Defining small-for-gestational-age: prescriptive versus descriptive birthweight standards.

UNLABELLED: Descriptive population-based birthweight standards possess low sensitivity in detecting infants with growth impairment. A prescriptive birthweight standard based on a 'healthy' subpopulation without risk factors for intrauterine growth restriction might be superior. We created two birthweight standards based on live born, singleton infants with gestational age 24-42 weeks and born in The Netherlands between 2000 and 2007. Inclusion criteria for the prescriptive birthweight standard were restricted to infants without congenital malformations, born to healthy mothers after uncomplicated pregnancies. We defined small-for-gestational-age (SGA) as birthweight <10th percentile and assessed the ability of both standards to predict adverse neonatal outcomes. The prescriptive birthweight standard identified significantly more infants as SGA, up to 38.0 % at 29 weeks gestation. SGA infants classified according to both standards as well as those classified according to the prescriptive birthweight standard only, were at increased risk of both major and minor adverse neonatal outcomes. The prescriptive birthweight standard was both more sensitive and less specific, with a maximum increase in sensitivity predicting bronchopulmonary dysplasia (+42.6 %) and a maximum decrease in specificity predicting intraventricular haemorrhage (-26.9 %) in infants aged 28-31 weeks. CONCLUSION: Prescriptive birthweight standards could improve identification of infants born SGA and at risk of adverse neonatal outcomes. WHAT IS KNOWN: • Descriptive birthweight standards possess low sensitivity in detecting growth restricted infants at risk of adverse neonatal outcomes. • Prescriptive standards could improve identification of very preterm small-for-gestational-age (SGA) infants at risk of intraventricular haemorrhage. What is New: • Prescriptive standards identify more preterm and term SGA infants at risk of major adverse neonatal outcomes. • Late preterm and term SGA infants classified according to the prescriptive standard are at increased risk of minor adverse neonatal outcomes with potentially harmful implications.

Population-based analysis of non-steroidal anti-inflammatory drug use among children in four European countries in the SOS project: what size of data platforms and which study designs do we need to assess safety issues?

BACKGROUND: Data on utilization patterns and safety of non-steroidal anti-inflammatory drugs (NSAIDs) in children are scarce. The purpose of this study was to investigate the utilization of NSAIDs among children in four European countries as part of the Safety Of non-Steroidal anti-inflammatory drugs (SOS) project. METHODS: We used longitudinal patient data from seven databases (GePaRD, IPCI, OSSIFF, Pedianet, PHARMO, SISR, and THIN) to calculate prevalence rates of NSAID use among children (0-18 years of age) from Germany, Italy, Netherlands, and United Kingdom. All databases contained a representative population sample and recorded demographics, diagnoses, and drug prescriptions. Prevalence rates of NSAID use were stratified by age, sex, and calendar time. The person-time of NSAID exposure was calculated by using the duration of the prescription supply. We calculated incidence rates for serious adverse events of interest. For these adverse events of interest, sample size calculations were conducted (alpha = 0.05; 1-beta = 0.8) to determine the amount of NSAID exposure time that would be required for safety studies in children. RESULTS: The source population comprised 7.7 million children with a total of 29.6 million person-years of observation. Of those, 1.3 million children were exposed to at least one of 45 NSAIDs during observation time. Overall prevalence rates of NSAID use in children differed across countries, ranging from 4.4 (Italy) to 197 (Germany) per 1000 person-years in 2007. For Germany, United Kingdom, and Italian pediatricians, we observed high rates of NSAID use among children aged one to four years. For all four countries, NSAID use increased with older age categories for children older than 11. In this analysis, only for ibuprofen (the most frequently used NSAID), enough exposure was available to detect a weak association (relative risk of 2) between exposure and asthma exacerbation (the most common serious adverse event of interest). CONCLUSIONS: Patterns of NSAID use in children were heterogeneous across four European countries. The SOS project platform captures data on more than 1.3 million children who were exposed to NSAIDs. Even larger data platforms and the use of advanced versions of case-only study designs may be needed to conclusively assess the safety of these drugs in children.

Using electronic health care records for drug safety signal detection: a comparative evaluation of statistical methods.

