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Use of the self-controlled case-series method in vaccine safety studies: review and recommendations for best practice

  • Y. G. WELDESELASSIE (a1), H. J. WHITAKER (a1) and C. P. FARRINGTON (a1)

The self-controlled case-series method was originally developed to investigate potential associations between vaccines and adverse events, and is now commonly used for this purpose. This study reviews applications of the method to vaccine safety investigations in the period 1995–2010. In total, 40 studies were reviewed. The application of the self-controlled case-series method in these studies is critically examined, with particular reference to the definition of observation and risk periods, control of confounders, assumptions and potential biases, methodological and presentation issues, power and sample size, and software. Comparisons with other study designs undertaken in the papers reviewed are also highlighted. Some recommendations are presented, with the emphasis on promoting good practice.

Corresponding author
*Author for correspondence: Professor C. P. Farrington, Department of Mathematics and Statistics, MCT Faculty, The Open University, Walton Hall, Milton Keynes MK7 6AA, UK. (Email:
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1.Farrington CP. Control without separate controls: evaluation of vaccine safety using case-only methods. Vaccine 2004; 22: 20642070.
2.Farrington CP, Nash J, Miller E. Case series analysis of adverse reactions to vaccines: A comparative evaluation. American Journal of Epidemiology 1996; 143: 11651173.
3.Farrington CP. Relative incidence estimation from case series for vaccine safety evaluation. Biometrics 1995; 51: 228235.
4.Farrington CP, Whitaker HJ. Semiparametric analysis of case series data (with Discussion). Journal of the Royal Statistical Society Series C 2006; 55: 553594.
5.Whitaker HJ, et al. Tutorial in biostatistics: the self-controlled case series method. Statistics in Medicine 2006; 25: 17681797.
6.Whitaker HJ, Hocine MN, Farrington CP. The methodology of self-controlled case series studies. Statistical Methods in Medical Research 2009; 18: 726.
7.Andrews NJ. Statistical assessment of the association between vaccination and rare adverse events post-licensure. Vaccine 2002; 20: S49S53.
8.Musonda P, Farrington CP, Whitaker HJ. Sample sizes for self-controlled case series studies. Statistics in Medicine 2006; 25: 26182631.
9.Ali M, et al. The use of a computerized database to monitor vaccine safety in Viet Nam. Bulletin of the World Health Organization 2005; 83: 604610.
10.Andrews N, et al. Does oral polio vaccine cause intussusception in infants? Evidence from a sequence of three self-controlled cases series studies in the United Kingdom. European Journal of Epidemiology 2001; 17: 701706.
11.Andrews N, et al. Recall bias, MMR, and autism. Archives of Disease in Childhood 2002; 87: 493494.
12.Andrews N, et al. Post-licensure safety of the meningococcal group C conjugate vaccine. Human Vaccines 2007; 3: 5963.
13.Andrews N, et al. Post-licensure comparison of the safety profile of diphtheria/tetanus/whole cell pertussis/haemophilus influenza type b vaccine and a 5-in-1 diphtheria/tetanus/acellular pertussis/haemophilus influenza type b/polio vaccine in the United Kingdom. Vaccine; 28: 72157220.
14.Burwen DR, et al. Evaluating adverse events after vaccination in the Medicare population. Pharmacoepidemiology and Drug Safety 2007; 16: 753761.
15.Cameron JC, et al. Oral polio vaccine and intussusception: A data linkage study using records for vaccination and hospitalization. American Journal of Epidemiology 2006; 163: 528533.
16.Dourado I, et al. Outbreak of aseptic meningitis associated with mass vaccination with a Urabe-containing measles-mumps-rubella vaccine – Implications for immunization programs. American Journal of Epidemiology 2000; 151: 524530.
17.Farrington P, et al. A new method for active surveillance of adverse events from diphtheria-tetanus-pertussis and measles-mumps-rubella vaccines. Lancet 1995; 345: 567569.
