To curb research misreporting, replace significance and confidence by compatibility: A Preventive Medicine Golden Jubilee article.

It is well known that the statistical analyses in health-science and medical journals are frequently misleading or even wrong. Despite many decades of reform efforts by hundreds of scientists and statisticians, attempts to fix the problem by avoiding obvious error and encouraging good practice have not altered this basic situation. Statistical teaching and reporting remain mired in damaging yet editorially enforced jargon of "significance", "confidence", and imbalanced focus on null (no-effect or "nil") hypotheses, leading to flawed attempts to simplify descriptions of results in ordinary terms. A positive development amidst all this has been the introduction of interval estimates alongside or in place of significance tests and P-values, but intervals have been beset by similar misinterpretations. Attempts to remedy this situation by calling for replacement of traditional statistics with competitors (such as pure-likelihood or Bayesian methods) have had little impact. Thus, rather than ban or replace P-values or confidence intervals, we propose to replace traditional jargon with more accurate and modest ordinary-language labels that describe these statistics as measures of compatibility between data and hypotheses or models, which have long been in use in the statistical modeling literature. Such descriptions emphasize the full range of possibilities compatible with observations. Additionally, a simple transform of the P-value called the surprisal or S-value provides a sense of how much or how little information the data supply against those possibilities. We illustrate these reforms using some examples from a highly charged topic: trials of ivermectin treatment for Covid-19.

Factor VIII levels and bleeding according to factor 8 (F8) mutation in pregnant carriers of haemophilia A: a multicentre retrospective cohort study.

This retrospective cohort study investigated the association between factor 8 (F8) genotype severity and factor VIII (FVIII) levels during pregnancy for 52 women (64 pregnancies) who were heterozygous carriers of mild, moderate or severe haemophilia A. There were no significant differences in FVIII levels for carriers of mild, moderate or severe haemophilia A at baseline [mean (SD) level: mild, 0·78 (0·22); moderate, 0·83 (0·33); severe, 0·70 (0·25) iu/ml; P = 0·81] or in the third trimester [mean (SD) level: mild, 1·42 (0·28); moderate, 1·47 (0·41); severe, 1·37 (0·49) iu/ml; P = 0·80). Post-partum haemorrhage rates were higher for carriers of severe haemophilia A (13/24; 54·2%) compared to carriers of mild haemophilia A (four of 14; 28·6%).

Can Styloid Process and Internal Carotid Artery Anatomy be Used to Predict Carotid Artery Dissection?

BACKGROUND: Carotid artery dissection is a common cause of stroke in the young. It has been related to the association of the carotid artery with fixed neighboring anatomical structures. This study assesses the association between styloid process length, internal carotid artery position and cervical carotid artery dissection (CCAD). This information would provide potential predicative radiological measurements, which could prevent delays in CCAD diagnosis. METHODS: Retrospective data was collected from 2 central London hospitals over 5 years. CCAD cases were identified from individuals who underwent computer topography angiography of the neck for suspected CCAD. The following data was collected: evidence of CCAD; bilateral styloid process length and presence of styloid-hyoid ligament calcification; bilateral styloid process-internal carotid distance; calcification of carotid arteries and whether their position was aberrant. Cases were dissection-side, age and gender matched with two non-dissection controls. RESULTS: Three hundred and fifty-five individuals were identified. Fifty individuals had CCAD, of which 4 had bilateral dissection. In individuals with CCAD, average styloid process length was 27.5 mm and styloid process-internal carotid distance was 5.14 mm. There was no significant association between styloid process length or styloid process-internal carotid distance, and CCAD when compared with matched controls. Internal carotid artery aberrancy was significant for nondissection. CONCLUSIONS: In this study, there was no association between styloid process length and styloid process-internal carotid distance with CCAD. These measurements can not be used to predict the possibility of a CCAD following trauma.

Case report: a fatal case of disseminated adenovirus infection in a non-transplant adult haematology patient.

