Time and chance: the stochastic nature of disease causation

On Dec, 31, 1664, Samuel Pepys, taking stock of the past year, confided to his diary: “I bless God, I never have been in so good plight as to my health … but I am at a great loss to know whether it be my Hare's foot, or taking every morning a pill of Turpentine, or my having left off the wearing of a gowne”.1We would be wrong to think that our current preoccupation with health is new. People have always been intensely concerned with what makes them sick and what keeps them well. What has changed since the 17th century is our expectations, not only of effective treatment, but also of a satisfactory explanation as to why we have become ill. For Pepys, illness and disease had to be accepted as part of the human predicament. Their causes were a matter of conjecture, and avoiding them required magic and good fortune. Nowadays, luck and magic have been replaced by risk factors. Health promotion messages lead people to believe that by adopting the right lifestyle they will stay well. Naturally, if they become ill, they demand a reason. If such a reason is not forthcoming, they imagine that this is because medical knowledge is still incomplete, and that further research will soon reveal the answer.The view that better knowledge of causation will allow us to understand why some people develop a disease whereas others do not, is widely shared by doctors and medical scientists. Think how often the introduction to a grant application contains the phrase, “the causes of X are poorly understood”, by which the authors imply that there are important, but as yet unidentified, causes waiting to be discovered and that, provided the committee has the vision to award funding, better prediction of disease occurrence and more effective prevention could be possible.Though we smile at Pepys' hare's foot amulet and turpentine pill, his doubts about their effectiveness might contain more truth than the aspirations of the grant applicants. Obviously, a patient with a disease must have been exposed to a combination of causes sufficient to induce that disease, but it does not necessarily follow that these causes are measurable or even identifiable. An analogy can be drawn with the throw of a die. The fact that a six is rolled does not mean that the die was heavily exposed to any risk factors for that outcome. Instead, this result is due to the operation of a complex set of circumstances (dimensions, shape, and weight of the die; the exact position of its centre of gravity; forces acting on it and its height above the ground when thrown; viscosity of the air; contour and elastic properties of the surface on which it landed, and so on), none of which could be shown to have a consistent effect on its own on whether the die rolls six—except, of course, in the trivial circumstance of dropping it very gently from minimum height with the six face up. In this essay we review the nature of disease causation, and argue that the role of stochastic processes is underappreciated. Advances in understanding of pathogenic mechanisms or genetic susceptibility might not enable us to explain why one person gets a disease and another does not

Fetal Origins of Adult Disease. A hypothesis about a mechanism for the programming of blood pressure and vascular disease in early life

1. There is now a great deal of evidence that people whose weight at birth was low tend to have higher blood pressure and increased risk of death from cardiovascular disease as adults.2. We argue that, in fetuses whose growth is impaired, synthesis of elastin in the walls of the aorta and large arteries is deficient and that this deficiency leads to permanent changes in the mechanical properties of these vessels.3. Over a lifetime, such changes could predispose an individual to higher blood pressure and cardiovascular disease

Growth in utero and cognitive function in adult life: follow up study of people born between 1920 and 1943

OBJECTIVES--To examine the relation between fetal growth and cognitive function in adult life. DESIGN--A follow up study of men and women whose birth weights and other measurements of body size had been recorded at birth. SETTING--Hertfordshire, Preston, and Sheffield. SUBJECTS--1576 men and women born in Hertfordshire, Sheffield, or Preston between 1920 and 1943. MAIN OUTCOME MEASURES--Intelligence quotient as measured by the AH4 test and amount of decline in cognitive function with age as estimated by the difference between score on the Mill Hill vocabulary test and score on the AH4 test. RESULTS--Score on the intelligence test was higher in people who had a large biparietal head diameter at birth, but it was not related to any other measure of body size or proportions. No association was found between decline in cognitive function and any measure of size or proportions at birth. CONCLUSION--Impaired fetal growth was not associated with poorer cognitive performance in adult life. Adaptations made by the fetus in response to conditions that retard its growth seem to be largely successful in maintaining brain development

