement Engagement and Participation, or co-production). Elsewhere, we utilise networks of networks, for example collaborating with the Membership Innovation Councils of the West Midlands Academic Health Science Network which draw in representatives from a wide cross section of organisations and professions who can then transmit our message to their respective organisations and local networks. Our experience tells us these vicarious contacts can often deliver some of the most useful engagement opportunities.

Finally, we have always been committed within CLAHRC to cross-site working and having our researchers and staff embedded as much as possible within healthcare organisations. This is in part to ensure our research remains grounded within the ‘real world’ of service delivery, rather than the dreaming spires (or concrete and glass tower blocks) of academia. However, we know that regardless of how well you plan and construct your network, some of the best ideas come about through chance encounters and corridor conversations. Nobel prize-winning economist Elinor Ostrom, much beloved by the CLAHRC WM team, elegantly described the value of ‘cheap talk’ in relation to collectively owned resources.[3] The visibility of our team can often prompt a brief exchange to rule in or out an idea for CLAHRC where a formal contact or approach might not have been made, making our ‘cheap talk’ meaningful through its context. Perhaps this is how we should see ourselves in CLAHRC West Midlands; as a finite but shared resource to the health and social care organisations within our region.

— Paul Bird, Head of Programmes (engagement)

References:

  1. RAWM. The West Midlands Voluntary and Community Sector. 2015.
  2. Rhodes C. Business Statistics. Briefing Paper No. 06152. 2018.
  3. Ostrom E. Beyond Markets and States: Polycentric Governance of Complex Economic Systems. Am Econ Rev. 2010; 100(3): 641-72.

Demand-Led Research: A Taxonomy

We have previously discussed research where a service manager decides that an intervention should be studied prospectively. We have made the point that applied research centres, such as CLAHRCs/ARCs, should be responsive to requests for such prospective evaluation. Indeed, the request or suggestion from a service manager to evaluate their intervention provides a rich opportunity for scientific discovery since the intervention is a charge to the service not to the research funder. In some cases many of the outcomes of interest may be collected from routine data systems. In such circumstances the research can be carried out at a fraction of the usual cost for prospective evaluations. Nor should it be assumed that research quality must suffer. We give two examples below where randomised designs were possible, one where individual staff members were randomised to different methods to encourage uptake of seasonal influenza vaccine and the other where a step wedge cluster design was used to evaluate roll out of a community health worker programme across a heath facility catchment area in Malawi. Data from these studies has been collected and is being analysed.


(1) Improvement Project Around Staffs’ Influenza Vaccine Uptake [1]
At the time of this study staff at University Hospitals Birmingham NHS Foundation Trust were invited to take up the Influenza vaccination every September, and then reminded regularly. This study involved staff being sent one of four randomised letters to see if it would directly influence vaccination uptake. One factor of the letters emphasised being invited by an authority figure; the other factor emphasised vaccination rates in peer hospitals.

(2) Evaluating the impact of a CHW programme… in Malawi [2]
This study estimated the effect a CHW programme had on a number of health outcomes, including retention in care for patients with chronic non-communicable diseases, and uptake of women’s health services. Eleven health centres / hospitals were arranged into six clusters, which were then randomised to receive the intervention programme at various, staggered points. Each cluster crossed over from being a control group to an intervention group until all received the intervention.


In previous articles [3][4] we have examined the practical problems that can be encountered in obtaining ethical approvals and registering demand-led studies. These problems arise because of the implicit assumption that researchers, not service managers, are responsible for the interventions that are the subject of study. In particular we have criticised the Ottawa declaration on the ethics of cluster studies for making this assumption. We have pointed out the harm that rigid adherence to the tenets of this declaration could do by limiting the value that society could reap from evaluations of the large number of natural experiments that are all around us.

However, demand-led research is not homogeneous and so the demands on service manager and researcher vary from case to case. The purpose of this news blog article is to attempt a taxonomy of demand-led research. Since we are unlikely to get this right on our first attempt, we invite readers to comment further.