18.Farrington CP, Miller E, Taylor B. MMR and autism: further evidence against a causal association. Vaccine 2001; 19: 3632–365.
19.France EK, et al. Risk of immune thrombocytopenic purpura after measles-mumps-rubella immunization in children. Pediatrics 2008; 121: e687e692.
20.Gold M, et al. Use of the Australian Childhood Immunisation Register for vaccine safety data linkage. Vaccine 2010; 28: 43084311.
21.Gwini SM, Coupland CAC, Siriwardena AN. The effect of influenza vaccination on risk of acute myocardial infarction: self-controlled case-series study. Vaccine 2011; 29: 11451149.
22.Hambidge SJ, et al. Safety of trivalent inactivated influenza vaccine in children 6 to 23 months old. Journal of the American Medical Association 2006; 296: 19901997.
23.Hocine MN, et al. Hepatitis B vaccination and first central nervous system demyelinating events: Reanalysis of a case-control study using the self-controlled case series method. Vaccine 2007; 25: 59385943.
24.Huang WT, et al. Lack of association between acellular pertussis vaccine and seizures in early childhood. Pediatrics 2010; 126: E263E269.
25.Hughes RA, et al. No association between immunization and Guillain-Barré syndrome in the United Kingdom, 1992 to 2000. Archives of Internal Medicine 2006; 166: 13011304.
26.Juurlink DN, et al. Guillain-Barré syndrome after influenza vaccination in adults – a population-based study. Archives of Internal Medicine 2006; 166: 22172221.
27.Kramarz P, et al. Does influenza vaccination exacerbate asthma? Analysis of a large cohort of children with asthma. Archives of Family Medicine 2000; 9: 617623.
28.Kramarz P, et al. Does influenza vaccination prevent asthma exacerbations in children? Journal of Pediatrics 2001; 138: 306310.
29.Miller E, et al. Bacterial infections, immune overload, and MMR vaccine. Archives of Disease in Childhood 2003; 88: 222223.
30.Miller E, et al. No evidence of an association between MMR vaccine and gait disturbance. Archives of Disease in Childhood 2005; 90: 292296.
31.Miller E, et al. Risks of convulsion and aseptic meningitis following measles-mumps-rubella vaccination in the United Kingdom. American Journal of Epidemiology 2007; 165: 704709.
32.Miller E, et al. Idiopathic thrombocytopenic purpura and MMR vaccine. Archives of Disease in Childhood 2001; 84: 227229.
33.Mullooly JP, et al. Wheezing lower respiratory disease and vaccination of full-term infants. Pharmacoepidemiology and Drug Safety 2002; 11: 2130.
34.Murphy TV, et al. Intussusception among infants given an oral rotavirus vaccine. New England Journal of Medicine 2001; 344: 564572.
35.Mutsch M, et al. Use of the inactivated intranasal influenza vaccine and the risk of Bell's palsy in Switzerland. New England Journal of Medicine 2004; 350: 896903.
36.Naleway AL, et al. Risk of immune hemolytic anemia in children following immunization. Vaccine 2009; 27: 73947397.
37.Payne DC, et al. Concurrent vaccinations and US military hospitalizations. Annals of Epidemiology 2007; 17: 697703.
38.Sardinas MAG, et al. Lack of association between intussusception and oral polio vaccine in Cuban children. European Journal of Epidemiology 2001; 17: 783787.
39.Smeeth L, et al. Risk of myocardial infarction and stroke after acute infection or vaccination. New England Journal of Medicine 2004; 351: 26112618.
40.Stowe J, et al. Idiopathic thrombocytopenic purpura and the second dose of MMR. Archives of Disease in Childhood 2001; 93: 182183.
41.Stowe J, et al. Bell's palsy and parenteral inactivated influenza vaccine. Human Vaccines 2006; 2: 110112.
42.Stowe J, et al. Investigation of the temporal association of Guillain-Barré syndrome with influenza vaccine and influenz-alike illness using the United Kingdom General Practice Research Database. American Journal of Epidemiology 2008; 169: 382388.