Patterns of prescribing of nutritional supplements in the United Kingdom

Background and Aims: A large number of prescriptions are issued for nutritional supplements under British National Formulary classifications 9.4.1 (foods for special diets) and 9.4.2 (enteral feeds), but little is known about the characteristics of the patients who receive them. We used the General Practice Research Database to examine patterns of prescribing of these supplements.Methods: We selected patients who had been prescribed supplements under classifications 9.4.1 and 9.4.2 during 1996–1997. Descriptive statistics were used to examine how prescribing varied. Results: 28644 patients received prescriptions during 1996–1997. Among the 27413 (96%) patients prescribed supplements for oral use, 14750 received supplements for enteral nutrition alone, 8122 received supplements for special diets alone and 4541 had both types of supplement. 51% of patients receiving supplements for special diets were <18 years. The commonest diagnoses among such children were milk intolerance (24%) and malnutrition (17%). 94% of patients receiving supplements for enteral nutrition were adult, 52% of whom had cancer or cardiovascular disease. Only 4% of patients had weight and height recorded prior to first prescription.Conclusions: The GPRD provides valuable information on the characteristics of patients prescribed nutritional supplements. But because only limited data are available on their nutritional status prior to supplementation, it is hard to assess whether general practitioners are prescribing these supplements appropriately

An epidemiological study of renal pathology in tuberous sclerosis complex

Objectives: To report the frequency of renal symptoms and complications of patients with tuberous sclerosis complex (TSC), to describe the ultrasonographic appearance of the kidneys in a population-based sample, and to investigate the relationship between a history of renal haemorrhage and renal lesions identified by ultrasonography.Patients and Methods: As part of an epidemiological study, 179 patients with TSC were identified as living in the Wessex Region in the South of England. Patients were interviewed and examined in their homes, to elicit the presence of renal symptoms or a history of renal complications. Renal ultrasonography was used in consenting patients in their homes.Results: There was a history of renal complications in 16 (9%) patients; 149 consented to interview and examination, and 19 gave a history of renal symptoms in the previous year; 124 had renal ultrasonography; 86 (69%) had renal angiomyolipomas and 37 (30%) had renal cysts. Large lesions (>3 cm in diameter) were strongly associated with a history of symptomatic bleeding, although significant haemorrhage occurred in a 6-year-old child with small angiomyolipomas.Conclusions: The formation of angiomyolipoma in TSC is common. Polycystic kidney disease, renal carcinoma and renal failure, although rare, occur in TSC. Most patients with angiomyolipomas have neither complications nor symptoms. There was no appreciable difference between the sexes in the risk of developing these lesions. Although less commonly seen in the very young, there is no identifiable relationship after adolescence between age and the risk of having a renal angiomyolipoma. Bleeding tends to occur from large lesions (>3 cm) but most such patients have remained asymptomatic to date

Risk of macular degeneration in users of statins: cross sectional study

Atherosclerosis and abnormalities of lipid metabolism are associated with an increased risk of age related macular degenerationthe Western world's main cause of blindness. Statins (hydroxymethyl glutaryl coenzyme A reductase inhibitors) modify patients' lipid profile and lower their risk of coronary heart disease. They also prevent stroke and, possibly, Alzheimer's disease. We report here an association between statin use and lower risk of age related macular degeneration

Glucocorticoid metabolism and the Metabolic Syndrome: associations in an elderly cohort

Objective: The phenotype of the Metabolic Syndrome (hypertension, insulin resistance and hyperlipidaemia) bears similarities to Cushing's Syndrome, in which the cause of these features is elevated cortisol production. We have investigated relationships between glucocorticoid production and features of the Metabolic Syndrome in a cohort of elderly subjects.Design: A cross-sectional analysis was carried out of a subset of a birthweight cohort from Sheffield.Methods: 92 men and 40 women (aged 69-75 y) representative of the original cohort were investigated. Features of the Metabolic Syndrome (blood pressure, BMI, waist hip ratio, fasting glucose, insulin and triglycerides) were recorded and urinary glucocorticoid metabolites were measured by gas chromatography mass spectrometry.Results: Total glucocorticoid metabolites were correlated with the overall phenotype of the Metabolic Syndrome (P = 0.002), whereas specific pathways of metabolism (activity of 11?-hydroxysteroid dehydrogenases and A-ring reductases) did not show significant associations. Specifically total glucocorticoid production increased with increasing systolic blood pressure (r = 0.21, P = 0.013), fasting glucose (r = 0.19, P = 0.02) and insulin (r = 0.23, P = 0.025). Glucocorticoid production was greater with increasing abdominal girth (r = 0.19, P = 0.033), but there was no association with enhanced metabolism via a specific pathway. Within this cohort, birthweight was not associated with total glucocorticoid metabolites. However, decreasing birthweight (P = 0.022), increasing obesity (P = 0.026) and increasing total glucocorticoid production (P = 0.009) were all independent predictors of fasting glucose.Conclusions: These data support the concept that cortisol production is enhanced in the Metabolic Syndrome, although they did not confirm the recent evidence that increased cortisol secretion is predicted by low birthweight.<br/