We discern two dimensions along which demand-led research may vary. First, the urgency dimension and second a dimension to describe the extent, if any, to which the researcher may have participated in the design of the intervention.

As a general rule, demand-led research is done under pressure of time. If there was no time pressure, then the research could be commissioned in the usual way through organisations such as the NIHR Service Delivery and Organisation Programme and the US Agency for Health Quality Research. Demand-led research is done under shorter lead times that are incompatible with the lengthy research cycle. However, permissible lead times for demand-led research vary from virtually no time to many months. In both of the studies above the possibility of the research was mooted only four or five months before roll-out of the index intervention was scheduled. We had to ‘scramble’ to develop protocols, obtain ethics approvals, and register the studies, as required for an experimental design, before roll-out ensued.

The second manner in which demand-led research may vary is in the extent of researcher involvement in design of the intervention itself. If the intervention is designed solely by the researcher or is co-produced, but under the researcher initiative, then this cannot be classified as demand-led. However, the intervention may be designed entirely by the service provider or it may be initiated by the service provider but with some input from the researcher. The vaccination intervention described in the box was initiated by the service who wished to include an incentive as part of a package of measures but they sought advice over the nature of the incentive from behavioural economists in our CLAHRC. On the other hand the intervention to train and deploy community health workers in Malawi was designed entirely by the service team with no input from the evaluation team whatsoever.

Contribution to research dominates because if the researcher makes no contribution to the intervention, then the researcher has little or no responsibility – full argument provided elsewhere.[4]

— Richard Lilford, CLAHRC WM Director

References:

  1. Lilford R, Schmidtke KA, Vlaev I, et al. Improvement Project Around Staffs’ Influenza Vaccine Uptake. Clinicaltrials.gov. NCT03637036. 2018.
  2. Dunbar EL, Wroe EB, Nhlema B, et al. Evaluating the impact of a community health worker programme on non-communicable disease, malnutrition, tuberculosis, family planning and antenatal care in Neno, Malawi: protocol for a stepped-wedge, cluster randomised controlled trial. BMJ Open. 2018; 8(7): e019473.
  3. Lilford RJ. Demand-Led Research. NIHR CLAHRC West Midlands News Blog. 18 January 2019.
  4. Watson S, Dixon-Woods M, Taylor CA, Wore EB, Dunbar EL, Chilton PJ, Lilford RJ. Revising ethical guidance for the evaluation of programmes and interventions not initiated by researchers. J Med Ethics. [In Press].

When Randomisation is not Enough: Masking for Efficacy Trials of Skin Disease, Ulcers and Wound Infections

In a previous News Blog [1] we discussed endpoint measurement for trials of wound infection, where the observers were not ‘blinded’ (not masked to the intervention group). Such an approach is simply not adequate, even if the observers use ‘strict criteria’.[1] This is because of subjectivity in the interpretation of the criteria and, more especially, because of reactivity. Reactivity means that observers are influenced, albeit sub-consciously, by knowledge of the group to which patients have been assigned (treatment or not). Such reactivity is an important source of bias in science.[2]

We are proposing a trial of a promising treatment for recurrent leprosy ulcers that we would like to carry out in the Leprosy Mission Hospital in Kathmandu, Nepal. We plan to conduct an efficacy trial of a regenerative medicine (RM) technique where a paste is made from the buffy coat layer of the patient’s own blood. This is applied to the ulcer surface at the time of dressing change. The only difference in treatment will be whether or not the RM technique is applied when the regular change of wet dressing is scheduled. We will measure, amongst other things, the rate of healing on the ulcers and time to complete healing and discharge from hospital.

Patients will be randomised so as to avoid selection bias and, as the primary endpoints in this efficacy trial are measured during the hospital sojourn (and patients seldom discharge themselves), we are mainly concerned with outcome bias as far as endpoints regarding ulcer size are concerned.

