Bradford-Hill Criteria For Causality Research Articles

Helicobacter pylori and colorectal neoplasms: a concise review.

Helicobacter pylori is the main etiological agent of all malignant tumors caused by an infectious disease. It is a major, at times dominant, factor in the pathogenesis of a large spectrum of diseases such as acute and chronic gastritis, gastric and duodenal ulcers, gastric carcinoma, and lymphoma. Epidemiological and experimental studies suggest that H. pylori chronic infection may be related to different extragastric diseases, including colorectal neoplasms. This concise review aims to explore the association of H. pylori infection with colorectal cancer and adenoma, including the recent epidemiological findings, the diagnostic methods employed to detect H. pylori and virulent factors, and the potentially involved mechanisms. Furthermore, is attempted to establish the current data integration for causal inference using the Bradford-Hill causality criteria. The weak, although global, strength of the epidemiological positive association between H. pylori infection and colonic neoplasms associated to new mechanisms postulated to explain this interaction, including intestinal dysbiosis, should stimulate future studies. Prospective confirmatory studies to establish the role of H. pylori eradication in the process of carcinogenic transformation of the colonic epithelium may define its eventual role in the treatment and prevention of colonic neoplasms.

Onchocerca volvulus and epilepsy: A comprehensive review using the Bradford Hill criteria for causation.

BackgroundThe possibility that onchocerciasis may cause epilepsy has been suggested for a long time, but thus far, an etiological link has not been universally accepted. The objective of this review is to critically appraise the relationship between Onchocerca volvulus and epilepsy and subsequently apply the Bradford Hill criteria to further evaluate the likelihood of a causal association.MethodsPubMed and gray literature published until September 15, 2020, were searched and findings from original research were synthesized. Adherence to the 9 Bradford Hill criteria in the context of onchocerciasis and epilepsy was determined to assess whether the criteria are met to strengthen the evidence base for a causal link between infection with O. volvulus and epilepsy, including the nodding syndrome.ResultsOnchocerciasis as a risk factor for epilepsy meets the following Bradford Hill criteria for causality: strength of the association, consistency, temporality, and biological gradient. There is weaker evidence supporting causality based on the specificity, plausibility, coherence, and analogy criteria. There is little experimental evidence. Considering the Bradford Hill criteria, available data suggest that under certain conditions (high microfilarial load, timing of infection, and perhaps genetic predisposition), onchocerciasis is likely to cause epilepsy including nodding and Nakalanga syndromes.ConclusionApplying the Bradford Hill criteria suggests consistent epidemiological evidence that O. volvulus infection is a trigger of epilepsy. However, the pathophysiological mechanisms responsible for seizure induction still need to be elucidated.

Acute kidney injury and adverse outcomes of critical illness: correlation or causation?

Critically ill patients who develop acute kidney injury (AKI) are more than twice as likely to die in hospital. However, it is not clear to what extent AKI is the cause of excess mortality, or merely a correlate of illness severity. The Bradford Hill criteria for causality (plausibility, temporality, magnitude, specificity, analogy, experiment & coherence, biological gradient and consistency) were applied to assess the extent to which AKI may be causative in adverse short-term outcomes of critical illness.Plausible mechanisms exist to explain increased risk of death after AKI, both from direct pathophysiological effects of renal dysfunction and mechanisms of organ cross-talk in multiple-organ failure. The temporal relationship between increased mortality following AKI is consistent with its pathophysiology. AKI is associated with substantially increased mortality, an association that persists after accounting for known confounders. A biological gradient exists between increasing severity of AKI and increasing short-term mortality. This graded association shares similar features to the increased mortality observed in ARDS; an analogous condition with a multifactorial aetiology. Evidence for the outcomes of AKI from retrospective cohort studies and experimental animal models is coherent however both of these forms of evidence have intrinsic biases and shortcomings. The relationship between AKI and risk of death is maintained across a range of patient ages, comorbidities and underlying diagnoses.In conclusion many features of the relationship between AKI and short-term mortality suggest causality. Prevention and mitigation of AKI and its complications are valid targets for studies seeking to improve short-term survival in critical care.

Intestinal dysbiosis and necrotizing enterocolitis: assessment for causality using Bradford Hill criteria.

