The self-controlled case series method was developed to investigate associations between acute outcomes and transient exposures, using only data on cases, that is, on individuals who have experienced the outcome of interest. Inference is within individuals, and hence fixed covariates effects are implicitly controlled for within a proportional incidence framework. We describe the origins, assumptions, limitations, and uses of the method. The rationale for the model and the derivation of the likelihood are explained in detail using a worked example on vaccine safety. Code for fitting the model in the statistical package STATA is described. Two further vaccine safety data sets are used to illustrate a range of modelling issues and extensions of the basic model. Some brief pointers on the design of case series studies are provided. The data sets, STATA code, and further implementation details in SAS, GENSTAT and GLIM are available from an associated website.

/pdf/tutorial-in-biostatistics-the-self-controlled-case-series-2c79y7rmmb.pdf

Tutorial in biostatistics: the self‐controlled case series method

https://autismoevaccini.files.wordpress.com/2014/05/vaccines-are-not-associated-with-autism.pdf

Vaccines are not associated with autism: An evidence-based meta-analysis of case-control and cohort studies

The new edition of "Immunisation Against Infectious Disease" (the Green Book), presents the latest information on vaccines and vaccination procedures for all the vaccine preventable infectious diseases that may occur in the UK or in travellers going outside of the UK. In particular, it deals with those immunisations that comprise the routine immunisation programme for all children from birth to adolescence. All health professionals that give immunisations or who provide information and advice on them - doctors, nurses, health visitors, midwives - will find that this edition of the Green Book has been fully updated, and it gives a comprehensive and invaluable source of current information. This publication, "Immunisation Against Infectious Disease 2006", supersedes the "Immunisation Against Infectious Disease 1996".

Immunisation against infectious disease

BACKGROUND AND AIM Decisions on public health issues are dependent on reliable epidemiological data. A comprehensive review of the literature was used to gather country-specific data on risk factors, prevalence, number of diagnosed individuals and genotype distribution of the hepatitis C virus (HCV) infection in selected European countries, Canada and Israel. METHODOLOGY Data references were identified through indexed journals and non-indexed sources. In this work, 13,000 articles were reviewed and 860 were selected based on their relevance. RESULTS Differences in prevalence were explained by local and regional variances in transmission routes or different public health measures. The lowest HCV prevalence (â?¤ 0.5%) estimates were from northern European countries and the highest (â?¥ 3%) were from Romania and rural areas in Greece, Italy and Russia. The main risk for HCV transmission in countries with well-established HCV screening programmes and lower HCV prevalence was injection drug use, which was associated with younger age at the time of infection and a higher infection rate among males. In other regions, contaminated glass syringes and nosocomial infections continue to play an important role in new infections. Immigration from endemic countries was another factor impacting the total number of infections and the genotype distribution. Approximately 70% of cases in Israel, 37% in Germany and 33% in Switzerland were not born in the country. In summary, HCV epidemiology shows a high variability across Europe, Canada and Israel. CONCLUSION Despite the eradication of transmission by blood products, HCV infection continues to be one of the leading blood-borne infections in the region.

https://onlinelibrary.wiley.com:443/doi/pdf/10.1111/j.1478-3231.2011.02539.x

A systematic review of hepatitis C virus epidemiology in Europe, Canada and Israel.