One obvious way to get around the problem of reactivity is to use a well described method in which truly masked observers, typically based off-site, measure ulcer size using photographs. Measurements are based on a sterile metal ruler positioned at the level of the ulcer to standardise the measurement irrespective of the distance of the camera. The measurement can be done manually or automated by computer (or both). But is that enough? It has been argued that bias can still arise, not at the stage where photographs are analysed, but rather at the earlier stage of photograph acquisition. This argument holds that, again perhaps sub-consciously, those responsible for taking the photograph can affect its appearance. The question of blinding / masking of medical images is a long-standing topic of debate.

The ‘gold standard’ method is to have an independent observer arrive on the scene at the appropriate time to make the observations (and take any photographs). Such a method would be expensive (and logistically challenging over long distances). So, an alternative would be to deploy such an observer for a random sub-set of cases. This method may work but it has certain disadvantages. First, it would be tricky to choreograph as it would disrupt the work flow in settings such as that described above. Second, to act as a method of audit, it would need to be used alongside the existing method (making the method still more ‘unwieldy’). Third, the method of preparing the wound would still lie in the hands of the clinical team, and arguably still be subject to some sort of subconscious ‘manipulation’ (unless the observer also provided the clinical care). Fourth, given that agreement would not be exact between observers, a threshold would have to be agreed regarding the magnitude of difference between the standard method and the monitoring method that would be regarded as problematic. Fifth, it would not be clear how to proceed if such a threshold was crossed. While none of these problems are necessarily insurmountable, they are sufficiently problematic to invite consideration of further methods. What might augment or replace standard third party analysis of photographic material?

Here we draw our inspiration from a trial of surgical technique in the field of ophthalmology/orbital surgery.[3] In this trial, surgical operations were video-taped in both the intervention and control groups. With permission of patients, we are considering such an approach in our proposed trial. The vast majority of ulcers are on the lower extremities, so patients’ faces would not appear in the videos. The videos could be arranged so that staff were not individually identifiable, though they could be redacted if and where necessary. We would like to try to develop a method whereby the photographs were directed in real time by remote video link, but pending the establishment of such a link, we propose that each procedure (dressing change) is video-taped, adhering to certain guidelines (for example, shot in high-definition, moving the camera to give a full view of the limb from all sides, adequate lighting, a measurement instrument is included in the shot, etc.). We propose that measurements are made both in the usual way (from mobile phone photographs), and from ‘stills’ obtained from the video-tapes. Each could be scored by two independent, off-site observers. Furthermore the videos could be used as a method of ‘ethnographic’ analysis of the process to surface any material differences between patients in each trial arm in lighting, preparation of ulcer sites, time spent on various stages of the procedure and photograph acquisition, and so on.

Would this solve the problem? After all, local clinicians would still prepare the ulcer site for re-bandaging and, insofar as they may be able to subconsciously manipulate the situation, this risk has not been vitiated. However, we hypothesise that the video will work a little like a black box on an aeroplane; it cannot stop things happening, but it provides a powerful method to unravel what did happen. The problem we believe we face is not deliberate maleficence, but subtle bias at the most. We think that by using the photographic approach, in accordance with guidelines for such an approach,[4] we already mitigate the risk of outcome measurement bias. We think that by introducing a further level of scrutiny, we reduce the risk of bias still further. Can the particular risk we describe here be reduced to zero? We think not. Replication remains an important safeguard to the scientific endeavour. We now turn our attention to this further safeguard.

Leprosy ulcers are far from the only type of ulcer to which the regenerative medicine solution proposed here is relevant. Diabetic ulcers, in particular, are similar to leprosy ulcers in that loss of neural sensation plays a large part in both. We have argued elsewhere that much can be learned by comparing the results of the same treatment across different disease classes. In due course we hope to collaborate with those who care for other types of skin ulcer so that we can compare and contrast and also to advance methodologically. Together we will seek the optimal method to limit expense and disruption of workflow while minimising outcome bias from reactive measurements.