In recent years, several studies have shown that premature infants who develop NEC frequently display enteric dysbiosis with increased Gram-negative bacteria for several days to weeks prior to NEC onset. The importance of these findings, for the possibility of a causal role of these bacteria in NEC pathogenesis, and for potential value of gut dysbiosis as a biomarker of NEC, is well-recognized. In this review, we present current evidence supporting the association between NEC in premature infants and enteric dysbiosis, and its evaluation using the Bradford Hill criteria for causality. To provide an objective appraisal, we developed a novel scoring system for causal inference. Despite important methodological and statistical limitations, there is support for the association from several large studies and a meta-analysis. The association draws strength from strong biological plausibility of a role of Gram-negative bacteria in NEC and from evidence for temporality, that dysbiosis may antedate NEC onset. The weakness of the association is in the low level of consistency across studies, and the lack of specificity of effect. There is a need for an improved definition of dysbiosis, either based on a critical threshold of relative abundances or at higher levels of taxonomic resolution.

Dietary Glycemic Index and Load and the Risk of Type 2 Diabetes: Assessment of Causal Relations

While dietary factors are important modifiable risk factors for type 2 diabetes (T2D), the causal role of carbohydrate quality in nutrition remains controversial. Dietary glycemic index (GI) and glycemic load (GL) have been examined in relation to the risk of T2D in multiple prospective cohort studies. Previous meta-analyses indicate significant relations but consideration of causality has been minimal. Here, the results of our recent meta-analyses of prospective cohort studies of 4 to 26-y follow-up are interpreted in the context of the nine Bradford-Hill criteria for causality, that is: (1) Strength of Association, (2) Consistency, (3) Specificity, (4) Temporality, (5) Biological Gradient, (6) Plausibility, (7) Experimental evidence, (8) Analogy, and (9) Coherence. These criteria necessitated referral to a body of literature wider than prospective cohort studies alone, especially in criteria 6 to 9. In this analysis, all nine of the Hill’s criteria were met for GI and GL indicating that we can be confident of a role for GI and GL as causal factors contributing to incident T2D. In addition, neither dietary fiber nor cereal fiber nor wholegrain were found to be reliable or effective surrogate measures of GI or GL. Finally, our cost–benefit analysis suggests food and nutrition advice favors lower GI or GL and would produce significant potential cost savings in national healthcare budgets. The high confidence in causal associations for incident T2D is sufficient to consider inclusion of GI and GL in food and nutrient-based recommendations.

Web of Causation between Dietary Patterns and Childhood Obesity: Applying Hill's Criteria

Abstract Since their publication in 1965, the Bradford Hill criteria for causality have been largely used as a framework for causal inference in epidemiology. We aim at employing this classical approach to shed new light onto the web of causation of childhood obesity. Although the fundamental cause of obesity is the long-term imbalance between energetic need and intake, this medical condition is multifactorial in its origin, influenced by genetic, behavioral, socioeconomic, and environmental factors. This imbalance leads to accumulation of excessive adipose tissue. Observational studies tend to mostly quantify association between dietary factors and accumulation of adipose tissue. On the other hand, multivariate analysis proved some of these associations to be spurious, therefore prospective trials are needed to demonstrate causality. Short term experimental studies have been conducted to identify unique dietary pattern changes on specific outcomes, but long term, community-based studies would offer more comprehensive answers on dietary pattern effects. We conducted a literature review on PubMed, Scopus, Web of Science, and Google Scholar. From a total of 323 papers identified at first stage, we further discuss the applicability of Bradford Hill criteria for 31 articles, by examples of dietary patterns and accumulation of excess body fat as exposure-response associations. We also put forward and analyzed the evidence prospective studies would bring, as foundation for future interventions.

Evidence of a Causal Relationship Between Smoking Tobacco and Schizophrenia Spectrum Disorders.