43.Stowe J, et al. No evidence of an increase of bacterial and viral infections following Measles, Mumps and Rubella vaccine. Vaccine 2009; 27: 14221425.
44.Tata LJ, et al. Does influenza vaccination increase consultations, corticosteroid prescriptions, or exacerbations in subjects with asthma or chronic obstructive pulmonary disease? Thorax 2003; 58: 835839.
45.Taylor B, et al. Autism and measles, mumps, and rubella vaccine: no epidemiological evidence for a causal association. Lancet 1999; 353: 20262029.
46.Taylor B, et al. No increased risk of relapse after meningococcal C conjugate vaccine in nephrotic syndrome. Archives of Disease in Childhood 2007; 92: 887889.
47.Ward KN, et al. Risk of serious neurologic disease after immunization of young children in Britain and Ireland. Pediatrics 2007; 120: 314321.
48.Zinman L, et al. Safety of influenza vaccination in patients with myasthenia gravis: A population-based study. Muscle and Nerve 2009; 40: 947951.
49.van der Maas NAT, et al. Acute cerebellar ataxia in the Netherlands: A study on the association with vaccinations and varicella zoster infection. Vaccine 2009; 27: 19701973.
50.France EK, et al. Safety of the trivalent inactivated influenza vaccine among children. Archives of Pediatric and Adolescent Medicine 2004; 158: 10311036.
51.Klein NP, et al. Measles-mumps-rubella-varicella combination vaccine and the risk of febrile seizures. Pediatrics 2010; 126: e1e8.
52.Farrington CP, Hocine MN. Within-individual dependence in self-controlled case series models for recurrent events. Journal of the Royal Statistical Society Series C 2010; 59: 457475.
53.Farrington CP, et al. Self-controlled case series analysis with event-dependent observation periods. Journal of the American Statistical Association 2011; 106: 417426.
54.Farrington CP, Whitaker HJ, Hocine MN. Case series analysis for censored, perturbed, or curtailed post-event exposures. Biostatistics 2009; 10: 316.
55.Kuhnert R, et al. A modified self-controlled case series method to examine association between multidose vaccinations and death. Statistics in Medicine 2011; 30: 666677.
56.Delaney JA, Suissa S. The case-crossover study design in pharmacoepidemiology. Statistical Methods in Medical Research 2009; 18: 5365.
57.Suissa S. Immortal time bias in pharmacoepidemiology. American Journal of Epidemiology 2007; 167: 492499.
58.Musonda P, et al. Self-controlled case series analyses: small-sample performance. Computational Statistics and Data Analysis 2008; 52: 19421957.
59.Navidi W. Bidirectional case-crossover designs for exposures with time trends. Biometrics 1998; 54: 596605.
60.Lumley T, Levy D. Bias in the case-crossover design: implications for studies of air pollution. Environmetrics 2000; 11: 689704.
61.Vines SK, Farrington CP. Within-subject exposure dependency in case-crossover studies. Statistics in Medicine 2001; 20: 30393049.
62.Whitaker HJ, Hocine MN, Farrington CP. On case-crossover methods for environmental time series data. Environmentrics 2007; 18: 157171.
63.Becker NG, Li Z, Kelman CW. The effect of transient exposures on the risk of an acute illness with low hazard rate. Biostatistics 2004; 5: 239248.
64.Glanz JM, et al. Four different study designs to evaluate vaccine safety were equally validated with contrasting limitations. Journal of Clinical Epidemiology 2006; 59: 808818.
65.Musonda P, et al. Monitoring vaccine safety using case series cumulative sum charts. Vaccine 2008; 26: 53585367.
66.Hocine MN, et al. Sequential case series analysis for pharmacovigilance. Journal of the Royal Statistical Society. Series A 2009; 172: 213236.
67.Hocine M, et al. Testing independence between two Poisson-generated multinomial variables in case-series and cohort studies. Statistics in Medicine 2005; 24: 40354044.
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