BACKGROUND: Drug safety monitoring relies primarily on spontaneous reporting, but electronic health care record databases offer a possible alternative for the detection of adverse drug reactions (ADRs). OBJECTIVES: To evaluate the relative performance of different statistical methods for detecting drug-adverse event associations in electronic health care record data representing potential ADRs. RESEARCH DESIGN: Data from 7 databases across 3 countries in Europe comprising over 20 million subjects were used to compute the relative risk estimates for drug-event pairs using 10 different methods, including those developed for spontaneous reporting systems, cohort methods such as the longitudinal gamma poisson shrinker, and case-based methods such as case-control. The newly developed method "longitudinal evaluation of observational profiles of adverse events related to drugs" (LEOPARD) was used to remove associations likely caused by protopathic bias. Data from the different databases were combined by pooling of data, and by meta-analysis for random effects. A reference standard of known ADRs and negative controls was created to evaluate the performance of the method. MEASURES: The area under the curve of the receiver operator characteristic curve was calculated for each method, both with and without LEOPARD filtering. RESULTS: The highest area under the curve (0.83) was achieved by the combination of either longitudinal gamma poisson shrinker or case-control with LEOPARD filtering, but the performance between methods differed little. LEOPARD increased the overall performance, but flagged several known ADRs as caused by protopathic bias. CONCLUSIONS: Combinations of methods demonstrate good performance in distinguishing known ADRs from negative controls, and we assume that these could also be used to detect new drug safety signals.

Withdrawal of statins and risk of subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Vascular endothelium, which can be affected by statins, is believed to play a substantial role in subarachnoid hemorrhage (SAH). Our objective was to estimate the association between use and withdrawal of statins and the risk of SAH. METHODS: We conducted a population-based case-control study within the PHARMO database. A case was defined as a person hospitalized for SAH (ICD-9-CM code 430) in the period January 1, 1998 to December 31, 2006. Ten randomly chosen controls were matched to each case on age, gender, and calendar date. RESULTS: During the study period 1004 incident cases of SAH were identified. Current use of statins did not significantly decrease the risk of SAH (OR=0.77, 95% CI 0.55 to 1.07). The odds ratio for recent withdrawal compared to nonusers was 1.62 (95% CI 0.96 to 2.73). Compared to current use, recent withdrawal was associated with an increased risk of SAH (OR=2.34, 95% CI 1.35 to 4.05). Interaction analysis showed that the effect of statin withdrawal was highest in patients who had also recently stopped antihypertensive drugs (OR=6.77, 95% CI 2.10 to 21.8). CONCLUSIONS: Current use of statins seems to lower the risk of SAH, although the reduction was not significant in new users. Statin withdrawal increased the risk of SAH by a factor 2, even more in patients who had also recently stopped their antihypertensive treatment.

The relation between postural stability and weight distribution in healthy subjects.

Knowledge of the effects of leg-loading asymmetry on postural control and control asymmetry during quiet upright standing in healthy young and middle-aged subjects is necessary before these relationships in patients with lateralized disorders can be assessed and understood. A posturographic procedure was developed, using a dual-plate force platform, during which 10 younger and 10 middle-aged healthy individuals were required to adopt various degrees of (a) symmetrical weight distributions (0, 5, 10, 20 and 30% of extra body weight loaded onto either leg). Postural control and control asymmetry were quantified by centre of pressure (CP) fluctuations in the lateral (LAT) and anterior-posterior (AP) directions under both feet together and individually. Subsequently, the relationship between weight distribution on one hand and postural control and control asymmetry on the other hand, was calculated. Results demonstrated that with increasing weight-bearing asymmetry (WBA), the overall control of postural sway velocity increased mainly in the LAT direction, where a first-order polynomial function fitted best. The asymmetry of control of postural sway velocity increased with increasing weight-bearing asymmetry in favour of the more loaded leg in LAT and AP directions. A first-order polynomial was used for both AP and LAT direction. Effects of weight-bearing asymmetry on postural control and control asymmetry are due to changes in the biomechanical constraints of upright standing. It was suggested that through increasing weight-bearing asymmetry the postural instability increased by reducing the efficiency of hip load/unload mechanisms and increasing the (compensatory) ankle moments.

Facial esthetics in adolescents and its relationship to "ideal" ratios and angles.