— Richard Lilford, CLAHRC WM Director

References:

  1. Lilford RJ. Before and After Study Shows Large Reductions in Surgical Site Infections Across Four African Countries. NIHR CLAHRC West Midlands News Blog. 10 August 2018.
  2. Kazdin AE. Unobtrusive measures in behavioral assessment. J Appl Behav Anal. 1979; 12: 713–24.
  3. Feldon SEScherer RWHooper FJ, et al. Surgical quality assurance in the Ischemic Optic Neuropathy Decompression Trial (IONDT)Control Clin Trials. 200324294-305.
  4. Bowen AC, Burns K, Tong SY, Andrews RM, Liddle R, O’Meara IM, et al. Standardising and assessing digital images for use in clinical trials: a practical, reproducible method that blinds the assessor to treatment allocation. PLoS One. 2014;9(11):e110395.

Barriers and Facilitators to Self-care of Leprosy in the Community – Report on a Stakeholder Consultation in Kathmandu, Nepal

The problem

Ulceration and deformity of the extremities, particularly the feet, are important complications of leprosy (known as Hansen’s disease in America). The pathophysiology of leprosy ulcers are similar to those of ulcers in diabetes mellitus – in both cases nerve damage leads to loss of sensation, which in turn leads to repetitive injury and ultimately ulceration. In addition, leprosy causes deformities, which increase the risk of repeated trauma and hence ulceration. Leprosy is a disease that affects the poorest of the poor; frequently those living in remote areas. The disease is highly stigmatising in the communities among whom it occurs leading to late presentation at healthcare facilities and hence a high incidence of ulceration among people who have contracted the disease. Once a person has had one ulcer, repeated ulceration is common, affecting at least 30% of patients.[1]

NIHR CLAHRC WM is working with The Leprosy Mission to develop interventions to prevent ulceration among high risk leprosy patients – especially those who have had previous ulcers. To this effect, we participated in a stakeholder meeting organised by colleagues Drs Deanna Hagge and Indra Napit at the Anandaban Hospital in Kathmandu, Nepal on 14 December 2018.

117 gb barriers and facilitators - image

©Paramjit Gill, 2018. Photo taken with permission of participants.

Stakeholders included leprosy-affected people, ulcer patients, administrative and clinical staff, representatives working on behalf of leprosy affected people, and two government officials. Stakeholders were asked to speak not only about barriers to prevention of ulcers but also possible means to overcome these barriers. All voices were heard and the meeting lasted for about two-hours.

First, we report themes relating to barriers to prevention that emerged during the stakeholder meeting. Second, we arrange them according to the well-known COM-B model [2] encompassing Capability, Opportunity and Motivation as factors affecting Behaviour. Finally, we consider what may be done to overcome the barriers.

Themes

The following themes emerged during the consultation:

  • Poverty. All were agreed that the need to work to provide the essentials of life increased the risk of placing pressure on vulnerable foot surfaces and of repeated trauma. Pressure to provide for self and family also increased the risk of late presentation of ulcers or their prodromal signs (so-called ‘hotspots’). One stakeholder commented “If a person cannot work for three months due to wound healing and not putting pressure on the ulcer then how do they live?
  • There was almost unanimous agreement that stigma was a problem, as it led to ‘denial’ (and hence late presentation) and failure to practice self-care and wear protective footwear, which might mark the wearer as a leprosy victim. The view was expressed that stigma reaches its highest intensity in remote rural locations – “some family members don’t know the person has leprosy so question self-care habits such as soaking the hands and feet…in rural areas patients need to hide the wounds and clean them in the night time so nobody sees.”
  • Poor information provision. Arguments regarding this barrier were more nuanced. While acknowledging that communication, especially communication pending discharge, was seldom perfect, there was also a feeling that staff tried hard and made a reasonable fist of communicating the essentials of preventative self-care. One stakeholder commented that “leprosy workers are not successful in convincing patients that their body is their responsibility and they have to look after it”. However, convincing patients can be hard, as many people afflicted with leprosy have poor functional literacy. Bridging the gulf in cultural assumptions between care givers and service users may be difficult in a single hospital stay – a point we pursue below.

