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• Game keepers, poachers, thin ice and disease definition
  Jim F Malone
  Published on: 25 September 2019
• Yes, bias is pervasive . .
  Richard Cooper
  Published on: 25 September 2019
• Expanding the scope – pursuing a fully integrated discourse on health
  Joachim P. Sturmberg
  Published on: 25 September 2019

• Published on: 25 September 2019

  Game keepers, poachers, thin ice and disease definition

  • Jim F Malone, Professor (Emeritus) of Medical Physics School of Medicine, Trinity College Dublin. Ireland

  The fine paper by Moynihan et al moves the goal posts in terms of how changes in disease definitions are made.1 They identify many of the problems involved, including financial conflicts of interest. Their proposal fails to address two issues. First, only the most problematic vested interests are dealt with and second, they fail to acknowledge and address the necessarily flawed evidence base they must work out of.
  The authors find that the present financial arrangements in industry almost inevitably introduce unacceptable biases to its advocacy positions. Interests, so compromised, must be excluded from panels determining disease definitions. On the other hand, Moynihan et al. allow for participation by medical specialists deeply in the related fields. Such groups can have compelling financial and/or professional interests, particularly where private practice or turf battles prevail. This situation, though noted in passing, is inadequately challenged, and it is at least arguable, that the professions are too influential. The biases of many professional groups identified (and others not mentioned) can be just as problematic as those of the industry.
  The paper favours an evidential approach without noting the endemic medical evidence crisis of the last decade.2 This must be part of any serious discourse in which the wider public is, inevitably, included. Among the problems, in no particular order are poor choice of question; biases and poor quality in study desig...

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  The fine paper by Moynihan et al moves the goal posts in terms of how changes in disease definitions are made.1 They identify many of the problems involved, including financial conflicts of interest. Their proposal fails to address two issues. First, only the most problematic vested interests are dealt with and second, they fail to acknowledge and address the necessarily flawed evidence base they must work out of.
  The authors find that the present financial arrangements in industry almost inevitably introduce unacceptable biases to its advocacy positions. Interests, so compromised, must be excluded from panels determining disease definitions. On the other hand, Moynihan et al. allow for participation by medical specialists deeply in the related fields. Such groups can have compelling financial and/or professional interests, particularly where private practice or turf battles prevail. This situation, though noted in passing, is inadequately challenged, and it is at least arguable, that the professions are too influential. The biases of many professional groups identified (and others not mentioned) can be just as problematic as those of the industry.
  The paper favours an evidential approach without noting the endemic medical evidence crisis of the last decade.2 This must be part of any serious discourse in which the wider public is, inevitably, included. Among the problems, in no particular order are poor choice of question; biases and poor quality in study design; inadequate attention to measurement quality, materials, methods and standards; inherent limitations in most, even the best of clinical trials (for example the duration of follow up or participation selection criteria); and defects in the statistical methods employed. These are so commonplace that it has been authoritatively asserted that almost all medical research is wrong.3 Shortcomings in many publications are taken as small or “venial sins” and easily forgiven and forgotten. But, medical research also harbours cardinal or deadly “mortal sins”, including plagiarism and fraud (note the contemporary measles problems). Excellence in policy development requires that gamekeepers and poachers be decisively separated, and the thin ice under the best evidence we have must be recognised for what it is, acknowledged and become part of the discourse with those it impacts on most.
  References
  1. Moynihan R, Brodersen J, Heath I, et al. Reforming disease definitions: a new primary care led, people-centred approach. BMJ Evidence-Based Medicine. 2019:bmjebm-2018-111148.
  2. Smith R. Medical research—still a scandal. 2018. https://blogs.bmj.com/bmj/2014/01/31/richard-smith-medical-research-stil...
  3. Ioannidis JPA (2005) Why Most Published Research Findings Are False. PLoS Med 2(8): e124. https://doi.org/10.1371/journal.pmed.0020124

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  Conflict of Interest:
  None declared.

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• Published on: 25 September 2019

  Yes, bias is pervasive . .

  • Richard Cooper, Physician Loyola University Medical Center

  I find this discussion unbalanced. Yes, bias is pervasive, and - unfortunately - primary care organizations are not exempt. Like, "the public" can be mislead - about chlorinated water and measles vaccination. But most importantly, put simply, expanding disease definitions usually means more patients to treat, and more cost to account for - this can be a negative incentive in health systems. I have witnessed on several occasions - including WHO BP treatment panels - a strong, explicit bias by primary care organizations to resist the evidence of benefit to treatment at lower levels of BP because it would increase patient loads. Historically the call to "not over-treat" goes back to the '60's, when many argued that "high BP was just like a fever - a symptom not a cause", and every step of progress has been to adopt lower targets. In my view, like it or not, pills are a new era in public health - much like vaccination. And, yes, wide use of safe, effective pills is being resisted for many of the same reasons. But progress cannot be denied, BP goals have declined from "never treat" to SBP of 120, with 80-90% decline in CVD - esp stroke. The US may have the bias toward more treatment (some doctors get patient for more visits . . ) but stroke rates are much lower than in Europe, and many dozens of US health systems have achieved the goal of 80% of treated patients with BP < 140, with excellent results. It shoul...