BACKGROUND: We report a fatal case of disseminated adenovirus infection in a non-transplant haematology adult patient with chronic lymphocytic leukaemia who had completed combination chemoimmunotherapy a few months before developing respiratory symptoms. In such non-transplant patients, monitoring for adenovirus in the blood is not routine. However, with adenoviruses, when there is a more peripheral (i.e. non-blood) site of infection such as the chest, serial adenovirus monitoring in blood for the duration of that illness may be warranted. CASE PRESENTATION: This case started with an initial bacterial chest infection that responded to treatment, followed by an adenovirus pneumonitis that disseminated to his blood a week later with levels of up to 92 million adenovirus DNA copies/ml. Despite prompt treatment with cidofovir, his respiratory function continued to deteriorate over the next two weeks and he was moved to intensive care. Intravenous immunoglobulin and ribavirin were subsequently added to his treatment. However, he died soon after this with a final adenovirus load of 20 million copies/ml in his blood. CONCLUSIONS: We recommend that even in non-transplant haematology patients, where such patients present with an acute respiratory adenovirus infection, teams should consider checking the blood for adenovirus to check for signs of disseminated infection. The earlier this can be tested, the earlier treatment can be initiated (if adenovirus positive), which may produce more successful clinical outcomes.

Time trends in biological fertility in Western Europe.

We investigated trends in biological fertility in a comprehensive analysis of 5 major European data sets with data on time to pregnancy (TTP) and proportion of contraceptive failures. In particular, we distinguished a period effect from a birth cohort effect (lifelong tendency) in both sexes. Attempts at conception not resulting in birth were excluded. We analyzed data on pregnancies occurring in 9,247 couples between 1953 and 1993 and performed sensitivity analyses to check the robustness of findings. Separate analyses of each time effect showed an increasing fertility trend. Mutually adjusted analyses demonstrated that this rise was visible as a male cohort effect for both TTP and contraceptive failure. On the other hand, the female birth cohort effect showed a slight fall in the first half of the study period for both TTP and contraceptive failure. As a period effect, fertility remained generally stable, the slight trends in TTP and contraceptive failure being in opposite directions, likely indicating an artifact. The rising trend accords with most previous evidence. The increasing trend in male fertility does not contradict the previously reported semen quality deterioration, the effects of which are calculated to be small. The declining female fertility accords with a falling dizygotic twinning rate during the same period.

Causal diagrams in systems epidemiology.

Methods of diagrammatic modelling have been greatly developed in the past two decades. Outside the context of infectious diseases, systematic use of diagrams in epidemiology has been mainly confined to the analysis of a single link: that between a disease outcome and its proximal determinant(s). Transmitted causes ("causes of causes") tend not to be systematically analysed.The infectious disease epidemiology modelling tradition models the human population in its environment, typically with the exposure-health relationship and the determinants of exposure being considered at individual and group/ecological levels, respectively. Some properties of the resulting systems are quite general, and are seen in unrelated contexts such as biochemical pathways. Confining analysis to a single link misses the opportunity to discover such properties.The structure of a causal diagram is derived from knowledge about how the world works, as well as from statistical evidence. A single diagram can be used to characterise a whole research area, not just a single analysis - although this depends on the degree of consistency of the causal relationships between different populations - and can therefore be used to integrate multiple datasets.Additional advantages of system-wide models include: the use of instrumental variables - now emerging as an important technique in epidemiology in the context of mendelian randomisation, but under-used in the exploitation of "natural experiments"; the explicit use of change models, which have advantages with respect to inferring causation; and in the detection and elucidation of feedback.

Mycotic internal carotid artery pseudoaneurysm secondary to Mycobacterium tuberculosis.

Mycobacterium tuberculosis is a rare causative agent for mycotic aneurysms of the extracranial carotid arteries. We describe a case of acute mycotic pseudoaneurysm and abscess in the right proximal internal carotid artery in close proximity to the carotid bifurcation, and subsequent management with antibiotic therapy, surgical debridement and resection with an end-to-end anastomosis.