INTRODUCTION: Many guidelines, norms, and ideal ratios and angles for attractive faces have been proposed in the literature. The aim of this study was to test the hypothesis that facial attractiveness in adolescents is related to ideal angles and ratios, as indicated in the literature. METHODS: Seventy-six laypeople viewed sets of photographs of 64 adolescents and rated them on a visual analog scale (VAS) from 0 to 100. The facial esthetic value of each subject was calculated as a mean VAS score. Three observers recorded the positions of 61 landmarks, and 45 were found to have acceptable reproducibility. Based on these 45 landmarks, 27 ideal ratios on frontal photographs and 26 ideal angles on lateral photographs were identified in the literature. These ratios and angles were calculated on each photograph, and their deviation from the ideal targets in the literature were determined. Each deviation was related to the VAS score. RESULTS: Two ratios and 3 angles had a significant negative correlation with the VAS scores, indicating that beautiful faces have less deviation from the ideal target than less beautiful faces. Together, these variables explained 28.7% of the variance. CONCLUSIONS: Few "ideal" ratios and angles have a significant relationship with facial esthetics in adolescents.

Risk of ischemic stroke and the use of individual non-steroidal anti-inflammatory drugs: A multi-country European database study within the SOS Project.

BACKGROUND AND PURPOSE: A multi-country European study using data from six healthcare databases from four countries was performed to evaluate in a large study population (>32 million) the risk of ischemic stroke (IS) associated with individual NSAIDs and to assess the impact of risk factors of IS and co-medication. METHODS: Case-control study nested in a cohort of new NSAID users. For each case, up to 100 sex- and age-matched controls were selected and confounder-adjusted odds ratios for current use of individual NSAIDs compared to past use calculated. RESULTS: 49,170 cases of IS were observed among 4,593,778 new NSAID users. Use of coxibs (odds ratio 1.08, 95%-confidence interval 1.02-1.15) and use of traditional NSAIDs (1.16, 1.12-1.19) were associated with an increased risk of IS. Among 32 individual NSAIDs evaluated, the highest significant risk of IS was observed for ketorolac (1.46, 1.19-1.78), but significantly increased risks (in decreasing order) were also found for diclofenac, indomethacin, rofecoxib, ibuprofen, nimesulide, diclofenac with misoprostol, and piroxicam. IS risk associated with NSAID use was generally higher in persons of younger age, males, and those with a prior history of IS. CONCLUSIONS: Risk of IS differs between individual NSAIDs and appears to be higher in patients with a prior history of IS or transient ischemic attack (TIA), in younger or male patients. Co-medication with aspirin, other antiplatelets or anticoagulants might mitigate this risk. The small to moderate observed risk increase (by 13-46%) associated with NSAIDs use represents a public health concern due to widespread NSAID usage.

Risk of acute myocardial infarction during use of individual NSAIDs: A nested case-control study from the SOS project.

BACKGROUND: Use of selective COX-2 non-steroidal anti-inflammatory drugs (NSAIDs) (coxibs) has been associated with an increased risk of acute myocardial infarction (AMI). However, the risk of AMI has only been studied for very few NSAIDs that are frequently used. OBJECTIVES: To estimate the risk of AMI for individual NSAIDs. METHODS: A nested case-control study was performed from a cohort of new NSAID users ≥18 years (1999-2011) matching cases to a maximum of 100 controls on database, sex, age, and calendar time. Data were retrieved from six healthcare databases. Adjusted odds ratios (ORs) of current use of individual NSAIDs compared to past use were estimated per database. Pooling was done by two-stage pooling using a random effects model (ORmeta) and by one-stage pooling (ORpool). RESULTS: Among 8.5 million new NSAID users, 79,553 AMI cases were identified. The risk was elevated for current use of ketorolac (ORmeta 2.06;95%CI 1.83-2.32, ORpool 1.80; 1.49-2.18) followed, in descending order of point estimate, by indometacin, etoricoxib, rofecoxib, diclofenac, fixed combination of diclofenac with misoprostol, piroxicam, ibuprofen, naproxen, celecoxib, meloxicam, nimesulide and ketoprofen (ORmeta 1.12; 1.03-1.22, ORpool 1.00;0.86-1.16). Higher doses showed higher risk estimates than lower doses. CONCLUSIONS: The relative risk estimates of AMI differed slightly between 28 individual NSAIDs. The relative risk was highest for ketorolac and was correlated with COX-2 potency, but not restricted to coxibs.

Relation Between Different Measures of Glycemic Exposure and Microvascular and Macrovascular Complications in Patients with Type 2 Diabetes Mellitus: An Observational Cohort Study.

