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

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

Intussusception, a potentially lethal condition with poorly understood etiology, is the most common cause of acute intestinal obstruction in children younger than 5 years old. In some cases, the condition has been associated with administration of the first licensed rotavirus vaccine, the reassortant rhesus-human tetravalent rotavirus vaccine (RRV-TV; RotaShield). No such association has to date been reported from large phase III safety trials with new rotavirus vaccines. As 2 new, live-attenuated oral rotavirus vaccines are currently under review for approval by the European Union regulatory authorities, a review of the clinical, etiologic and epidemiologic aspects of intussusception in Europe is urgently needed. We conducted a review of Medline literature, published from 1995 onwards on intussusception in the World Health Organization's European Region. The results are compared with data from previous reviews and other regions. The classic triad of intussusception symptoms (abdominal pain, abdominal mass, bloody stools) was present in 29-33% of patients according to the medical literature reviewed. Conservative treatment (barium, air or saline enema) was the rule (81% of cases), and few complications were observed during treatment. Treatment outcome was generally favorable, with recurrence occurring in approximately 1 in 10 patients, and only 1 death reported. Structural lead points were seen in 3% of patients; no other reliable data on the etiology of intussusception were found. The incidence of acute intussusception in young children in Europe, according to 6 heterogeneous hospital-based studies, ranged from 0.66 to 2.24 per 1000 children in inpatient departments and from 0.75 to 1.00 per 1000 children in emergency departments. Peak incidences were found in children 3-9 months of age. There are still gaps in our knowledge of intussusception with respect to its etiology and especially by which mechanisms RRV-TV might have caused it to occur. Data from regions outside Europe showed that rotavirus infection and disease are not associated with intussusception. As new rotavirus vaccines become available for use in Europe, postlicensure surveillance for intussusception is indicated and may be instrumental in further understanding the epidemiology of this condition and in further assessing the safety of future vaccines.

Intussusception among young children in Europe

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

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

Background Measles, mumps, rubella, and varicella (chickenpox) are serious diseases that can lead to serious complications, disability, and death. However, public debate over the safety of the trivalent MMR vaccine and the resultant drop in vaccination coverage in several countries persists, despite its almost universal use and accepted effectiveness. This is an update of a review published in 2005 and updated in 2012. Objectives To assess the effectiveness, safety, and long- and short-term adverse effects associated with the trivalent vaccine, containing measles, rubella, mumps strains (MMR), or concurrent administration of MMR vaccine and varicella vaccine (MMR+V), or tetravalent vaccine containing measles, rubella, mumps, and varicella strains (MMRV), given to children aged up to 15 years. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2019, Issue 5), which includes the Cochrane Acute Respiratory Infections Group's Specialised Register, MEDLINE (1966 to 2 May 2019), Embase (1974 to 2 May 2019), the WHO International Clinical Trials Registry Platform (2 May 2019), and ClinicalTrials.gov (2 May 2019). Selection criteria We included randomised controlled trials (RCTs), controlled clinical trials (CCTs), prospective and retrospective cohort studies (PCS/RCS), case-control studies (CCS), interrupted time-series (ITS) studies, case cross-over (CCO) studies, case-only ecological method (COEM) studies, self-controlled case series (SCCS) studies, person-time cohort (PTC) studies, and case-coverage design/screening methods (CCD/SM) studies, assessing any combined MMR or MMRV / MMR+V vaccine given in any dose, preparation or time schedule compared with no intervention or placebo, on healthy children up to 15 years of age. Data collection and analysis Two review authors independently extracted data and assessed the methodological quality of the included studies. We grouped studies for quantitative analysis according to study design, vaccine type (MMR, MMRV, MMR+V), virus strain, and study settings. Outcomes of interest were cases of measles, mumps, rubella, and varicella, and harms. Certainty of evidence of was rated using GRADE. Main results We included 138 studies (23,480,668 participants). Fifty-one studies (10,248,159 children) assessed vaccine effectiveness and 87 studies (13,232,509 children) assessed the association between vaccines and a variety of harms. We included 74 new studies to this 2019 version of the review. Effectiveness Vaccine effectiveness in preventing measles was 95% after one dose (relative risk (RR) 0.05, 95% CI 0.02 to 0.13; 7 cohort studies; 12,039 children; moderate certainty evidence) and 96% after two doses (RR 0.04, 95% CI 0.01 to 0.28; 5 cohort studies; 21,604 children; moderate certainty evidence). The effectiveness in preventing cases among household contacts or preventing transmission to others the children were in contact with after one dose was 81% (RR 0.19, 95% CI 0.04 to 0.89; 3 cohort studies; 151 children; low certainty evidence), after two doses 85% (RR 0.15, 95% CI 0.03 to 0.75; 3 cohort studies; 378 children; low certainty evidence), and after three doses was 96% (RR 0.04, 95% CI 0.01 to 0.23; 2 cohort studies; 151 children; low certainty evidence). The effectiveness (at least one dose) in preventing measles after exposure (post-exposure prophylaxis) was 74% (RR 0.26, 95% CI 0.14 to 0.50; 2 cohort studies; 283 children; low certainty evidence). The effectiveness of Jeryl Lynn containing MMR vaccine in preventing mumps was 72% after one dose (RR 0.24, 95% CI 0.08 to 0.76; 6 cohort studies; 9915 children; moderate certainty evidence), 86% after two doses (RR 0.12, 95% CI 0.04 to 0.35; 5 cohort studies; 7792 children; moderate certainty evidence). Effectiveness in preventing cases among household contacts was 74% (RR 0.26, 95% CI 0.13 to 0.49; 3 cohort studies; 1036 children; moderate certainty evidence). Vaccine effectiveness against rubella, using a vaccine with the BRD2 strain which is only used in China, is 89% (RR 0.11, 95% CI 0.03 to 0.42; 1 cohort study; 1621 children; moderate certainty evidence). Vaccine effectiveness against varicella (any severity) after two doses in children aged 11 to 22 months is 95% in a 10 years follow-up (rate ratio (rr) 0.05, 95% CI 0.03 to 0.08; 1 RCT; 2279 children; high certainty evidence). Safety There is evidence supporting an association between aseptic meningitis and MMR vaccines containing Urabe and Leningrad-Zagreb mumps strains, but no evidence supporting this association for MMR vaccines containing Jeryl Lynn mumps strains (rr 1.30, 95% CI 0.66 to 2.56; low certainty evidence). The analyses provide evidence supporting an association between MMR/MMR+V/MMRV vaccines (Jeryl Lynn strain) and febrile seizures. Febrile seizures normally occur in 2% to 4% of healthy children at least once before the age of 5. The attributable risk febrile seizures vaccine-induced is estimated to be from 1 per 1700 to 1 per 1150 administered doses. The analyses provide evidence supporting an association between MMR vaccination and idiopathic thrombocytopaenic purpura (ITP). However, the risk of ITP after vaccination is smaller than after natural infection with these viruses. Natural infection of ITP occur in 5 cases per 100,000 (1 case per 20,000) per year. The attributable risk is estimated about 1 case of ITP per 40,000 administered MMR doses. There is no evidence of an association between MMR immunisation and encephalitis or encephalopathy (rate ratio 0.90, 95% CI 0.50 to 1.61; 2 observational studies; 1,071,088 children; low certainty evidence), and autistic spectrum disorders (rate ratio 0.93, 95% CI 0.85 to 1.01; 2 observational studies; 1,194,764 children; moderate certainty). There is insufficient evidence to determine the association between MMR immunisation and inflammatory bowel disease (odds ratio 1.42, 95% CI 0.93 to 2.16; 3 observational studies; 409 cases and 1416 controls; moderate certainty evidence). Additionally, there is no evidence supporting an association between MMR immunisation and cognitive delay, type 1 diabetes, asthma, dermatitis/eczema, hay fever, leukaemia, multiple sclerosis, gait disturbance, and bacterial or viral infections. AUTHORS' CONCLUSIONS: Existing evidence on the safety and effectiveness of MMR/MMRV vaccines support their use for mass immunisation. Campaigns aimed at global eradication should assess epidemiological and socioeconomic situations of the countries as well as the capacity to achieve high vaccination coverage. More evidence is needed to assess whether the protective effect of MMR/MMRV could wane with time since immunisation.