There has been emerging evidence of an association between tobacco smoking and schizophrenia spectrum disorders (SSD). Two meta-analyses have reported that people who smoke tobacco have an ~2-fold increased risk of incident schizophrenia or psychosis, even after adjusting for confounding factors. This study aimed to critically appraise the research which has examined the association between tobacco smoking and SSD against the Bradford Hill criteria for causality, to determine the strength of the evidence for a causal relationship. Eight longitudinal studies (seven cohort studies and one case control study) were identified which examined tobacco smoking as an exposure and psychosis as an outcome. All seven cohort studies were assessed as being of high quality using the Newcastle-Ottawa Scale. Six of the eight studies found a statistically significant positive association between tobacco smoking and onset of SSD. These studies reported a consistent association with a moderate to large effect size and a dose response relationship. The studies adjusted for multiple potential confounders including age, sex, socioeconomic status, shared genetic risk, prodromal symptoms, and comorbid cannabis and other substance use. The studies did not adjust for exposure to childhood trauma or prenatal tobacco. There was substantial though inconclusive evidence supporting a causal relationship between tobacco smoking and increased risk of SSD. If a causal relationship does exist, nicotine is most likely responsible for this association. This raises serious public health concerns about the increasing use of e-cigarettes and other products, particularly by adolescents whose nicotine use may increase their risk of SSD. Research is urgently needed to examine the association between e-cigarette use and incident psychosis, particularly in adolescents and young adults.

LDL-C does not cause cardiovascular disease: a comprehensive review of the current literature

ABSTRACTIntroduction: For half a century, a high level of total cholesterol (TC) or low-density lipoprotein cholesterol (LDL-C) has been considered to be the major cause of atherosclerosis and cardiovascular disease (CVD), and statin treatment has been widely promoted for cardiovascular prevention. However, there is an increasing understanding that the mechanisms are more complicated and that statin treatment, in particular when used as primary prevention, is of doubtful benefit.Areas covered: The authors of three large reviews recently published by statin advocates have attempted to validate the current dogma. This article delineates the serious errors in these three reviews as well as other obvious falsifications of the cholesterol hypothesis.Expert commentary: Our search for falsifications of the cholesterol hypothesis confirms that it is unable to satisfy any of the Bradford Hill criteria for causality and that the conclusions of the authors of the three reviews are based on misleading statistics, exclusion of unsuccessful trials and by ignoring numerous contradictory observations.

Impact des benzodiazépines sur les fonctions cognitives et le risque de démence. Revue des arguments de causalité issus des études observationnelles

Benzodiazepines are a source of well-known adverse reactions related to their pharmacological properties: memory disorders, falls in the elderly, confusion and sedation, drug addiction. The impact of their chronic use on cognitive decline and dementia has been the subject of many studies for two decades. From 25 studies identified in the international literature from 1997 to 2017, the Bradford-Hill causality criteria were systematically applied. Fifteen studies found a statistically significant association with a deleterious effect, two a protective effect and eight did not find any association. The most recent studies using a longer delay to take into account a protopathic bias did not find any association or any dose-effect relationship. The majority of studies suggest impaired cognitive functions for contemporary consumption or those closest to the event being studied. Finally, the biological plausibility remains discussed. The question of the role of benzodiazepines in the onset of dementia remains open, and other studies attempting to limit previous methodological drawbacks should be carried out.

Perspective: Scientific and ethical concerns pertaining to animal models of autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA).

The autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA) was first described in 2011. The aluminium containing adjuvants of vaccines were stated to be one of the main causes of the condition. Other disorders associated with ASIA include siliconosis, Gulf war syndrome, sick building syndrome and the macrophagic myositis syndrome. We have recently reviewed ASIA as defined by its authors. We have shown that the definition of ASIA is imprecise and includes all patients with an autoimmune disorder as well as potentially the entire population. Application of the Bradford Hill criteria for causality does not support ASIA as an outcome of exposure to aluminium containing adjuvants in vaccines. The advocates of ASIA highlight animal models as evidence for the existence of the disorder. However, as this review will demonstrate, animal models purporting to support the existence of ASIA have methodological, analytical and ethical flaws which, in our view, refute the existence of the condition. Three publications by the advocates of ASIA were recently retracted from peer-reviewed journals. We call for an immediate moratorium on animal experiments of ASIA until an independent inquiry has been conducted to determine the existence of a clinically relevant syndrome, identifiable as ASIA in humans.