BACKGROUND.The prevalence of pervasive developmental disorders has increased in recent years. Links with the measles component of the measles-mumps-rubella vaccine and the cumulative exposure to thimerosal through other vaccines have been postulated. OBJECTIVES.The purpose of this work was to estimate the pervasive developmental disorder prevalence in Montreal, Canada, in cohorts born from 1987 to 1998 and evaluate the relationship of trends in pervasive developmental disorder rates with: (1) changes in cumulative exposure to ethylmercury (thimerosal) occurring through modifications in the immunization schedule of young children and (2) trends in measles-mumps-rubella vaccination use rates and the introduction of a 2‐measles-mumps-rubella dosing schedule during the study period. METHODS.We surveyed 27 749 children born from 1987 to 1998 attending 55 schools from the largest Anglophone school board. Children with pervasive developmental disorders were identified by a special needs team. The cumulative exposure by age 2 years to thimerosal was calculated for 1987‐1998 birth cohorts. Ethylmercury exposure ranged from medium (100‐125 g) from 1987 to 1991 to high (200‐225 g) from 1992 to 1995 to nil from 1996 onwards when thimerosal was entirely discontinued. Measles-mumps-rubella coverage for each birth cohort was estimated through surveys of vaccination rates. The immunization schedule included a measles-mumps-rubella single dose at 12 months of age up to 1995, and a second measles-mumps-rubella dose at 18 months of age was added on after 1996. RESULTS.We found 180 children (82.8% males) with a pervasive developmental disorder diagnosis who attended the surveyed schools, yielding a prevalence for pervasive developmental disorder of 64.9 per 10 000. The prevalence for specific pervasive developmental disorder subtypes were, for autistic disorder: 21.6 of 10 000; for pervasive developmental disorder not otherwise specified: 32.8 of 10 000; and for Asperger syndrome: 10.1 of 10 000. A statistically significant linear increase in pervasive developmental disorder prevalence was noted during the study period. The prevalence of pervasive developmental disorder in thimerosalfree birth cohorts was significantly higher than that in thimerosal-exposed cohorts (82.7 of 10 000 vs 59.5 of 10 000). Using logistic regression models of the preva

Pervasive Developmental Disorders in Montreal, Quebec, Canada: Prevalence and Links With Immunizations

Objective. After concerns about the possible toxicity of thimerosal-containing vaccines in the United States, this study was designed to investigate whether there is a relationship between the amount of thimerosal that an infant receives via diphtheria-tetanus-whole-cell pertussis (DTP) or diphtheria-tetanus (DT) vaccination at a young age and subsequent neurodevelopmental disorders. Methods. A retrospective cohort study was performed using 109 863 children who were born from 1988 to 1997 and were registered in general practices in the United Kingdom that contributed to a research database. The disorders investigated were general developmental disorders, language or speech delay, tics, attention-deficit disorder, autism, unspecified developmental delays, behavior problems, encopresis, and enuresis. Exposure was defined according to the number of DTP/DT doses received by 3 and 4 months of age and also the cumulative age-specific DTP/DT exposure by 6 months. Each DTP/DT dose of vaccine contains 50 μg of thimerosal (25 μg of ethyl mercury). Hazard ratios (HRs) for the disorders were calculated per dose of DTP/DT vaccine or per unit of cumulative DTP/DT exposure. Results. Only in 1 analysis for tics was there some evidence of a higher risk with increasing doses (Cox9s HR: 1.50 per dose at 4 months; 95% confidence interval [CI]: 1.02–2.20). Statistically significant negative associations with increasing doses at 4 months were found for general developmental disorders (HR: 0.87; 95% CI: 0.81–0.93), unspecified developmental delay (HR: 0.80; 95% CI: 0.69–0.92), and attention-deficit disorder (HR: 0.79; 95% CI: 0.64–0.98). For the other disorders, there was no evidence of an association with thimerosal exposure. Conclusions. With the possible exception of tics, there was no evidence that thimerosal exposure via DTP/DT vaccines causes neurodevelopmental disorders.

/pdf/thimerosal-exposure-in-infants-and-developmental-disorders-a-5chjt6j1sj.pdf

Thimerosal Exposure in Infants and Developmental Disorders: A Retrospective Cohort Study in the United Kingdom Does Not Support a Causal Association

Background: MMR vaccine has been reported to cause gait disturbance, and this possible association has been claimed to support the MMR-causes-autism theory. 

Aims: To determine whether any association between gait disturbance and MMR vaccination exceeds the age related background rate of gait disturbance, using record linkage and self control case series analyses. 

Methods: MMR vaccination records were linked to hospital admission and general practitioner attendance data. An increased rate of gait problems with onset in various intervals in the 60 day period after MMR vaccination was looked for in children aged 12 to <24 months. 

Results: No evidence of an increased rate of hospital admission or general practice consultations for gait disturbance was found in the putative post-vaccination risk periods. 

