Question

A cohort study was conducted to examine the association between serum nutrient levels collected from males in 1975 and the development of prostate cancer diagnosed after 1985. The following results were obtained for serum levels of vitamins A and E tested in blood samples taken from the study participants upon entering the study:

	Relative risks for prostate cancer by quartile of serum nutrients (from lowest to highest)
Nutrient	Lowest Quartile	2nd quartile	3rd quartile	Highest quartile
Vitamin A	1.00	0.83	0.65	0.41
Vitamin E	1.00	1.72	1.69	1.00

1. What Hill criteria for making causal inferences support the conclusion from the study that higher levels of vitamin A are protective against prostate cancer? Provide detailed explanation.

Answer 1

We used the Bradford Hill guidelines to derive a causation score based on 4 criteria(strength, consistency, temporality, and coherence) for each dietary exposure in cohort studies and examined for consistency with the findings of randomized trials.

Bradford Hill's criteria had been widely accepted as useful guidelines for investigating causality in epidemiologicalstudies but their value has been questioned because they have become somewhat outdated. ^[2]

In addition, their method of application is debated.^{[citation needed]} Some proposed options how to apply them include:

1. Using a counterfactualconsideration as the basis for applying each criterion.^[3]
2. Subdividing them into three categories: direct, mechanistic and parallelevidence, expected to complement each other. This operational reformulation of the criteria has been recently proposed in the context of evidence-based medicine.^[4]
3. Considering confounding factors and bias.^[5]
4. Using Hill’s criteria as a guide, but not considering them to give definitive conclusions.^[6]
5. Separating causal association and interventions, because interventions in public health are more complex than can be evaluated by use of Hill’s criteria^[7]

An argument against the use of Bradford Hill criteria as exclusive considerations in proving causality is that the basic mechanism of proving causality is not in applying specific criteria—whether those of Bradford Hill or counterfactual argument—but in scientific common sense deduction.^[8] Others argue that the specific study from which data has been produced is important, and while the Bradford Hill criteria may be applied to test causality in these scenarios, the study type may rule out deducing or inducing causality, and the criteria are only of use in inferring the best explanation of this data.^[9]

Debate over the scope of application of the criteria includes, whether they can be applied to social sciences.^[10]The argument proposes that there are different motives behind defining causality; the Bradford Hill criteria applied to complex systems such as health sciences are useful in prediction models where a consequence is sought; explanation models as to why causation occurred are deduced less easily from Bradford Hill criteria because the instigation of causation, rather than the consequence, is needed for these models.

Prostate cancer risk was examined in relation to intakes of fruit, vegetables, β-carotene and retinol. Subjects were a cohort of 1985 men previously to asbestos who participated in a cancer prevention programme of β-carotene and retinol supplements that commenced in July 1990. Diet was assessed at entry to the programme. Ninety-seven cases of prostate cancer were identified during follow-up until the end of 2004. A decreased prostate cancer risk was observed with increasing intakes of vitamin C-rich vegetables, including bell peppers and broccoli. Fruit, other vegetables and vitamin A intakes did not appear to be strong factors in the development of prostate cancer in this study.

Scientists funded by Yorkshire Cancer Research at the University of York have discovered that retinoic acid – a chemical made from vitamin A which is supplied in our diet by carrots, green vegetables and liver – can turn specific genes within prostate cancer stem cellsback on, reducing the ability of the cancer to invade surrounding tissue.

The findings suggest that Vitamin A related compounds could be used to enhance clinical treatments for prostate cancer.

Professor Norman Maitland, Director of the YCR Cancer Research Unit in the Department of Biology at York, said: "Cancer arises from healthy cells going wrong. Certain controls can be turned off which allows the cancer to progress. For example, normal cells gain the ability to grow and invade the surrounding tissues.

"We have found that specific 'twin' genes are turned off in malignant prostate cancer stem cells. When we turn them back on using retinoic acid, the cancer becomes less aggressive.

"All-trans retinoic acid is already used treat another type of cancer called acute promyelomcytic leukaemia (APL) and has been hugely successful in improving survival rates. For prostate cancer, our work suggests that retinoic acid would not need to kill the cancer stem cells, but simply switch them to a more treatable form. Our discovery suggests a clinical use of this compound to treat prostate cancer."

Nearly 41,000 men are diagnosed with prostate cancer every year in the UK, and although around 80% survive for five years, more than 10,000 men die annually from the disease.

Professor Maitland added: "It has been known for many years that low vitamin A in samples of men's blood is associated with prostate cancer, but nobody knew the mechanisms involved. This is an exciting new development which links an element from our diet to prostate cancer stem cells."

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