Evidence for chronic mechanical irritation as a causative factor in oral cancer: application of Bradford Hill criteria

Chronic mechanical irritation (CMI) of the oral mucosa has been proposed as a risk factor for oral cancer (OC), but the available evidence is limited and controversial. One of the main limitations is the lack of proper criteria to define and classify CMI. The objective of this narrative review is to apply the Bradford Hill causality criteria to assess such an association based on the published literature. The level of evidence is not conclusive, mainly due to methodological shortcomings. Hence, to systematize future CMI research, we recommend the following items should be included: a clear definition for CMI, ascertaining any temporal association, recording all types of CMI: dental, prosthetic, and functional. Finally, it is important to emphasize that studies dealing with risk factors for OC should not only be restricted to established factors such as tobacco, alcohol, and areca nut consumption but should also consider other factors including the patient’s dental condition. In this regard, CMI, tooth loss, periodontal disease, and many others could be included. The causality criteria set out by Bradford Hill could be used for studying different controversial risk factors for OC.

Evidence for the effectiveness of minimum pricing of alcohol: a systematic review and assessment using the Bradford Hill criteria for causality

ObjectivesTo assess the evidence for price-based alcohol policy interventions to determine whether minimum unit pricing (MUP) is likely to be effective.DesignSystematic review and assessment of studies according to Preferred Reporting...

A critical assessment of the association between postnatal toxoplasmosis and epilepsy in immune-competent patients

While postnatal toxoplasmosis in immune-competent patients is generally considered a self-limiting and mild illness, it has been associated with a variety of more severe clinical manifestations. The causal relation with some manifestations, e.g. myocarditis, has been microbiologically proven, but this is not unequivocally so for other reported associations, such as with epilepsy. We aimed to systematically assess causality between postnatal toxoplasmosis and epilepsy in immune-competent patients. A literature search was performed. The Bradford Hill criteria for causality were used to score selected articles for each component of causality. Using an arbitrary but defined scoring system, the maximal score was 15 points (13 for case reports). Of 704 articles, five case reports or series and five case–control studies were selected. The strongest evidence for a causal relation was provided by two case reports and one case–control study, with a maximal causality score of, respectively, 9/13, 10/13 and 10/15. The remaining studies had a median causality score of 7 (range 5–9). No selection bias was identified, but 6/10 studies contained potential confounders (it was unsure whether the infection was pre- or postnatal acquired, or immunodeficiency was not specifically excluded). Based on the evaluation of the available literature, although scanty and of limited quality, a causal relationship between postnatal toxoplasmosis and epilepsy seems possible. More definite proof requires further research, e.g. by performing Toxoplasma serology in all de novo epilepsy cases.

Task-Specific Dystonia in Professional Musicians. A Systematic Review of the Importance of Intensive Playing as a Risk Factor.

Focal dystonia in professional musicians is a movement disorder that manifests itself during playing. It is a multifactorial condition in which a genetic predisposition and exogenous factors both play a role. Evidence suggests that intensive playing is a risk factor for the development of task-specific dystonia in professional musicians. This review is based on pertinent publications (1950-2013) retrieved by a systematic search in medical and musicological databases. The references of the retrieved publications were also considered in the search. 16 articles with clinical information on a total of 1144 affected musicians were reviewed systematically. Their overall quality was intermediate to poor, and a meta-analysis was therefore not possible. The Bradford Hill criteria were applied to study a possible causative link between intensive playing and musician's dystonia. Musician's dystonia generally arises after at least ten years of intensive playing (corresponding to roughly 10 000 hours of practice). An association was found between the affected limb and the type of instrument: the limb that is subject to the greatest fine motor demands is the one most commonly affected. The average age of onset is 28 to 44 years. The Bradford Hill causality criteria indicate that intensive playing is related to the development of musician's dystonia. In particular, the association of the type of instrument with the site of dystonia supports this thesis. The findings imply that task-specific dystonia in professional musicians should be included in the list of occupational diseases in Germany.

Bradford Hill Criteria and the Case for γ‐Tocopherol as an Essential Dietary Nutrient in the Prevention of Nitrogen Oxide‐mediated Cellular Damage and Associated Chronic Diseases of Aging.