Conclusions: This study provides no evidence for a causal association between MMR and gait disturbance.

https://adc.bmj.com/content/archdischild/90/3/292.full.pdf

No evidence of an association between MMR vaccine and gait disturbance

(Accepted 7 November 2008; ﬁrst published online 23 December 2008)SUMMARYSurveillance reports and prevalence studies have indicated that injecting drug users (IDUs)contribute more to the hepatitis C epidemic in the United Kingdom than any other risk group.Information on both the prevalence and incidence of hepatitis C in IDUs is therefore essential tounderstanding the epidemiology of this infection. The prevalence of hepatitis C in specimens fromthe Unlinked Anonymous Prevalence Monitoring Programme collected in 1995, 1996, 1998, 1999,2000, and 2001 was determined using residual syphilis serology specimens from IDUs attending15 genitourinary medicine (GUM) clinics in and outside London. These specimens were tested forantibodies to hepatitis C virus (anti-HCV). Using this cross-sectional design, anti-HCV-negativespecimens were tested for HCV RNA to identify incident infections during the ‘window’ period ofinfection, and thus to estimate HCV incidence. Results of the multivariable analysis showed thatthere was marked variation in prevalence by clinic (P<0.0001) and age (P<0.0001). Overall themajority of infections were in males and the overall prevalence in injectors declined over the studyperiod from 36.9%to28.7%. The annual incidence in these injectors was estimated as being 3.01%(95% CI 1.25–6.73). Over the study period HCV incidence decreased by 1.2% per year. Genotypingof the incident infections identiﬁed the most common genotype as type 1 with type 3 being morefrequently seen after 1998. Of the prevalent infections, genotype 1 was the most common. The studyhas conﬁrmed a higher prevalence of anti-HCV in IDUs in the London area compared to thoseoutside London. How representative of the current injecting drug user population are IDUsattending GUM clinics is unclear. Even so, such studies allow prevalence and incidence to beestimated in individuals who have ever injected drugs and inform ongoing public health surveillance.Key words: Genotype, hepatitis C virus, incidence, injecting drug users, prevalence, windowperiod infections.INTRODUCTIONNational surveillance indicates that most diagnosedhepatitis C virus (HCV) infections in England andWales are in current or ex-injecting drug users (IDUs)[1, 2]. It is therefore important to obtain accurateestimates of the incidence and prevalence of HCVinfection in IDUs. A number of studies in IDUs inthe United Kingdom, have found evidence of HCVinfection in 30–60% of injectors [3–5]. There are,however, no proven laboratory markers of recently

Prevalence and incidence of hepatitis C in injecting drug users attending genitourinary medicine clinics.

Introduction: The overuse of blood tests burdens the healthcare system and can detrimentally impact patient care. Risks of frequent blood sampling include infection and clinician-induced anemia, which can negatively impact patients and their families. Pediatric cancer patients are particularly vulnerable as they are immunocompromised with a small blood volume. Four blood tests had become a daily practice. Therefore, we aimed to reduce the number of blood tests taken per bed day within the inpatient pediatric cancer unit by 15% within 8 months. Methods: This quality improvement project combined several strategies to reduce test frequency and empower clinicians on the rationale for blood test ordering. Recommendations were developed collaboratively presented in a summary table. Targeted behavior-change methodology built engagement and momentum for the change. All clinicians were challenged to STOP and THINK about why a test is necessary for each patient. The primary outcome measure was the frequency of the tests taken per bed day. Frequency was compared between pre- and postimplementation plus follow-up periods across 2019–2021. Results: 26,941 blood tests were captured in 1,558 admissions. The intervention led to an overall blood test reduction of 37% over 8 months. Liver Function Tests were the standout, with a 52% decrease in test frequency. Conclusions: A strategy incorporating education and culture change, combined with clear guidance on testing frequency, significantly reduced the ordering frequency of blood tests without increased patient harm.

Rethinking Blood Testing in Pediatric Cancer Patients: A Quality Improvement Approach