Analysis according to the ‘trans-theoretical’, COM-B model

We have arranged the above themes using the COM-B model in the Figure. This figure is used to inform the design of interventions that address multiple barriers to healthy behaviours.

117 gb barriers and facilitators to self-care - figure

(With thanks to Dr Laura Kudrna for her advice).

Designing acceptable interventions

Principles not prescriptions

Interventions to improve care are like guidelines or recipes, not prescriptions. They should not be applied in a one size fits all manner – local implementers should always adapt to context [3] – an intervention as promulgated is not identical to the intervention implemented.[4] Thus, an intervention description at the international level must leave plenty of scope for adaptation of principles to local circumstances that vary within and between countries. For example, peer groups may be more feasible in high than in low burden settings while the development of local health services may determine the extent to which ‘horizontal’ integration between specialist leprosy and general services is possible.

Capability issues

Starting with Capability, there was a feeling that this was not where the main problem lay; patients generally left hospital with the equipment and knowledge that they needed to prepare for life in the community. Our stakeholders said that patients had access to protective footwear (although innovations, such as three dimensional printing to adapt footwear to particular types of defect, would be welcome). Likewise, as stated above, gains to be achieved by an ‘enhanced discharge’ process might be limited. This is for three reasons. First, patients usually receive rather thorough counselling in how to care for themselves during their hospital stay. Second, they usually know the measures to take. Third, understanding is seldom sufficient to bring about behaviour change – school girls who become pregnant are seldom unaware of contraception, for example. In conclusion, a hospital based intervention might not be the most propitious use of scarce resources. This, of course, does not preclude ongoing facility based research to improve treatment and protective methods, nor does it preclude facility outreach activities as we now discuss.

Enhancing ‘Opportunity’

The main barrier identified at the stakeholder meeting seemed to lie in the area of opportunity. Two important principles were established in the meeting. First, since ulcer prevention is an ongoing process its centre of gravity must be located where people live, that is, in the community. Second, peer-supported self-care is a model of established success in leprosy [5][6] (as it has been in diabetes).[7] Two corollaries flow from these considerations. First, where peer support has not been established, this deficiency should be corrected with support from facility based leprosy services. This may take different forms in high burden areas, where groups of people can come together, compared to low burden settings. This suggests that m-health, especially m-consulting, would be particularly useful in low burden settings. Second, where peer support exists (in the form of self-care groups) it should be strengthened, again with support from local facilities who can provide know-how, materials and, we think, inspiration/leadership for ongoing strengthening of locality based support groups. Such support, it was argued, not only provides technical know-how, but importantly, psychological support, to foster resilience and mitigate the pernicious effects of stigma. Telecommunication, when available, will have an important role in coordinating and supporting community self-care. We heard stories of people having to travel for three days to reach a facility; of having to find their way back to remote rural locations with recently healed ulcers on deformed feet and having to complete their journeys on foot. There is a prima facie case that providing mobile telephones will be cost-effective (save in locations so remote they fall outside mobile phone coverage). There was considerable support in the stakeholder meeting for personalised care plans. While accepting the need to individualise, an individual’s needs are not stable. Thus, while specific plans should be made at discharge, it is in the community that adaptations must be made according to changing clinical circumstances, work requirements and personal preferences. In all of the above initiatives, the specialist leprosy services should act as a source of information and psychological/emotional support. Especially in low burden areas, they can act like a poisons facility poisons reference service, providing know how to patients and care providers as and when necessary.

Motivation

As per the legend to our figure, we think that promoting opportunity and motivation go hand in hand in the case of community and outreach services for patients with leprosy who are at risk of ulcers as a result of local anaesthesia and limb deformities. Stigma aggravates the practical and psychological effects of the disease and includes a loss of self-worth and ‘self-stigma’.[8] People with leprosy often have something akin to a ‘crushed spirit’ or ‘chronic depression’ depending on the label one wants to use. Peer supported, facility enabled, self-care may improve motivation. Moreover, emotional support may enable people who have the stigmata left over from active infection to become ambassadors for the condition and help reduce social stigma.