INTRODUCTION: This retrospective cohort study investigated the relation between different measures of glycemic exposure and micro- and macrovascular complications among patients with type 2 diabetes. METHODS: The analysis included patients receiving oral antihyperglycemic agents between 1 January 2006 and 31 December 2014 from the General Practitioner Database from the PHARMO Database Network. All recorded HbA1c levels during follow-up were used to express glycemic exposure in four ways: index HbA1c, time-dependent HbA1c, exponential moving average (EMA) and glycemic burden. Association between glycemic exposure and micro-/macrovascular complications was analyzed by estimating hazard ratios and 95% confidence intervals using an adjusted (time-dependent) Cox proportional hazards model. RESULTS: The analysis included 32,725 patients (median age, 65 years; 47% female). Median follow-up was 5.4 years; median number of HbA1c measurements per patient was 18.0. From all measures, HbA1c at index showed the weakest relation between all micro-/macrovascular complications, with coronary artery disease (CAD) having the highest HR (95% CI): 1.18 (1.04-1.34) for HbA1c ≥64 mmol/mol (8%). The time-dependent HbA1c model showed a significant association only for microvascular complications, with retinopathy having the highest HR (95% CI): 1.55 (1.40-1.73) for HbA1c ≥64 mmol/mol (8%). EMA-defined exposure showed similar findings, although the effect of retinopathy was more pronounced [HR (95% CI): 1.81 (1.63-2.02) for HbA1c ≥64 mmol/mol (8%)] and was also predictive for CAD [HR (95% CI): 1.29 (1.10-1.50) for HbA1c ≥64 mmol/mol (8%)]. A statistically significant relation with glycemic burden was found for all selected micro-/macrovascular complications, with retinopathy having the highest HR (95%): 2.60 (2.19-3.07) for glycemic burden years >3. CONCLUSION: This study shows that greater and more prolonged exposure to hyperglycemia increases the risk of micro- and macrovascular complications. FUNDING: Janssen Pharmaceutica NV.

Non-steroidal anti-inflammatory drugs and risk of heart failure in four European countries: nested case-control study.

OBJECTIVES: To investigate the cardiovascular safety of non-steroidal anti-inflammatory drugs (NSAIDs) and estimate the risk of hospital admission for heart failure with use of individual NSAIDs. DESIGN: Nested case-control study. SETTING: Five population based healthcare databases from four European countries (the Netherlands, Italy, Germany, and the United Kingdom). PARTICIPANTS: Adult individuals (age ≥18 years) who started NSAID treatment in 2000-10. Overall, 92 163 hospital admissions for heart failure were identified and matched with 8 246 403 controls (matched via risk set sampling according to age, sex, year of cohort entry). MAIN OUTCOME MEASURE: Association between risk of hospital admission for heart failure and use of 27 individual NSAIDs, including 23 traditional NSAIDs and four selective COX 2 inhibitors. Associations were assessed by multivariable conditional logistic regression models. The dose-response relation between NSAID use and heart failure risk was also assessed. RESULTS: Current use of any NSAID (use in preceding 14 days) was found to be associated with a 19% increase of risk of hospital admission for heart failure (adjusted odds ratio 1.19; 95% confidence interval 1.17 to 1.22), compared with past use of any NSAIDs (use >183 days in the past). Risk of admission for heart failure increased for seven traditional NSAIDs (diclofenac, ibuprofen, indomethacin, ketorolac, naproxen, nimesulide, and piroxicam) and two COX 2 inhibitors (etoricoxib and rofecoxib). Odds ratios ranged from 1.16 (95% confidence interval 1.07 to 1.27) for naproxen to 1.83 (1.66 to 2.02) for ketorolac. Risk of heart failure doubled for diclofenac, etoricoxib, indomethacin, piroxicam, and rofecoxib used at very high doses (≥2 defined daily dose equivalents), although some confidence intervals were wide. Even medium doses (0.9-1.2 defined daily dose equivalents) of indomethacin and etoricoxib were associated with increased risk. There was no evidence that celecoxib increased the risk of admission for heart failure at commonly used doses. CONCLUSIONS: The risk of hospital admission for heart failure associated with current use of NSAIDs appears to vary between individual NSAIDs, and this effect is dose dependent. This risk is associated with the use of a large number of individual NSAIDs reported by this study, which could help to inform both clinicians and health regulators.

Multiplex ligation-dependent probe amplification for the detection of chromosomal gains and losses in formalin-fixed tissue.