The gap between evidence discovery and actual causal relationships.

The concept of causation in epidemiology can be illuminated by situating the discussion within a more general concept of causation in biology: "a causal relationship is one that has a mechanism that by its operation makes a difference". Mechanism and difference-making are complementary, and discovery can proceed from either direction; each type of evidence can be qualitative or quantitative. An explanation becomes fully convincing only when supported by both. In biology, causation is typically stochastic and/or multiple. Multiple causation can be analysed statistically/epidemiologically, even though it is not truly (ontologically) stochastic. This requires some degree of regularity in the outcome variable, plus sufficient variation in the exposure(s). The analysis then demonstrates co-variations between exposure(s) and outcome that regularly occur. Rose's important distinction of "causes of incidence" and "causes of cases" should be reconceptualised in terms of epidemiological visibility, raising the possibility of epidemiological "dark matter".

Superior ophthalmic vein thrombosis secondary to COVID-19: an index case.

Superior ophthalmic vein thrombosis is a very rare condition, known to have a profound negative impact on vision and eye movement function and is usually associated with orbital infections, inflammation, tumors, or carotid cavernous fistulae. There is an increased risk of arterial and venous thrombosis associated with COVID-19, the presence of which is related to a significantly increased risk of mortality. We report an index case of superior ophthalmic vein thrombosis in a 61-year-old male patient who was diagnosed with COVID-19 pneumonitis and a concomitant saddle pulmonary embolus. He was swiftly treated with low molecular weight heparin which led to the resolution of the thrombosis within 3 weeks. This case highlights the importance of considering this entity in the context of COVID-19 as well as providing prompt treatment to reduce the risk of complications.

What has happened to human fertility?

Semen quality appears to have declined in recent decades in some populations, e.g. north-western Europe. At the same time, couple fertility may have increased. Hypotheses are suggested for this apparent inconsistency. Alongside the deterioration of spermatogenesis there is clear evidence of an increase in other related problems, notably testicular cancer. The sharply rising trend in this condition started a century ago--decades earlier than sometimes thought. This and other evidence clearly indicates an environmental origin, but there is also a definite genetic component. The relationship of genetics and environment is discussed in the context of the puzzle that infertility is inherited, which appears to be impossible from an evolutionary standpoint. Poor semen quality is related not only to testicular cancer but also to zygote development, in which cancer-like disruption of the genetic apparatus is observed, with serious implications for offspring health. This needs to be seen in the context that human reproduction is prone to a higher degree of impairment than that of other mammalian species, in relation to spermatogenesis, couple fertility, early pregnancy loss and embryonic aneuploidy; female- and male-mediated pathways are both implicated. It is unclear whether such human specificity originated on an evolutionary/genetic or a historico-social timescale, which is important in relation to pathogenesis. The evidence clearly indicates that the currently most popular explanation for male reproductive system impairment, the endocrine disruption hypothesis, cannot explain the main features of the descriptive epidemiology. An alternative pathogenesis is outlined, and some possible exposures considered that could be responsible.

Improving the use of evidence in health impact assessment.

OBJECTIVE: Health impact assessment (HIA) has been proposed as one mechanism that can inform decision-making by public policy-makers. However, HIA methodology has been criticized for a lack of rigour in its use of evidence. The aim of this work was to formulate, develop and test a practical guide to reviewing publicly available evidence for use in HIA. The term evidence includes all scientific assessments, whether research studies in peer-reviewed journals or previous HIAs. METHODS: The formulation and development of the guide involved substantial background research, qualitative research with the target audience, substantial consultations with potential users and other stakeholders, a pilot study to explore content, format and usability, and peer review. Finally, the guide was tested in practice by invited volunteers who used it to appraise existing HIA evidence reviews. FINDINGS: During development, a wealth of data was generated on how the guide might be applied in practice, on terminology, on ensuring clarity of the text and on additional resources needed. The final guide provides advice on reviewing quantitative and qualitative research in plain language and is suitable for those working in public health but who may not have experience in reviewing evidence. During testing, it enabled users to discriminate between satisfactory and unsatisfactory evidence reviews. By late 2009, 1700 printed and 2500 downloaded copies of the guide had been distributed. CONCLUSION: Substantive and iterative consultation, though time-consuming, was pivotal to producing a simple, systematic and accessible guide to reviewing publicly available research evidence for use in HIA.