Discussion

It is not enough to say that people suffering the stigma of leprosy should integrate with their communities rather than live in institutions or ‘colonies’, without taking steps to enable them to live in those communities. Such steps are of two types:

  • Community level action in supporting /facilitating communities to replace stigma by embracing people with leprosy and actively supporting them.
  • Individual support for people with leprosy who are likely to encounter stigma, but who need to prevail in the face of discrimination.

Interventions need to be achievable at low unit cost. So the plan is to design an intervention for propagation across many health systems and to evaluate how it is assimilated locally and what effects it has, within and across multiple contexts. The intervention we propose will involve facility outreach to educate people and ‘teach the teachers’ in communities with the aim of enhancing self-care. There are other actions that might be taken to support people with leprosy (and for that matter other people with disabilities) in the community. One set of measures are those that may alleviate the grinding poverty that many people with leprosy suffer, for instance by providing small loans, non-conditional cash transfers and enterprise coaching. Such interventions, targeting the poorest of the poor have been evaluated and some have proven effective.[9] They may be applicable to people who bear the effects of leprosy and we would be keen to join in the evaluation of such interventions. Information technology would seem to have a large role, as stated above. Diplomatic overtures to opinion formers, such as community leaders, may reduce stigma, especially if people who suffer from ulcers are themselves empowered to advocate on behalf of fellow sufferers. It may be the case that improving care for leprosy sufferers will have spill-over effects on other people with ulcer conditions or physical disabilities. The CLAHRC WM Director would like to thank Drs Indra Napit and Deanna Hagge for organising an excellent meeting, and the attendees for giving their time and sharing their experiences.

–Prof Richard Lilford, Dr Indra Napit and Ms Jo Sartori

References:

  1. Kunst, H. Predisposing factors for recurrent skin ulcers in leprosy. Lepr Rev. 2000;1(3):363-8.
  2. Michie S, van Stralen MM, West R. The behaviour change wheel: a new method for characterising and designing behaviour change interventions. Implement Sci. 2011;6:42.
  3. Lilford RJ. Implementation science at the crossroads. BMJ Qual Saf. 2018; 27:331-2.
  4. Lilford RJ. Context is Everything in Service Delivery Research. NIHR CLAHRC West Midlands News Blog. 27 October 2017.
  5. Deepak S, Estivar Hansine P, Braccini C. Self-care groups of leprosy-affected people in Mozambique. Lepr Rev. 2013;84:4.
  6. Benbow C, Tamiru T. The experience of self-care groups with people affected by leprosy: ALERT, Ethiopia. Lepr Rev. 2001;72:311-21.
  7. Tricco AC, Ivers NM, Grimshaw JM, et al. Effectiveness of quality improvement strategies on the management of diabetes: a systematic review and meta-analysis. Lancet. 2012; 379: 2252-61.
  8. World Health Organization. Global Leprosy Strategy 2016-2020. Geneva: WHO; 2016.
  9. Banerjee A, Karlan D, Zinman J. Six Randomized Evaluations of Microcredit: Introduction and Further StepsAm Econ J Appl Econ. 2015; 7(1): 1-21.

A Bigger Risk Than Climate Change?

There are many future risks to our planet. The risk that seems to cause most concern is climate change. I share these concerns. However, there are some risks which, if they materialised, would be even worse than those of climate change. An asteroid strike, such as the collision 66 million years ago, is in this category. But this is a most improbable event, essentially 0% in the next 50 years.[1] There is, however, a risk that would be absolutely catastrophic, and whose probability of occurring is not remote. I speak, of course, of nuclear strike.