Molecular analysis on formalin-fixed paraffin-embedded tissue is of increasing importance in diagnostic histopathology and tumor research. Multiplex ligation-dependent probe amplification (MLPA) is a technique that can be used for detection of copy number alterations of up to 45 different DNA sequences in one experiment. It can be performed on partially degraded DNA, which makes this technique very suitable for analysis of formalin-fixed lesions. We tested the reliability of MLPA by analyzing DNA isolated from formalin-fixed melanomas that were previously characterized by comparative genomic hybridization (CGH), and additionally the applicability of MLPA was tested by analyzing 29 routinely processed melanocytic lesions. MLPA appears to be a reliable and efficient method to evaluate DNA copy number changes as 86% of the loci tested revealed concordant CGH results. Discordance mainly involved alterations that were detected by MLPA and not by CGH probably due to a combination of lower resolution of CGH and occasionally false positive MLPA results. For application of MLPA in a diagnostic setting, different probes on a specific region of interest should be used to prevent false positive MLPA results. In a research setting as well as in a diagnostic setting, MLPA is a fast technique to screen large numbers of formalin-fixed lesions for DNA gains and losses.

Immune status and eustachian tube function in recurrence of otitis media with effusion.

OBJECTIVE: To study the combined role of immune status and eustachian tube function in the development of recurrent bilateral otitis media with effusion (OME). DESIGN: Prospective cohort study. SETTING: Three academic and general hospitals. PATIENTS: Children aged 2 to 7 years with a first clinical episode of bilateral OME that persisted for at least 3 months; 136 (81%) of 168 eligible children participated. All children received bilateral tympanostomy tubes at study entry. MAIN OUTCOME MEASURE: Recurrence of bilateral OME within 6 months after tube extrusion. RESULTS: Univariate analyses of various immunologic factors (IgA, IgG1, IgG2, IgG3, IgG4, mannose-binding lectin, and the FcgammaRIIa-H/R131 genotype) and eustachian tube function (forced response test) did not show any significant associations with bilateral OME recurrence. Multivariate analyses showed that children with closing pressures higher than the 75th percentile and IgA or IgG2 levels below the 50th percentile of the cohort were more likely to develop recurrent OME than children with closing pressures higher than the 75th percentile and IgA or IgG2 levels above the 50th percentile. The corresponding risk ratios were 6.3 (95% confidence interval [CI], 1.0-40.1) for IgA level and 3.0 (95% CI, 1.1-8.2) for IgG2 level. The multivariate analyses also revealed that increasing serum levels of functional mannose-binding lectin were associated with decreasing probabilities of developing recurrent OME (odds ratio, 0.7; 95% CI, 0.6-1.0). CONCLUSION: Recurrence of bilateral OME after tympanostomy tube placement is more likely in children with a combination of low IgA or low IgG2 levels with poor eustachian tube function and decreased levels of mannose-binding lectin.

Spouse controls in family case-control studies: a methodological consideration.

In case-control studies on familial aggregation of disease, spouses may be chosen as convenient controls. In this article the pros and cons of this control group are discussed. It is argued that the use of spouse controls can be time- and cost-efficient, because of easy accessibility and their ability to provide proxy data on the patients' relatives if necessary. Furthermore, with spouse controls a higher response rate and less recall bias can be expected compared to population controls. A theoretical drawback is the possibility of assortative mating related to genetic susceptibility of the disease under study. Using a simulation study it is illustrated that even strong assortative mating on a factor, which is strongly correlated with a true risk factor under study, will have a negligible effect on the observed extent of familial aggregation.

Replication of the OMOP experiment in Europe: evaluating methods for risk identification in electronic health record databases.