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  I find this discussion unbalanced. Yes, bias is pervasive, and - unfortunately - primary care organizations are not exempt. Like, "the public" can be mislead - about chlorinated water and measles vaccination. But most importantly, put simply, expanding disease definitions usually means more patients to treat, and more cost to account for - this can be a negative incentive in health systems. I have witnessed on several occasions - including WHO BP treatment panels - a strong, explicit bias by primary care organizations to resist the evidence of benefit to treatment at lower levels of BP because it would increase patient loads. Historically the call to "not over-treat" goes back to the '60's, when many argued that "high BP was just like a fever - a symptom not a cause", and every step of progress has been to adopt lower targets. In my view, like it or not, pills are a new era in public health - much like vaccination. And, yes, wide use of safe, effective pills is being resisted for many of the same reasons. But progress cannot be denied, BP goals have declined from "never treat" to SBP of 120, with 80-90% decline in CVD - esp stroke. The US may have the bias toward more treatment (some doctors get patient for more visits . . ) but stroke rates are much lower than in Europe, and many dozens of US health systems have achieved the goal of 80% of treated patients with BP < 140, with excellent results. It should be noted that goal implies a mean treated BP of ~ 120 (since the SD = 20 for SBP). We recently showed that meeting SPRINT-based guidelines would reduce CVD deaths by > 100k per year in the US.

  Let us not be professional "anti-vaxers" . . SPRINT showed highly significant reduction in all cause, CVD, and modest improvement in cognitive function. There was no excess of permanent harm. Statins likewise have made enormous contribution to reduction in CVD, and are unfortunately resisted by some Nordic countries (eg, Norway) with continued high rates of CHD, While few patients with CKD develop CRF, many die of CVD, and thus CKD is a major risk factor, and like diabetes should usually prompt the use of a statin.

  For CVD we can now rely on evidence, Overwhelmingly trials and the historical trajectory of disease rates support broad treatment of risk - with medication if necessary.

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  Conflict of Interest:
  None declared.

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• Published on: 25 September 2019

  Expanding the scope – pursuing a fully integrated discourse on health

  • Joachim P. Sturmberg, A/Prof of General Practice; President - International Society for Systems and Complexity Sciences for Health University of Newcastle

  Expanding the scope – pursuing a fully integrated discourse on health

  Thank you for starting a long overdue discussion about the largely “insidious vested interest driven” activity of disease redefinition. Clearly this is causing high risks to the health and well-being of people and communities [1]. However, I think, there is a need to expand the emerging discourse on three front right at the beginning, especially the complex adaptive epistemology of health, a clear elaboration of the limitation of statistics as a means to “prove the truth”, and more fundamentally, the consideration of “biological plausibility”, i.e. the need to focus on integrated network physiology, in considering what are healthy “normal” indicators across the lifespan.

  (1) The paper tangentially alludes to the epistemic issues of defining health, illness, dis-ease and disease. Putting it in this way infers as a presupposition that health, illness, dis-ease and disease are distinctively “different things” – essentially a reflection of the reductionist tradition of thought of the past 350 yrs. In the first instance health in all it’s forms is subjective in nature [2], and must be distinguished from the objective features of pathology we use to define disease. As most generalist health professionals know at the end of a consultation patients fall into one of four principle clusters:
  • Subjectively healthy with no identifiable pathology
  • Subjectively health with well-defined path...

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  Expanding the scope – pursuing a fully integrated discourse on health

  Thank you for starting a long overdue discussion about the largely “insidious vested interest driven” activity of disease redefinition. Clearly this is causing high risks to the health and well-being of people and communities [1]. However, I think, there is a need to expand the emerging discourse on three front right at the beginning, especially the complex adaptive epistemology of health, a clear elaboration of the limitation of statistics as a means to “prove the truth”, and more fundamentally, the consideration of “biological plausibility”, i.e. the need to focus on integrated network physiology, in considering what are healthy “normal” indicators across the lifespan.

  (1) The paper tangentially alludes to the epistemic issues of defining health, illness, dis-ease and disease. Putting it in this way infers as a presupposition that health, illness, dis-ease and disease are distinctively “different things” – essentially a reflection of the reductionist tradition of thought of the past 350 yrs. In the first instance health in all it’s forms is subjective in nature [2], and must be distinguished from the objective features of pathology we use to define disease. As most generalist health professionals know at the end of a consultation patients fall into one of four principle clusters:
  • Subjectively healthy with no identifiable pathology
  • Subjectively health with well-defined pathology
  • Subjectively unhealthy/ill/in dis-ease with no identifiable pathology
  • Subjectively unhealthy/ill/in dis-ease with identifiable pathology

  Patterns typically arise from complex adaptive nonlinear interactions between the elements of a system. Of note, the patterns of health and “unhealth” are emergent outcomes arising as the result of interactions within the hierarchical complex adaptive networks of our external environment (top level) and our biological blueprint (bottom level). Importantly, the higher levels constrain what the lower levels can do [3] – explaining why and how our external contexts positively and negatively influence how we realise/or fail to realise or biologically given health potential [4].