Vaccines for measles, mumps, rubella, and varicella in children

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

District general hospital paediatrics in this country is not keeping up with changes in the pattern of diseases, the need for specialisation, advances in secondary community and primary health care, the demands of training, the associated need for innovative service developments and research. Most present paediatric units are too small to provide safe and cost effective care; most do not meet the required standards for care or training. Adjacent units should combine to form larger comprehensive specialist children's services, incorporating specialist community care, increased day care facilities, and with fewer but larger units providing 24 hour care. Paediatrics is changing. The average duration of hospital stay for medical problems continues to fall, suggesting that most children are less seriously ill than hitherto when admitted. Primary care continues to develop. General practitioners are doing more and dealing competently with many problems previously referred. Other community child health services are also doing more, including work previously done in hospital paediatric units. The interface between primary and secondary care is constantly changing and is often blurred, with similar clinical problems dealt with by general practitioners in some areas and specialist paediatricians in others. General practitioners provide most child health medical care but need back-up and support, especially for rare or complex problems. The quality of back-up and support tends to vary; the Audit Commission reported' a more than fourfold variation in admission rates for asthma suggesting that many paediatric units were admitting unnecessarily. Overall admission rates for most conditions are apparently not falling and may possibly be rising; it is likely this is not real, but reflects changes in definitions (consultant episodes replacing hospital discharges) and better recording of data with improved information systems, associated with the need to keep better records in the more market oriented NHS. The pattern of disease is changing. Many children are surviving previously fatal conditions such as cancer or cystic fibrosis; new patterns of disease are appearing (for example, changing types of cerebral palsy in association with the survival of very preterm babies); and certain chronic conditions, for example, diabetes, severe asthma and eczema, have shown a marked increase in prevalence over recent decades. When children with these conditions require inpatient treatment, they are likely to require high dependency care or intensive care, not often available and often not optimally provided in small units. Most care for these and other conditions, however, is not critical and should be provided on an outpatient or ambulatory basis, close to where the families live to ensure minimal disruption to relationships and schooling.

https://adc.bmj.com/content/archdischild/71/4/360.full.pdf

How many inpatient paediatric units do we need

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No evidence of an association between MMR vaccine and gait disturbance

How many inpatient paediatric units do we need