care
4.4.1 The derivation and validation of a clinical prediction rule
In the early stages of this thesis (to end 2007), several prediction rules based on clinical features from the patients’ history or physical examination had been developed for estimating the risk of serious bacterial infections overall (236, 237) and specific serious bacterial
infections. (238-243) The prediction rules available at the time are described in Table 4.1. They were, however, of questionable appropriateness for clinical practice. Some had key
methodological limitations (e.g. predictors were not identified and combined using
multivariable statistical techniques), (237, 240, 243) or were limited to use in very young age groups (e.g. babies). (238, 242) Others had been derived in tertiary settings or in populations with a higher incidence of serious bacterial infection prior to the introduction of routine vaccination against Haemophilus influenzae type b and Streptococcus pneumoniae. (236, 237) Further to this, only one of these models had been externally validated (237) and in the
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validation studies, the potential of the tool to rule out serious infection was variable when used in conjunction with laboratory tests. (244-246)
Table 4.1. Clinical prediction rules comprised of predictors from history or physical examination for serious bacterial infection overall or specific serious bacterial infections in children (published to end 2007)
Clinical prediction rule
Predictors included in the rule Methodological and/or generalisability limitations All serious infections
Bleeker et al., 2001 (236)
Duration of fever, history of poor micturition, history of vomiting, age >1 year, temperature, chest wall retractions, poor peripheral circulation
Derived in children <36 months
Derived in tertiary paediatric hospital with prevalence of serious bacterial infection 25%
Yale observation scale McCarthy et al., 1982
(237)
Quality of cry, reaction to parents’, state variation, colour, state of hydration, response to social overtures
Derived in children <24 months
Derived in tertiary paediatric hospital with prevalence of serious illness 12%
Derived prior to vaccination Haemophilus influenzae and pneumococcus
Pneumonia
Crain et al., 1991 (238)
Cough, tachypnoea, rales, retractions, rhonchi, rhinorrhoea, wheezing
Derived in infants <2 months.
Model not derived using multivariable statistical analysis
Meningitis
Joffe et al., (239)
Suspicious findings on neurological and or physical examination, physician visit in previous 48 hours, convulsions on arrival at emergency department, a focal seizure
Outcome not verified in all children.
Model not derived using multivariable statistical analysis
Offringa et al., 1992 (240)
Petechiae, nuchal rigidity, coma Model not derived using multivariable statistical analysis Pantell et al.,
2004 (242)
Abnormal appearance, age, temperature Derived in infants < 3 months Oostenbrink et
al., 2001 (241)
Duration of main complaint, vomiting, meningeal irritation, cyanosis, petechiae, disturbed consciousness
Derived in emergency department in children with meningeal signs and prevalence of serious infection 44%
Bacteraemia
Schwartz & Wientzen, 1982 (243)
Appearance, appetite, cry, resistance to examination
Derived in children <36 months
Derived prior to vaccination Haemophilus influenzae and pneumococcus
Model not derived using multivariable statistical analysis
The prediction rules available at the time were thus judged to be unsuitable for the
identification of serious bacterial infection in children presenting to primary care settings. It is acknowledged that methods have since been developed for updating existing rules to
overcome differences between the derivation population and the population of interest (62, 247). However, methodological guidance on prediction rule updating was not available at the time this program of research was being conducted.
Given the limitations of the existing prediction rules and absence at the time of
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a prediction rule comprised of predictors from the patients’ history and physical examination, using data sourced from primary care and low prevalence emergency department settings. The dataset to be used for this purpose was a prospective cohort study of 700 children aged 3 months to 16 years attending the Paediatric Assessment Unit at the University Hospital Coventry and Warwickshire NHS Trust in the United Kingdom with suspected acute infection. Just over half the children in this cohort (51%) were referred from primary care, 28.3% were self-referrals and the remainder (16.6%) emergency ambulance transfers. I then planned to validate this rule in multiple datasets being compiled by an international collaboration of researchers in the area. (222) In addition, simplified versions of the rule were to be derived and the accuracy and reclassification ability of the simplified prediction rules compared to the original prediction rule.
4.4.2 Determination of the diagnostic value of C-reactive protein (CRP)
Despite the widespread use of C-reactive protein (CRP) in some countries and its increasing uptake in others at the time (throughout 2006 and 2007), the diagnostic value of CRP for identifying serious infections in children was uncertain and had not been systematically
studied. In order to inform of the ability of CRP to accurately identify serious bacterial infection in children at first presentation, and its added value beyond existing clinical information, two studies were proposed. The first was a systematic review of the accuracy and independent value of CRP for serious bacterial and bacterial infection in non-hospitalised children. The second study was a modelling study to determine the added value of CRP over and above patient history and clinical examination. In this study, the area under the receiver operating characteristic curve (AUROC) of the derived rule, comprised of predictors from the patients’ history and physical examination (the base model), was to be compared to a model containing both the CRP test value and the derived rule (the extended model).