  (2) Related to the above is the question about the “nature of evidence”, and by implication if and how the “scientific method” can create evidence for the observable phenomena of the living world. Is there truly any cause-and-effect relationship between one defined intervention to a group of people with their individual dynamic responses to the challenges of their interconnected and interdependent external and internal networks that regulate their health?

  Even if there seems to be a statistically significant correlation between a dependent variable and a set of independent variables, it does not prove a causal relationship [5]. As Austin Bradford Hill as far back as 1965 pointed out establishing causation requires a “plurality of reasoning strategies”—strength of association between variables, consistency of results between studies, specificity of variables, temporality, biological gradient, plausibility, coherence, experimental evidence, and analogy [6].

  (3) Variables in living system are distributed along a Pareto, rather than a Gaussian distribution [7, 8]. This means that only extreme values at the far end of a parameter’s are likely “truly abnormal”. This impacts the biological plausibility of many disease definitions – the nonlinear distribution of a particular value is not causally related to the occurrence of disease or pre-disease. In addition, as Rothman has shown, a single or even a couple of features may be necessary, but are not sufficient, to define any disease [9].

  For example, the diagnosis of hypertension as a BP reading > 120/80 lacks physical and biological plausibility. The circulation of blood is required to ensure adequate oxygen supply to all tissues. Flow = pressure/resistance, i.e. oxygen supply (flow) is dramatically lowered by reducing blood pressure or increasing resistance. Rising blood pressure with increasing age is a – to be expected – compensatory mechanism to maintain adequate oxygen supply in light of the narrowing of blood vessels and rising resistance [10]. As Port has shown rising blood pressure over age – within limits – has no impact on morbidity or mortality [11].

  A second example relates to statin drugs – their benefit on improved cardiac mortality results from blocking the inflammation mediated by the Rho/ ROCK enzyme pathways in endothelial plaques [12, 13], not the drug’s side effect, the – easily measurable (and marketable) – lowering of cholesterol [14]. Most notable, and unsurprisingly, the benefit of statins is independent of the initial cholesterol level, and equal across the varied racially normal distribution ranges [15, 16].

  References
  1. Moynihan R, Brodersen J, Heath I, Johansson M, Kuehlein T, Minué-Lorenzo S, et al. Reforming disease definitions: a new primary care led, people-centred approach. BMJ Evidence-Based Medicine. 2019:bmjebm-2018-111148.
  2. Sturmberg JP. The personal nature of health. J Eval Clin Pract. 2009;15(4):766-9.
  3. Ellis GFR. Top-down causation and emergence: some comments on mechanisms. Interface Focus. 2012;2(1):126-40.
  4. Sturmberg JP, Picard M, Aron DC, Bennett JM, Bircher J, deHaven MJ, et al. Health and Disease—Emergent States Resulting From Adaptive Social and Biological Network Interactions. Frontiers in Medicine. 2019;6:59.
  5. Sturmberg JP. Evidence‐based medicine—Not a panacea for the problems of a complex adaptive world. J Eval Clin Pract. 2019;26:early view.
  6. Hill AB. The Environment and Disease: Association or Causation? Proc R Soc Med. 1965;58(5):295-300.
  7. West GB. The origin of universal scaling laws in biology. Physica A: Statistical Mechanics and its Applications. 1999;263(1–4):104-13.
  8. West BJ. Homeostasis and Gauss Statistics: barriers to understanding natural variability. J Eval Clin Pract. 2010;16(3):403–8.
  9. Rothman KJ. Causes. Am J Epidemiol. 1976;104(6):587-92.
  10. Sturmberg J. Hype and Tension in Hypertension. Debating the Latest Hypertension Guidelines. European Journal for Person Centered Healthcare. 2018;6(1):128-37.
  11. Port S, Demer L, Jennrich R, Walter D, Garfinkel A. Systolic blood pressure and mortality. Lancet. 2000;355(3):175-80.
  12. Hansson GK, Hermansson A. The immune system in atherosclerosis. Nature Immunology. 2011;12(3):204-12.
  13. Wei C-Y, Huang K-C, Chou Y-H, Hsieh P-F, Lin K-H, Lin W-W. The Role of Rho-Associated Kinase in Differential Regulation by Statins of Interleukin-1β- and Lipopolysaccharide-Mediated Nuclear Factor κB Activation and Inducible Nitric-Oxide Synthase Gene Expression in Vascular Smooth Muscle Cells. Mol Pharmacol. 2006;69(3):960-7.
  14. Bennett JM, Reeves G, Billman G, Sturmberg JP. Inflammation, nature’s way to efficiently respond to all types of challenges: Implications for understanding and managing “the epidemic” of chronic diseases Frontiers in Medicine. 2018(5):316.
  15. Kromhout D. On the waves of the Seven Countries Study; a public health perspective on cholesterol. Eur Heart J. 1999;20(11):796-802.
  16. Sturmberg JP, Miles A. The Complex Nature of Knowledge. In: Sturmberg JP, Martin CM, editors. Handbook of Systems and Complexity in Health. New York: Springer 2013. p. 39-62.

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  Conflict of Interest:
  None declared.

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