***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: We performed a Monte Carlo study to evaluate the effect of the number of events per variable ( EPV ) analyzed in logistic regression analysis . The simulations were based on data from a cardiac trial of 673 patients in which 252 deaths occurred and seven variables were cogent predictors of mortality ; the number of events per predictive variable was ( 252/7 =) 36 for the full sample . For the simulations , at values of EPV = 2 , 5 , 10 , 15 , 20 , and 25 , we r and omly generated 500 sample s of the 673 patients , chosen with replacement , according to a logistic model derived from the full sample . Simulation results for the regression coefficients for each variable in each group of 500 sample s were compared for bias , precision , and significance testing against the results of the model fitted to the original sample . For EPV values of 10 or greater , no major problems occurred . For EPV values less than 10 , however , the regression coefficients were biased in both positive and negative directions ; the large sample variance estimates from the logistic model both overestimated and underestimated the sample variance of the regression coefficients ; the 90 % confidence limits about the estimated values did not have proper coverage ; the Wald statistic was conservative under the null hypothesis ; and paradoxical associations ( significance in the wrong direction ) were increased . Although other factors ( such as the total number of events , or sample size ) may influence the validity of the logistic model , our findings indicate that low EPV can lead to major problems Associations between historical , presenting , and treatment-related characteristics and relapse within 8 weeks after a moderate to severe asthma exacerbation were studied in a cohort of 284 adult asthmatics . Data were collected prospect ively , and a multivariate model was developed and internally vali date d. Within 10 days , only 8 % had relapsed , increasing to 45 % by 8 weeks . Three variables that could be identified at the time of discharge were independently associated with relapse . These included : having made three or more visits to an emergency department in the prior 6 months ( hazard ratio ( HR ) = 2.3 , 95 % CI = 1.6 - 3.4 ) ; difficulty performing work or activities as a result of physical health in the 4 weeks prior ( HR = 2.7 , 95 % CI = 1.6 - 4.3 ) ; discontinuing hospital-based treatment for the exacerbation within 24 hours without having achieved a peak expiratory flow rate of at least 50 % of predicted ( HR = 2.6 , 95 % CI = 1.6 - 4.1 ) . These risk factors may help to identify patients with poorly controlled asthma in need of more intensive and comprehensive management A representation and interpretation of the area under a receiver operating characteristic ( ROC ) curve obtained by the " rating " method , or by mathematical predictions based on patient characteristics , is presented . It is shown that in such a setting the area represents the probability that a r and omly chosen diseased subject is ( correctly ) rated or ranked with greater suspicion than a r and omly chosen non-diseased subject . Moreover , this probability of a correct ranking is the same quantity that is estimated by the already well-studied nonparametric Wilcoxon statistic . These two relationships are exploited to ( a ) provide rapid closed-form expressions for the approximate magnitude of the sampling variability , i.e. , st and ard error that one uses to accompany the area under a smoothed ROC curve , ( b ) guide in determining the size of the sample required to provide a sufficiently reliable estimate of this area , and ( c ) determine how large sample sizes should be to ensure that one can statistically detect differences in the accuracy of diagnostic techniques BACKGROUND Identifying patients at risk of future severe asthma exacerbations , those whose asthma might be less treatment responsive , or both might guide treatment selection . OBJECTIVE We sought to investigate predictors for failure to achieve Global Initiative for Asthma (GINA)-defined good current asthma control and severe exacerbations on treatment and to develop a simple risk score for exacerbations ( RSE ) for clinical use . METHODS A large data set from 3 studies comparing budesonide/formoterol maintenance and reliever therapy with fixed-dose inhaled corticosteroid/long-acting β2-agonist therapy was analyzed . Baseline patient characteristics were investigated to determine dominant predictors for uncontrolled asthma at 3 months and for severe asthma exacerbations within 12 months of commencing treatment . The RSE , right censored at 6 months to include all 3 studies , was based on the dominant predictors for exacerbations in two thirds of the data set and vali date d in one third . RESULTS Patients ( n = 7446 ) whose symptoms were not controlled on GINA treatment steps 3 and 4 and with 1 or more exacerbations ( as judged by a clinician based on patient records , history , or both ) in the previous year were included . On multivariate analysis , GINA step , reliever use , postbronchodilator