BACKGROUND: The Observational Medical Outcomes Partnership (OMOP) has just completed a large scale empirical evaluation of statistical methods and analysis choices for risks identification in longitudinal observational healthcare data. This experiment drew data from four large US health insurance claims databases and one US electronic health record (EHR) database, but it is unclear to what extend the findings of this study apply to other data sources. OBJECTIVE: To replicate the OMOP experiment in six European EHR databases. RESEARCH DESIGN: Six databases of the EU-ADR (Exploring and Understanding Adverse Drug Reactions) database network participated in this study: Aarhus (Denmark), ARS (Italy), HealthSearch (Italy), IPCI (the Netherlands), Pedianet (Italy), and Pharmo (the Netherlands). All methods in the OMOP experiment were applied to a collection of 165 positive and 234 negative control drug-outcome pairs across four outcomes: acute liver injury, acute myocardial infarction, acute kidney injury, and upper gastrointestinal bleeding. Area under the receiver operator characteristics curve (AUC) was computed per database and for a combination of all six databases using meta-analysis for random effects. We provide expected values of estimation error as well, based on negative controls. RESULTS: Similarly to the US experiment, high predictive accuracy was found (AUC >0.8) for some analyses. Self-controlled designs, such as self-controlled case series, IC temporal pattern discovery and self-controlled cohort achieved higher performance than other methods, both in terms of predictive accuracy and observed bias. CONCLUSIONS: The major findings of the recent OMOP experiment were also observed in the European databases.

Panel perception of change in facial aesthetics following orthodontic treatment in adolescents.

The aim of the study was to evaluate the influence of the characteristics of panel members, the effects of gender and Angle Class of adolescent patients on their change in facial aesthetics following orthodontic treatment, and to assess the optimal panel size for epidemiological studies on changes in facial aesthetics after orthodontic treatment. A panel of 74 adult laymen (35 males and 39 females) and a panel of 87 orthodontists (37 males and 50 females) evaluated sets of three post-treatment standardized photographs (one frontal, one three-quarter smiling, and one lateral) of 64 adolescent orthodontic patients in relation to the pre-treatment sets of the same patient on a five-point scale. The main effects of professional background, age, gender, and geographic region of the panel members on the aesthetic scores, as well as their first order interactions were evaluated by multilevel models. Professional background, age, gender, and geographical region of panel members have an influence on the evaluation of the change of facial aesthetics following orthodontic treatment. The effect of gender and Angle Class of the patients on the scores was evaluated by two-way analysis of variance. There was no difference in the mean scores for boys and girls. Improvement of facial aesthetics by orthodontic treatment was significant for Class I, Class II division 1, and Class II division 2 patients, but not for Class III patients. Based on the intraclass correlation coefficient, a panel of nine randomly selected orthodontists, a panel of 14 randomly selected laymen, or a mixed panel of 13 individuals is sufficient to obtain reliable results in the aesthetic evaluation of adolescent faces, using photographs and a five-point scale.

Intravascular volume administration: a contributing risk factor for intracranial hemorrhage during extracorporeal membrane oxygenation?

OBJECTIVE: The objective of this study was to determine the relationship between the frequency and total volume of intravascular volume administration and the development of intracranial hemorrhage during venoarterial extracorporeal membrane oxygenation. METHODS: In a retrospective, matched, case-control study, 24 newborns who developed an intracranial hemorrhage during venoarterial extracorporeal membrane oxygenation treatment were compared with 40 control subjects. Both groups were analyzed for gestational age, gender, race, Apgar scores at 1 and 5 minutes, birth weight, cardiopulmonary resuscitation before venoarterial extracorporeal membrane oxygenation, age at the start of treatment, duration of treatment, worst arterial blood gas sample preceding treatment, activated clotting time values, need for platelet transfusions, mean blood pressure, and the use of inotropics and steroids before the treatment. For both groups, total number and volume of intravascular infusions of normal saline, pasteurized plasma protein solution, erythrocytes, and platelets during the first 24 hours of treatment were determined. Variables were analyzed in their relationship to intracranial hemorrhage by using univariate and multivariate conditional logistic regression. RESULTS: The only statistically significant difference in patient characteristics between the case patients and control subjects was arterial blood gas values. Newborns who developed intracranial hemorrhage during the treatment received both a statistically significantly higher number and a statistically significantly higher total volume of intravascular volume administrations compared with control patients. After adjustment for pH, Paco(2), and Pao(2) in the multivariate analysis, we found a significant relation between the development of intracranial hemorrhage and >8 infusions or >300 mL of volume infusion in the first 8 hours and >10 infusions in the first 24 hours of treatment. CONCLUSIONS: The number and total volume of intravascular volume administration in the first 8 and 24 hours of venoarterial extracorporeal membrane oxygenation treatment are statistically significantly related to the development of intracranial hemorrhage.

Gene expression analysis for the prediction of recurrence in patients with primary Ta urothelial cell carcinoma.