The nutrition field is awash with recommendations for the benefits of “antioxidants” for the prevention of chronic diseases of aging, e.g. cancer, yet evidence of efficacy in humans for individual antioxidants is limited to cell culture, animal studies, or to epidemiologic associations. Indeed, large clinical trials with relatively high doses of the most promising antioxidant agents, β‐carotene and α‐tocopherol, have paradoxically demonstrated pro‐carcinogenic effects in humans. γ‐Tocopherol is an ubiquitous dietary antioxidant which is typically found at micromolar levels in humans. It possesses unique antioxidant properties that specifically target nitrogen oxide species capable of damaging DNA in cells. Data from published studies of the chemistry of γ‐tocopherol, its biology, its epidemiology, its effects on animal models of disease and clinical effects of decreased levels in humans are assessed in light of the Bradford Hill criteria for causality in order to establish a prima facie case for the essentiallity of γ‐tocopherol in human nutrition. While the epidemiology of γ‐tocopherol is uniquely complex, its coherence with fundamental studies of γ‐tocopherol and the plausibility provided by our understanding of its chemical mechanism of action and unique biological effects add considerable weight to epidemiological and clinical observations of its associations with chronic diseases of aging. Taken together, the evidence supports a beneficial effect of and possible requirement for moderate intake of γ‐tocopherol in the diet, however, it is unlikely that significantly higher intake beyond levels found in the typical American diet would offer additional benefit.

Chronic Aluminum Intake Causes Alzheimer's Disease: Applying Sir Austin Bradford Hill's Causality Criteria

Industrialized societies produce many convenience foods with aluminum additives that enhance various food properties and use alum (aluminum sulfate or aluminum potassium sulfate) in water treatment to enable delivery of large volumes of drinking water to millions of urban consumers. The present causality analysis evaluates the extent to which the routine, life-long intake, and metabolism of aluminum compounds can account for Alzheimer's disease (AD), using Austin Bradford Hill's nine epidemiological and experimental causality criteria, including strength of the relationship, consistency, specificity, temporality, dose-dependent response, biological rationale, coherence with existing knowledge, experimental evidence, and analogy. Mechanisms that underlie the risk of low concentrations of aluminum relate to (1) aluminum's absorption rates, allowing the impression that aluminum is safe to ingest and as an additive in food and drinking water treatment, (2) aluminum's slow progressive uptake into the brain over a long prodromal phase, and (3) aluminum's similarity to iron, in terms of ionic size, allows aluminum to use iron-evolved mechanisms to enter the highly-active, iron-dependent cells responsible for memory processing. Aluminum particularly accumulates in these iron-dependent cells to toxic levels, dysregulating iron homeostasis and causing microtubule depletion, eventually producing changes that result in disconnection of neuronal afferents and efferents, loss of function and regional atrophy consistent with MRI findings in AD brains. AD is a human form of chronic aluminum neurotoxicity. The causality analysis demonstrates that chronic aluminum intake causes AD.

Is puberty a risk factor for back pain in the young? a systematic critical literature review

Back pain is a common condition that starts early in life and seems to increase markedly during puberty. A systematic review was performed in order to investigate the link between puberty and back pain, using some Bradford Hill criteria for causality. We sought to obtain answers to the following questions: 1) Is there an association between puberty and back pain? If so, how strong is this association? And do the results remain unchanged also when controlling for age and sex? 2) Are the results of the studies consistent? 3) Is there a dose-response, showing a link between the increasing stages of puberty and the subsequent prevalence of back pain? 4) Is there a temporal link between puberty and back pain? A systematic critical literature review. Systematic searches were made in March 2014 in PubMed, Embase, CINAHL and PsycINFO including longitudinal or cross-sectional studies on back pain for subjects <19 years, written in French or English. The review process followed the AMSTAR recommendations. Interpretation was made using some of the Bradford-Hill criteria for causality. Four articles reporting five studies were included, two of which were longitudinal. 1) Some studies show a weak and others a strong positive association between puberty and back pain, which remains after controlling for age and sex; 2) Results were consistent across the studies; 3) There was a linear increase of back pain according to the stage of puberty 4) Temporality has not been sufficiently studied. All our criteria for causality were fulfilled or somewhat fulfilled indicating the possibility of a causal link between puberty and back pain. Future research should focus on specific hypotheses, for example investigating if there could be a hormonal or a biomechanical aspect to the development of back pain at this time of life.

