The Value of Risk-Factor (“Black-Box”) Epidemiology

Risk-factor epidemiology has been denigrated by some as an empty search for associations, unguided by underlying theory. It has been defended for occasionally identifying useful (if poorly understood) potential interventions. We further defend risk-factor epidemiology as a valuable source of seemingly unrelated facts that await coherent explanation by novel theories and that provide empiric tests of theories. We illustrate these points with a theory that invokes lipid peroxidation as an explanation of an apparently incoherent accumulation of facts about renal-cell carcinoma.1 The example illustrates the value of viewing epidemiologic, laboratory, and clinical observations as a body of facts demanding explanation by proposed causal theories, whether or not those observations were collected with any hypothesis in mind.

[1]  J. Salonen,et al.  The Kuopio Atherosclerosis Prevention Study (KAPS): effect of pravastatin treatment on lipids, oxidation resistance of lipoproteins, and atherosclerotic progression. , 1995, The American journal of cardiology.

[2]  A. Dobrian,et al.  Development of hypertension in a rat model of diet-induced obesity. , 2000, Hypertension.

[3]  G. Aykaç-toker,et al.  Increased lipid peroxidation in serum and low-density lipoproteins associated with aging in humans. , 2002, International journal for vitamin and nutrition research. Internationale Zeitschrift fur Vitamin- und Ernahrungsforschung. Journal international de vitaminologie et de nutrition.

[4]  C. Shapira,et al.  Low density lipoprotein isolated from patients with essential hypertension exhibits increased propensity for oxidation and enhanced uptake by macrophages: a possible role for angiotensin II. , 1994, Atherosclerosis.

[5]  R. Solà,et al.  Simvastatin decreases aldehyde production derived from lipoprotein oxidation. , 1999, The American journal of cardiology.

[6]  J. Morrow,et al.  Antioxidant supplementation decreases lipid peroxidation biomarker F(2)-isoprostanes in plasma of smokers. , 2002, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[7]  G. Martiny-Baron,et al.  Reversion of deregulated expression of vascular endothelial growth factor in human renal carcinoma cells by von Hippel-Lindau tumor suppressor protein. , 1996, Cancer research.

[8]  The imbalance between thromboxane and prostacyclin in preeclampsia is associated with an imbalance between lipid peroxides and vitamin e in maternal blood , 1992, American journal of obstetrics and gynecology.

[9]  N. Tejani,et al.  Renal-cell carcinoma and mesangiocapillary glomerulonephritis presenting as severe pre-eclampsia. , 1978, New York state journal of medicine.

[10]  P. Cin,et al.  Precancerous Lesions in the Kidney , 2000, Scandinavian journal of urology and nephrology. Supplementum.

[11]  R. de Caterina,et al.  Low-Density Lipoprotein Level Reduction by the 3-Hydroxy-3-Methylglutaryl Coenzyme-A Inhibitor Simvastatin Is Accompanied by a Related Reduction of F2-Isoprostane Formation in Hypercholesterolemic Subjects: No Further Effect of Vitamin E , 2002, Circulation.

[12]  D A Savitz,et al.  In defense of black box epidemiology. , 1994, Epidemiology.

[13]  L. V. Van Gaal,et al.  The in vitro oxidizability of lipoprotein particles in obese and non-obese subjects. , 1998, Atherosclerosis.

[14]  M. Yu,et al.  Increased risk of renal cell carcinoma subsequent to hysterectomy. , 1999, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[15]  S. Okada,et al.  Subacute nephrotoxicity and induction of renal cell carcinoma in mice treated with ferric nitrilotriacetate. , 1987, Cancer research.

[16]  B Järvholm,et al.  Obesity, hypertension, and the risk of kidney cancer in men. , 2000, The New England journal of medicine.

[17]  T. Vasankari,et al.  EFFECT OF WEIGHT REDUCTION ON LDL OXIDATION 747 , 1997 .

[18]  Petr Skrabanek,et al.  The Poverty of Epidemiology , 2015, Perspectives in biology and medicine.

[19]  D. Mikhailidis,et al.  Statins and Renal Function , 2002, Angiology.

[20]  L. V. van Tits,et al.  Atorvastatin and simvastatin in patients on hemodialysis: effects on lipoproteins, C-reactive protein and in vivo oxidized LDL. , 2003, Journal of nephrology.

[21]  Y. Masubuchi,et al.  A possible mechanism of naproxen-induced lipid peroxidation in rat liver microsomes. , 2001, Pharmacology & toxicology.

[22]  R. Klausner,et al.  Post-transcriptional regulation of vascular endothelial growth factor mRNA by the product of the VHL tumor suppressor gene. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[23]  M Linet,et al.  Cancer incidence in a population-based cohort of patients hospitalized with diabetes mellitus in Denmark. , 1997, Journal of the National Cancer Institute.

[24]  M. Yu,et al.  Hypertension, obesity and their medications in relation to renal cell carcinoma. , 1998, British Journal of Cancer.