Objective. After concerns about the possible toxicity of thimerosal-containing vaccines in the United States, this study was designed to investigate whether there is a relationship between the amount of thimerosal that an infant receives via diphtheria-tetanuswhole-cell pertussis (DTP) or diphtheria-tetanus (DT) vaccination at a young age and subsequent neurodevelopmental disorders. Methods. A retrospective cohort study was performed using 109 863 children who were born from 1988 to 1997 and were registered in general practices in the United Kingdom that contributed to a research database. The disorders investigated were general developmental disorders, language or speech delay, tics, attention-deficit disorder, autism, unspecified developmental delays, behavior problems, encopresis, and enuresis. Exposure was defined according to the number of DTP/DT doses received by 3 and 4 months of age and also the cumulative age-specific DTP/DT exposure by 6 months. Each DTP/DT dose of vaccine contains 50 g of thimerosal (25 g of ethyl mercury). Hazard ratios (HRs) for the disorders were calculated per dose of DTP/DT vaccine or per unit of cumulative DTP/DT exposure. Results. Only in 1 analysis for tics was there some evidence of a higher risk with increasing doses (Cox’s HR: 1.50 per dose at 4 months; 95% confidence interval [CI]: 1.02–2.20). Statistically significant negative associations with increasing doses at 4 months were found for general developmental disorders (HR: 0.87; 95% CI: 0.81– 0.93), unspecified developmental delay (HR: 0.80; 95% CI: 0.69–0.92), and attention-deficit disorder (HR: 0.79; 95% CI: 0.64–0.98). For the other disorders, there was no evidence of an association with thimerosal exposure. Conclusions. With the possible exception of tics, there was no evidence that thimerosal exposure via DTP/DT vaccines causes neurodevelopmental disorders. Pediatrics 2004;114:584–591; cohort study, neurodevelopment, safety, thimerosal, thiomersal, vaccines. ABBREVIATIONS. Hg, mercury; WHO, World Health Organization; VSD, Vaccine Safety Datalink; CDC, Centers for Disease Control and Prevention; HMO, health maintenance organization; ADD, attention-deficit disorder; GPRD, General Practice Research Database; ICD, International Classification of Diseases; DTP, diphtheria-tetanus-whole-cell pertussis; DT, diphtheria, tetanus; GP, general practitioner; HR, hazard ratio; CI, confidence interval. Inorganic mercury (Hg) poses a potential risk of neurodevelopmental and renal toxicity in young children.1,2 Cumulative exposure to an organic mercury–containing compound, methylmercury, can also produce neurologic or renal damage as it has a long half-life and can cross the blood-brain barrier, where it accumulates and is converted to inorganic mercury. Guidelines to limit cumulative exposure to methylmercury have been drawn up by various agencies and incorporate a wide margin of safety. The maximum daily dose specified by these different agencies varies by nearly 5-fold, the most stringent being the guideline of the Environmental Protection Agency in the United States that specifies a maximum daily exposure to Hg of 0.1 g/kg extrapolated from data on methylmercury exposure. These guidelines are reproduced by Pichichero.2 Ethylmercury, a related organic mercury compound, is a constituent of thimerosal, an antibacterial agent used in certain nonlive vaccines. Ethylmercury has a much shorter half-life than methylmercury, being rapidly excreted via the stools after parenteral administration such that blood levels remain substantially below the safe threshold.2 Nevertheless, the guidelines to limit cumulative methylmercury exposure have been translated to ethylmercury.3 In the United States, increases during the 1990s in the number of childhood vaccines that contained thimerosal, which contains 49.6% Hg by weight, led to questions about safety because the maximum cumulative exposure in some US children was 187.5 g Hg by 6 months of age, which would have exceeded the stringent Environmental Protection Agency limit. Although there is no evidence that this level of Hg exposure via ethylmercury was likely to or had actually caused any harm, a joint statement was issued by the American Academy of Pediatrics and the Public Health Service in 1999 recommending the removal of thimerosal from vaccines as soon as possible, as a precautionary measure.4 Although the World Health Organization (WHO) supported in principle the move toward thimerosal-free vaccines, it nevertheless recommended that vaccines that contain thimerosal continue to be used in the meantime because the From the *Statistics Unit and ‡Immunisation Department, Health Protection Agency, Communicable Disease Surveillance Centre, London, United Kingdom; §Centre for Community Child Health, Royal Free and University College Medical School, Royal Free Campus, London, United Kingdom; and Morbidity and Health Care Team, Office for National Statistics, London, United Kingdom. Accepted for publication Mar 15, 2004. DOI: 10.1542/peds.2003-1177-L Reprint requests to (E.M.) Immunisation Department, Health Protection Agency, Communicable Disease Surveillance Centre, 61 Colindale Ave, London NW9 5EQ, United Kingdom. E-mail: liz.miller@hpa.org.uk PEDIATRICS (ISSN 0031 4005). Copyright © 2004 by the American Acad-

Cohort Study in the United Kingdom Does Not Support a Causal Association Thimerosal Exposure in Infants and Developmental Disorders: A Retrospective

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