Methodological issues in analyzing time trends in biologic fertility: protection bias.

One method of assessing biologic fertility is to measure time to pregnancy (TTP). Accidental pregnancies do not generate a valid TTP value and lead to nonrandom missing data if couples experiencing accidental pregnancies are more fertile than the general population. If factors affecting the rate of accidental pregnancies, such as availability of effective contraception and induced abortion, vary over time, then the result may be protection bias in the estimates of fertility time trends. Six European data sets were analyzed to investigate whether evidence of protection bias exists in TTP studies of fertility trends in Europe over the past 50 years. Couples experiencing accidental pregnancies tended to be more fertile than the general population. However, trends in accidental pregnancy rates were inconsistent across countries and were insufficient to produce substantial bias in fertility trends in simulated data. Where protection bias is suspected, the authors demonstrate use of 2 multiple imputation methods to generate realizations for the missing TTP values for accidental pregnancies. Simulation studies show that both methods successfully reduce or eliminate protection bias. The authors also demonstrate that standard sensitivity analyses for dealing with accidental pregnancies provide an upper bound on the extent of any bias.

A global perspective on energy: health effects and injustices.

The exploitation of fossil fuels is integral to modern living and has been a key element of the rapid technological, social, and cultural changes of the past 250 years. Although such changes have brought undeniable benefits, this exploitation has contributed to a burden of illness through pollution of local and regional environments, and is the dominant cause of climate change. This pattern of development is therefore unsustainable at a global level. At the same time, about 2.4 billion of the world's population, disadvantaged by lack of access to clean energy, are exposed to high levels of indoor air pollutants from the inefficient burning of biomass fuels. Even in high-income countries, many people live in fuel poverty, and throughout the world, increasingly sedentary lifestyles (to which fossil-fuel-dependent transport systems contribute) are leading to chronic disease and injuries. Energy security is also an issue of growing concern to many governments in both the developed and developing world, and a potential source of international tension and conflict. In this Series, we examine the opportunities to improve health, reduce climate effects, and promote development through realistic adjustments in the way energy and food are produced and consumed.

Health, livelihoods, and nutrition in low-income rural systems.

BACKGROUND: Absolute poverty remains a major challenge: the proportion of the world population living with hunger, food insecurity, and undernutrition has fallen, but the absolute number remains stubbornly large. An even larger number of people have enough to eat but suffer from severe micronutrient deficiencies. OBJECTIVES: To provide a conceptual framework showing the interdependence of hunger and poverty with ill health among the rural poor. METHODS: Review of the relevant health, nutrition, agriculture, and economics literature and organization of the findings into a systems framework. RESULTS: Economic growth is not a sufficient answer to rural poverty. The predicament of poor households can be represented in terms of a self-reinforcing cycle involving nutrition, health, and productivity. The degree of poverty limits the quantity and quality of food intake. Macro- and micronutrient deficiencies interfere with child growth and development and impair immune function, resulting in a predisposition to infectious diseases. Health status strongly influences the quantity and quality of labor and achieved educational status. The high risk of child mortality prevents households from going through the demographic transition to smaller families and better-educated children. The death of a working adult may be catastrophic for the household. This self-reinforcing cycle means that the beneficial effects of an intervention are propagated around the cycle, potentiating its impact. Each main element--nutrition, health, and productivity--also has numerous other determinants and can be influenced by interventions. Interventions that increase the carrying capacity of the household's environment are likely to be more sustainable than "technical fixes," such as lifesaving medical treatment. CONCLUSIONS: The self-reinforcing cycle is likely to be self-perpetuating without outside intervention. For any rural area where poverty reduction is planned, the key bottlenecks need to be identified. This can be done by using a causal diagram, as described in this paper.