There are two issues to consider: the degree of the catastrophe, and its probability of occurring. Regarding the extent of the catastrophe, one can refer to the website Nukemap. Here one finds evidence-based apocalyptic predictions. In order to make sense of these it is necessary to appreciate that nuclear bombs destroy human life in three zones radiating out from the epicentre: the fire ball; the shock wave; and the area of a residual radiation (whose direction depends on prevailing winds). If a relatively small atomic bomb, such as a 455 kiloton bomb from a nuclear submarine, landed on Glasgow, it would kill an estimated quarter of a million people and injure half a million, not taking into account radiation damage. The bomb released by the Soviets into the upper atmosphere at 50 megatons (Tsar Bomba) would, if it landed on London, kill over 4.5 million people and injure 3 million more (again not including the radiation damage that would most likely spread across northern Europe). Daugherty, Levi and Van Hippel calculate that deployment of only 1% of the world’s nuclear armaments would cause up to 56 million deaths and 61 million casualties in the book ‘The Medical Implications of Nuclear War‘.[2] Clearly, larger conflagrations pose an existential threat that could wipe out the whole of the northern hemisphere. When I look at my lovely grandchildren, sleeping in their beds at night, I sometimes think of that. And all of the above harms exclude indirect effects resulting from collapse of law and order, financial systems, supply chains, and so on.

So, nuclear war could be catastrophic, but to calculate the net expected burden of disease and disability we need to know the probability of its occurrence. The risk of nuclear strike must be seen as material. During, and immediately following, the Cold War there were at least three points at which missile strikes were imminent. They were all a matter of miscalculation. The most likely cause of nuclear war is a false positive signal of a strike, perhaps simulated by a terrorist group. These risks are increasing since at least eight countries now have nuclear weapons. The risk of a single incident, leading to the death of, say, 1 million people, might be as high as 50% over the next 50 years according to some models.[3] Another widely cited figure from Hellman is 2% per year.[4] The risk of an attack with retaliatory strikes, and hence over 50 million dead, would be lower – say 10% over the next 50 years. Identifying the risk of future events may seem quixotic, but not trying to do so is like the ostrich putting its head in the sand. Using slogans such as ‘alarmist’ is simply a way of avoiding uncomfortable thoughts better confronted. Let us say the risk of a strike with retaliation is indeed 10% over 50 years, and that 50 million causalities will result. If the average causality is 40 years of age, then the expected life years lost over 50 years would be about 200,000,000 (50m x 40 x 0.1). This is without discounting, but why would one discount these lives on the basis of current time-preferences?

Given the high expected loss of life (life years multiplied by probability), it seems that preventing nuclear war is up there with climate change. The effects of nuclear war are immediate and destroy infrastructure, while climate change provides plenty of warning and infrastructure can be preserved, even if at high cost. Avoiding nuclear war deserves no less attention. In 2014 the World Health Organization published a report that estimated that climate change would be responsible for 241,000 additional deaths in the year 2030, which is likely an underestimate as their model could not quantify a number of causal pathways, such as economic damage, or water scarcity.[5] But we have time to adapt and reduce this risk – nuclear war would be sudden and would disrupt coping mechanisms, leading to massive social and economic costs, along with large numbers of deaths and people diseased or maimed for life. Nuclear strike is public health enemy number one in my opinion. It is difficult to pursue the possible options to reduce this risk without entering the world of politics, so this must be pursued within the pages of your News Blog.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Sentry: Earth Impact Monitoring. Impact Risk Data. 2018.
  2. Daugherty W, Levi B, Von Hippel F. Casualties Due to the Blast, Heat, and Radioactive Fallout from Various Hypothetical Nuclear Attacks on the United States. In: Solomon F & Marston RQ (eds.) The Medical Implications of Nuclear War. Washington, D.C.: National Academies Press (US); 1986.
  3. Barrett AM, Baum SD, Hostetler K. Analyzing and Reducing the Risks of Inadvertent Nuclear War Between the United States and Russia. Sci Glob Security. 2013; 21: 106-33.
  4. Hellman ME. Risk Analysis of Nuclear Deterrence. The Bent of Tau Beta Pi. 2008 : Spring: 14-22.
  5. World Health Organization. Quantitative risk assessment of the effects of climate change on selected causes of death, 2030s and 2050s. Geneva: World Health Organization, 2014.