[25]  K. Rothman,et al.  Policy Recommendations in Epidemiology Research Papers , 1993 .

[26]  M. Runge,et al.  Induction of vascular endothelial growth factor in balloon-injured baboon arteries. A novel role for reactive oxygen species in atherosclerosis. , 1997, Circulation research.

[27]  A. Takeshita,et al.  Greater Oxidative Stress in Healthy Young Men Compared With Premenopausal Women , 2002, Arteriosclerosis, thrombosis, and vascular biology.

[28]  S. Okada,et al.  Sex Hormone‐dependent Renal Cell Carcinogenesis Induced by Ferric Nitrilotriacetate in Wistar Rats , 1995, Japanese journal of cancer research : Gann.

[29]  M. Yu,et al.  Regular use of analgesics is a risk factor for renal cell carcinoma , 1999, British Journal of Cancer.

[30]  J L Warren,et al.  Rising incidence of renal cell cancer in the United States. , 1999, JAMA.

[31]  P. Skrabanek The epidemiology of errors , 1993, The Lancet.

[32]  T. Lash,et al.  A Sensitivity Analysis to Separate Bias Due to Confounding from Bias Due to Predicting Misclassification by a Variable That Does Both , 2000, Epidemiology.

[33]  Jian-Min Yuan,et al.  Lipid peroxidation: a novel and unifying concept of the etiology of renal cell carcinoma (United States) , 2002, Cancer Causes & Control.

[34]  P. Boyle,et al.  Cancers of the kidney and urinary tract in patients on dialysis for end-stage renal disease: analysis of data from the United States, Europe, and Australia and New Zealand. , 2003, Journal of the American Society of Nephrology : JASN.

[35]  D. A. Chow Reduced tumorigenicity of threshold syngeneic tumor inocula in XID‐bearing mice treated with natural antibodies , 1995, International journal of cancer.

[36]  A. M. al Senaidy,et al.  Effects of smoking on serum levels of lipid peroxides and essential fat-soluble antioxidants. , 1997, Nutrition and health.

[37]  S. Greenland When Should Epidemiologic Regressions Use Random Coefficients? , 2000, Biometrics.

[38]  A. Wolk,et al.  The role of diabetes mellitus in the aetiology of renal cell cancer , 1999, Diabetologia.

[39]  L. Appel,et al.  Association between cigarette smoking and lipid peroxidation in a controlled feeding study. , 1997, Circulation.

[40]  T. Akçay,et al.  EFFECT OF SEX HORMONES ON LIPID PEROXIDATION IN WOMEN WITH POLYCYSTIC OVARY SYNDROME, HEALTHY WOMEN, AND MEN , 2001, Endocrine research.

[41]  Gary James Jason,et al.  The Logic of Scientific Discovery , 1988 .

[42]  J. Morrow,et al.  Factors associated with oxidative stress in human populations. , 2002, American journal of epidemiology.

[43]  J. Hankin,et al.  Cruciferous vegetables in relation to renal cell carcinoma , 1998, International journal of cancer.

[44]  S Greenland,et al.  Basic methods for sensitivity analysis of biases. , 1996, International journal of epidemiology.

[45]  U. Das,et al.  Are free radicals involved in the pathobiology of human essential hypertension? , 1993, Free radical research communications.

[46]  C. Hsieh,et al.  Pregnancy and risk of renal cell cancer: a population-based study in Sweden , 2002, British Journal of Cancer.

[47]  P. Skrabanek Has risk-factor epidemiology outlived its usefulness? , 1993, American journal of epidemiology.

[48]  W. Kaelin,et al.  Negative regulation of hypoxia-inducible genes by the von Hippel-Lindau protein. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[49]  S. Toyokuni,et al.  Formation of 8‐hydroxy‐2′‐deoxyguanosine and 4‐hydroxy‐2‐nonenal‐modified proteins in human renal‐cell carcinoma , 1994, International journal of cancer.

[50]  C. Drevon,et al.  Peroxidation of LDL from combined-hyperlipidemic male smokers supplied with omega-3 fatty acids and antioxidants. , 1997, Arteriosclerosis, thrombosis, and vascular biology.

[51]  S. Hashimoto N-ethyl-N-hydroxyethylnitrosamine によるラット腎腫瘍発生過程における高脂血症治療剤の影響に関する研究 , 1992 .

[52]  E. Hickey,et al.  Diclofenac induced in vivo nephrotoxicity may involve oxidative stress-mediated massive genomic DNA fragmentation and apoptotic cell death. , 2001, Free radical biology & medicine.

[53]  P Skrabanek,et al.  The emptiness of the black box. , 1994, Epidemiology.

[54]  M. Uysal,et al.  Lipid peroxidation in patients with essential hypertension. , 1986, International journal of clinical pharmacology, therapy, and toxicology.

[55]  H. Adami,et al.  International renal‐cell cancer study. VIII. Role of diuretics, other anti‐hypertensive medications and hypertension , 1995, International journal of cancer.