OBJECTIVES: The individual recurrence-free period after primary surgery of patients with Ta urothelial cell carcinoma (UCC) cannot be predicted accurately. This study aims at discriminating between patients with primary Ta UCC and long or short recurrence-free periods. METHODS: We investigated mRNA expression of 23 genes in 44 primary Ta tumours (23 and 21 tumours were from patients with long [>or=4 yr] or short [

Accurate prediction of need for invasive treatment in alpha1-blocker treated patients with benign prostatic hyperplasia not possible: bootstrap validation analysis.

OBJECTIVES: Frequently, statistically significant prognostic factors are reported in published studies with suggestions that disease management should be modified. However, the clinical relevance of such factors is rarely quantified. We evaluated the accuracy of predicting the need for invasive treatment among patients with benign prostatic hyperplasia treated conservatively with alpha1-blockers. METHODS: Information on eight prognostic factors was collected from 280 patients treated with alpha1-blockers. Using the proportional hazards regression coefficients, a risk score for retreatment was calculated for each patient. The analyses were repeated on 1000 groups of 280 patients sampled from the original case series. The results from these "bootstrap analyses" were compared with the original results. RESULTS: Three statistically significant predictors of retreatment were identified. The 20% of patients with the greatest risk score had an 18-month risk of retreatment of only 20% (this should ideally approach 100%). Analyses of less than one half of all the bootstrap samples resulted in the same three significant prognostic factors. The 20% of patients with the greatest risk score in each of the 1000 samples experienced a highly variable risk of retreatment of 0% to 42%. CONCLUSIONS: Strongly significant predictors for retreatment suggest the need for a change in disease management, but 4 of the 5 high-risk patients would be overtreated with a modified policy. The subclassification of patients with a relatively low risk and high risk of retreatment appeared far from accurate. Internal validation procedures may warn against the invalid translation of statistical significance into clinical relevance.

Prediction of recurrence in Ta urothelial cell carcinoma by real-time quantitative PCR analysis: a microarray validation study.

Accurate prediction of tumor recurrence in patients with superficial urothelial cell carcinoma (UCC) might result in a significant reduction of invasive follow-up cystoscopies. A recent study identified a panel of 26 genes from a large cDNA microarray analysis of bladder tumors that discriminated between early- and late-recurring patients with superficial Ta tumors (Dyrskjøt et al., Nat Genet 2003;33:90-6). We aimed to validate this panel of genes in 44 primary Ta UCCs (23 and 21 tumors from patients with short or prolonged recurrence-free periods, respectively), by real-time quantitative PCR. Statistical analysis showed marginal significant different mRNA expression levels between the 2 patient groups. To evaluate a supplementary effect of genes for the identification of patients with short or prolonged recurrence-free intervals, forward logistic regression analysis was applied. This revealed that a combination of the expression profiles of the genes HNRPK, LTB4DH and ANP32B resulted in the best performance, although the combination only marginally increased the predictive value of HNRPK alone. Comparing the receiver-operating-characteristic curves for HNRPK expression among patients with short or prolonged recurrence-free periods, revealed an area under the curve of 0.696 (95% CI, 0.537-0.855). Using the median HNRPK expression level as cut-off, a sensitivity of 69.6% and a specificity of 71.4% were obtained for the identification of patients with short or prolonged recurrence-free periods, respectively. In conclusion, we were not able to confirm the microarray gene expression pattern of the 26 genes shown by Dyrskjøt et al. The discovery of accurate recurrence predictive markers, therefore, remains a challenge.

Bayes' theorem: a negative example of a RCT on grommets in children with glue ear.

Bayesian inference presupposes that practitioners' belief in the effectiveness of medical intervention is the product of prior belief and recent evidence from studies. Although increasingly used, up to now the posterior belief calculated according to the theorem has not been compared with an empirically measured posterior belief. We conducted a RCT, which was preceded by elicitation of prior beliefs among ENT-surgeons, and which was followed by elicitation of posterior beliefs among ENT-surgeons, 1 year after completion of the trial. We compared the posterior beliefs of ENT-surgeons about the effect of grommets in children with glue ears, as predicted by Bayes' theorem with actual measured posterior beliefs. The distribution of the measured posterior beliefs was not in line with the calculated posterior, but almost identical to the distribution of the measured prior beliefs. The results showed that our trial had little or no impact on the beliefs of the ENT-surgeons, i.e. they did not adjust their belief to the extent that was expected according to Bayes' theorem.