A Qualitative Systematic Review of the Literature Supporting a Causal Relationship between Exit-Site Infection and Subsequent Peritonitis in Patients with End-Stage Renal Disease Treated with Peritoneal Dialysis

The objective of our research was to summarize and review evidence supporting a causal relationship between exit-site infection and peritonitis in peritoneal dialysis (PD) patients. We undertook a qualitative review of studies retrieved from MEDLINE, EMBASE, and PubMed, and supplemented that process with a hand search of references and abstracts in the literature. Our quality criteria were based on the Paediatric Risk of Mortality guidelines, definitions, and recommendations from the International Society for Peritoneal Dialysis (ISPD), and the Bradford Hill criteria for causality. All identified abstracts were reviewed for content. Of 776 abstracts, 59 were selected for full-text evaluation, and 22 of those met the ISPD criteria for good-quality research in PD-related infections. Of the 22 eligible studies, 9 met the study's quality criteria and were included in the summative analysis. No articles reported sufficient data for a quantitative analysis. Information on study design, study population characteristics, definitions, peritonitis rates, exit-site care protocol, exit-site treatment protocol, follow-up period, potential bias, and outcomes was extracted. Criteria for including data in the final study were determined using ISPD guidelines. Of the 9 included studies, 8 suggested that a history of exit-site infection increased the risk for subsequent peritonitis. Of those studies, 3 met 5 causality criteria, 4 met 4 causality criteria, and 1 met 3 causality criteria. The literature provides weak evidence to support a causal relationship between exit-site infection and subsequent peritonitis. Few criteria for causation were met. We were unable to attribute causation and could assume an association only. The exclusion of studies focusing on PD-related tunnel infections may be viewed as both a strength and a limitation of the present work.

Quality of case reports of adverse drug reactions with psychotropic drugs: a 25‐year review

Case reports of adverse reactions with psychotropic drugs can be useful in raising hypotheses, to be tested with more rigorous study designs. However such reports have significant methodological drawbacks, making it hard to determine causality. We undertook a systematic assessment of the quality of case reports and small case series published within Human Psychopharmacology over 25 years. For reports of adverse drug reactions, modified Bradford Hill criteria for causality (for consistency, strength, specificity, temporal relationship and plausibility) were used to ascertain the quality of the account. Reports which had been cited at least 10 times by December 2010 were examined in detail, to assess their overall contribution in extending understanding and influencing clinical practice. Of 40 reports of adverse drug reactions, only seven were sufficiently robust for confidence in probable or possible causality. Nine reports had been cited more than 10 times: the five most frequently cited reports of adverse drug reactions described movement disorders, suicidal thoughts and discontinuation symptoms with SSRIs: clinical relevance was high, but their quality was not markedly greater than less frequently cited reports. Nearly all reports of adverse drug reactions, published in a single journal over 25 years, were insufficiently robust to demonstrate probable causality. Reports that are cited frequently become influential because of their potential clinical relevance, rather than due to their methodological quality.

Examining the evidence on the causal effect of HAART on transmission of HIV using the Bradford Hill criteria.

In recent years, evidence has accumulated regarding the ability of HAART to prevent HIV transmission. Early supportive evidence was derived from observational, ecological and population-based studies. More recently, a randomized clinical trial showed that immediate use of HAART led to a 96% decrease in HIV transmission events within HIV serodiscordant heterosexual couples. However, the generalizability of the effect of HAART, and the population-level impact on HIV transmission continues to generate substantial debate. We, therefore, conducted a review of the evidence regarding the preventive effect of HAART on HIV transmission within the context of the Bradford Hill criteria for causality. Taken together, we find the accumulated evidence supporting HIV treatment as prevention meets each of the Bradford Hill criteria for causality. We conclude that the opportunity cost of inaction while waiting for additional evidence on the generalizability of effect in other risk groups is too high. Efforts should be redoubled to mobilize the financial capital and political will to optimize implementation of HIV Treatment as Prevention strategies on a wide scale.