[56]  K. Yagi,et al.  Female hormones act as natural antioxidants--a survey of our research. , 1997, Acta biochimica Polonica.

[57]  S. Olusi Obesity is an independent risk factor for plasma lipid peroxidation and depletion of erythrocyte cytoprotectic enzymes in humans , 2002, International Journal of Obesity.

[58]  S. Hashimoto [Study on the effects of the hypocholesteremic agents, cholestyramine and compactin on the induction of renal tumors in rats by N-ethyl-N-hydroxyethyl nitrosamine]. , 1992, Nihon Hinyokika Gakkai zasshi. The japanese journal of urology.

[59]  J. Fraumeni,et al.  Reproductive factors and the risk of renal cell cancer among women , 1995, International journal of cancer.

[60]  H. Adami,et al.  International renal‐cell cancer study. V. Reproductive factors, gynecologic operations and exogenous hormones , 1995, International journal of cancer.

[61]  H. Adami,et al.  International renal cell cancer study. VII. role of diet , 1996, International journal of cancer.

[62]  C. Redman,et al.  Circulating markers of oxidative stress are raised in normal pregnancy and pre‐eclampsia , 1998, British journal of obstetrics and gynaecology.

[63]  J. Mclaughlin,et al.  International renal‐cell‐cancer study. VI. The role of medical and family history , 1996, International journal of cancer.

[64]  S. Okada,et al.  Vitamin E inhibits apoptosis, DNA modification, and cancer incidence induced by iron-mediated peroxidation in Wistar rat kidney. , 1997, Cancer research.

[65]  H. Tamai,et al.  Antioxidant vitamin levels in plasma and low density lipoprotein of obese girls. , 1998, Free radical research.

[66]  S. Toyokuni,et al.  Combined histochemical and biochemical analysis of sex hormone dependence of ferric nitrilotriacetate-induced renal lipid peroxidation in ddY mice. , 1990, Cancer research.

[67]  G. Darlington,et al.  Risk factors for renal cell carcinoma: results of a population-based case-control study , 1993, Cancer Causes & Control.

[68]  Carl V Phillips,et al.  Quantifying and Reporting Uncertainty from Systematic Errors , 2003, Epidemiology.

[69]  Henk-Jan Guchelaar,et al.  The risk of cancer in users of statins. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[70]  J. Knight,et al.  Reference intervals for plasma lipoperoxides: age-, sex-, and specimen-related variations. , 1987, Clinical chemistry.

[71]  M. H. Heycock,et al.  Papers , 1971, BMJ : British Medical Journal.

[72]  A. Avcı,et al.  Aspirin impairs antioxidant system and causes peroxidation in human erythrocytes and guinea pig myocardial tissue , 2001, Human & experimental toxicology.

[73]  J. Morrow,et al.  Vitamin E ameliorates enhanced renal lipid peroxidation and accumulation of F2-isoprostanes in aging kidneys. , 1998, American journal of physiology. Regulatory, integrative and comparative physiology.

[74]  S. Toyokuni,et al.  Localization of hydroxynonenal protein adducts in normal human kidney and selected human kidney cancers. , 1999, Free radical biology & medicine.

[75]  J. Mckenney Potential Nontraditional Applications of Statins , 2003, The Annals of pharmacotherapy.

[76]  Mimi C. Yu,et al.  Tobacco use in relation to renal cell carcinoma. , 1998, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[77]  David M. Eddy,et al.  Meta-analysis by the confidence profile method , 1992 .

[78]  T. Ishikawa,et al.  Inhibitory effect of probucol on nephrotoxicity induced by ferric nitrilotriacetate (Fe-NTA) in rats. , 1995, Carcinogenesis.

[79]  C Poole,et al.  Low P-Values or Narrow Confidence Intervals: Which Are More Durable? , 2001, Epidemiology.

[80]  Timothy L Lash,et al.  Semi-Automated Sensitivity Analysis to Assess Systematic Errors in Observational Data , 2003, Epidemiology.

[81]  S. Sharma,et al.  Antioxidant effect of beta-carotene on hypoxia induced oxidative stress in male albino rats. , 2002, Journal of ethnopharmacology.

[82]  T. Vasankari,et al.  Reduced oxidized LDL levels after a 10-month exercise program. , 1998, Medicine and science in sports and exercise.

[83]  S Greenland,et al.  Sensitivity Analysis, Monte Carlo Risk Analysis, and Bayesian Uncertainty Assessment , 2001, Risk analysis : an official publication of the Society for Risk Analysis.

[84]  Sander Greenland,et al.  The Impact of Prior Distributions for Uncontrolled Confounding and Response Bias , 2003 .

[85]  E. Gerbino,et al.  Lipid hydroperoxide and markers of renal disease susceptibility in African‐Caribbean and Caucasian patients with Type 2 diabetes mellitus , 2001, Diabetic medicine : a journal of the British Diabetic Association.

[86]  S. Boks,et al.  Priapism Caused by Infection and an Inflammatory Process in the Pelvic Region , 2003, Urologia Internationalis.