FEV1 , and 5-item Asthma Control Question naire score were dominant ( all P < .001 ) predictors for both the risk of uncontrolled asthma and severe exacerbations . Additional dominant predictors for uncontrolled asthma were smoking status and asthma symptom scores and an additional predictor for severe exacerbation was body mass index . An exponential increase in risk was observed with increments in RSE based on 5 selected predictors for exacerbations . CONCLUSION Risk of uncontrolled asthma at 3 months and a severe exacerbation within 12 months can be estimated from simple clinical assessment s. Prospect i ve validation of these predictive factors and the RSE is required . Use of these models might guide the management of asthmatic patients RATIONALE To evaluate the association between asthma exacerbations and the decline in lung function , as well as the potential effects of an inhaled corticosteroid , budesonide , on exacerbation-related decline in patients with asthma . OBJECTIVES To determine whether severe asthma exacerbations are associated with a persistent decline in lung function . METHODS The START ( inhaled steroid treatment as regular therapy in early asthma ) study was a 3-year , r and omized , double-blind study of 7,165 patients ( 5 - 66 yr ) with persistent asthma for less than 2 years , to determine whether early intervention with low-dose inhaled budesonide prevents severe asthma-related events ( exacerbations requiring hospitalization or emergency treatment ) and decline in lung function . MEASUREMENTS AND MAIN RESULTS There were 315 patients who experienced at least one severe asthma exacerbation , of which 305 were analyzable , 190 in the placebo group and 115 in the budesonide group . In the placebo group , the change in post-bronchodilator FEV(1 ) % predicted from baseline to the end of the study , in patients who did or did not experience a severe exacerbation was -6.44 % and -2.43 % , respectively ( P < 0.001 ) . A significant difference was seen in both children and in adults , but not in adolescents . In the budesonide group , the change in the post-bronchodilator FEV(1 ) % predicted in patients who did or did not experience a severe exacerbation was -2.48 % and -1.72 % , respectively ( P = 0.57 ) . The difference in magnitude of reduction afforded by budesonide , in patients who experienced at least one severe asthma-related event compared with those who did not , was statistically significant ( P = 0.042 ) . CONCLUSIONS Severe asthma exacerbations are associated with a more rapid decline in lung function . Treatment with low doses of inhaled corticosteroid is associated with an attenuation of the decline Asthma is a common cause of emergency care attendance in low- and middle-income countries ( LMICs ) . While few prospect i ve studies of predictors for emergency care attendance have been undertaken in high-income countries , none have been performed in a LMIC . We followed a cohort of 5–15-year-old children treated for asthma attacks in emergency rooms of public health facilities in Esmeraldas City , Ecuador . We collected blood and nasal wash sample s , and performed spirometry and exhaled nitric oxide fraction measurements . We explored potential predictors for recurrence of severe asthma attacks requiring emergency care over 6 months ’ follow-up . We recruited 283 children of whom 264 ( 93 % ) were followed-up for ≥6 months or until their next asthma attack . Almost half ( 46 % ) had a subsequent severe asthma attack requiring emergency care . Predictors of recurrence in adjusted analyses were ( adjusted OR , 95 % CI ) younger age ( 0.87 , 0.79–0.96 per year ) , previous asthma diagnosis ( 2.2 , 1.2–3.9 ) , number of parenteral corticosteroid courses in previous year ( 1.3 , 1.1–1.5 ) , food triggers ( 2.0 , 1.1–3.6 ) and eczema diagnosis ( 4.2 , 1.02–17.6 ) . A parsimonious Cox regression model included the first three predictors plus urban residence as a protective factor ( adjusted hazard ratio 0.69 , 95 % CI 0.50–0.95 ) . Laboratory and lung function tests did not predict recurrence . Factors independently associated with recurrent emergency attendance for asthma attacks were identified in a low-re source LMIC setting . This study suggests that a simple risk- assessment tool could potentially be created for emergency rooms in similar setting s to identify higher-risk children on whom limited re sources might be better focused . Among children in a low-re source setting in Latin America , younger age , an established asthma diagnosis and history of severe asthma attacks in the previous year were associated with recurrence of severe asthma attacks , irrespective of biomarkers 
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None of the identified models modelled recurrent exacerbations , instead favouring either presence/absence of an event , or time to first or specified event .
Current prognostic models for asthma exacerbations are heterogeneous in methodology , but reported c-statistics suggest a clinical ly useful model could be created .
Studies were consistent in lacking robust validation and in not modelling serial events .