An adaptive significance of morning sickness? Trivers-Willard and Hyperemesis Gravidarum.

Nausea during pregnancy, with or without vomiting, is a common early indication of pregnancy in humans. The severe form, Hyperemesis Gravidarum (HG), can be fatal. The aetiology of HG is unknown. We propose that HG may be a proximate mechanism for the Trivers-Willard (T-W) evolutionary hypothesis that mothers in poor condition should favor daughters. Using Swedish linked registry data, 1987-2005, we analyze all pregnancies that resulted in an HG admission and/or a live birth, 1.65 million pregnancies in all. Consistent with the T-W hypothesis, we find that: (i) HG is associated with poor maternal condition as proxied by low education; (ii) HG in the first two months of pregnancy is associated with a 7% point increase in live girl births; and (iii) HG affected pregnancies have a 34-percent average rate of inferred pregnancy loss, higher among less educated women.

Improving health through policies that promote active travel: a review of evidence to support integrated health impact assessment.

BACKGROUND: Substantial policy changes to control obesity, limit chronic disease, and reduce air pollution emissions, including greenhouse gasses, have been recommended. Transportation and planning policies that promote active travel by walking and cycling can contribute to these goals, potentially yielding further co-benefits. Little is known, however, about the interconnections among effects of policies considered, including potential unintended consequences. OBJECTIVES AND METHODS: We review available literature regarding health impacts from policies that encourage active travel in the context of developing health impact assessment (HIA) models to help decision-makers propose better solutions for healthy environments. We identify important components of HIA models of modal shifts in active travel in response to transport policies and interventions. RESULTS AND DISCUSSION: Policies that increase active travel are likely to generate large individual health benefits through increases in physical activity for active travelers. Smaller, but population-wide benefits could accrue through reductions in air and noise pollution. Depending on conditions of policy implementations, risk tradeoffs are possible for some individuals who shift to active travel and consequently increase inhalation of air pollutants and exposure to traffic injuries. Well-designed policies may enhance health benefits through indirect outcomes such as improved social capital and diet, but these synergies are not sufficiently well understood to allow quantification at this time. CONCLUSION: Evaluating impacts of active travel policies is highly complex; however, many associations can be quantified. Identifying health-maximizing policies and conditions requires integrated HIAs.

Semen quality analysis and the idea of normal fertility.

The World Health Organization (WHO) has extensively revised its manual for semen analysis, and seeks to provide reference limits for semen quality parameters. This raises the question of what is meant by 'normal' (excluding the use of this term to denote a Gaussian distribution). It could be taken in a purely statistical sense, using a biologically arbitrary cut-off point to denote an abnormal level, typically the extreme 5 percent of the population. Alternatively, 'normal' could be defined according to the biological concept of normality and abnormality, in terms of the point at which biological function becomes impaired. Either of these can be used in descriptive epidemiology, for example, to study trends, but in the case of fertility, both semen quality and functional fertility (time to pregnancy) are continuous variables with no clear threshold. The WHO manual uses the biological meaning of normal, in that it provides the semen parameter distributions for men who have recently fathered pregnancies that took 12 months or less to conceive. However, what is really needed is the same information the other way around: given a particular semen test result, what should be expected in terms of ability to conceive, and how long it is likely to take. In considering epidemiological research, the focus has been mainly on internal comparisons, rather than reference limits, but it would be beneficial if more attention were paid to the absolute levels and to what these mean in terms of function-in other words, if the data were better calibrated biologically.