The search for biomarkers in the critically ill: a cautionary tale.

The search for biomarkers has been described as a dismal patchwork of fragmented research. We review biomarkers in sepsis in the critically ill in terms of conventional single circulating proteins. Despite sepsis biomarker publications trebling over the past 6 years, currently only one, procalcitonin, has materialised promise.

New initiatives in critical care: distinguishing hype from hope.

Recent viewpoints on critical care have expressed frustration at the slow development of new therapeutic agents and the failure of investigator-initiated trials. Several new directions have been proposed: personalised medicine and the embracing of "omic" technologies, resolving the heterogeneity of treatment effects, and adaptive trial designs. We examine these approaches in the context of analysis of randomised controlled trials (RCTs).

Assessing changes over time in healthcare provider performance: addressing regression to the mean over multiple time points.

In recent years, the evaluation of healthcare provider performance has become standard for governments, insurance companies, and other stakeholders. Often, performance is compared across providers using indicators in one time period, for example a year. However it is often important to assess changes in the performance of individual providers over time.

Identifying unusual performance in Australian and New Zealand intensive care units from 2000 to 2010.

Background: The Australian and New Zealand Intensive Care Society (ANZICS) Adult Patient Database (APD) collects voluntary data on patient admissions to Australian and New Zealand intensive care units (ICUs). This paper presents an in-depth statistical analysis of risk-adjusted mortality of ICU admissions from 2000 to 2010 for the purpose of identifying ICUs with unusual performance.

Methods: A cohort of 523,462 patients from 144 ICUs was analysed.

Statistical process control of mortality series in the Australian and New Zealand Intensive Care Society (ANZICS) adult patient database: implications of the data generating process.

Background: Statistical process control (SPC), an industrial sphere initiative, has recently been applied in health care and public health surveillance. SPC methods assume independent observations and process autocorrelation has been associated with increase in false alarm frequency.

Methods: Monthly mean raw mortality (at hospital discharge) time series, 1995-2009, at the individual Intensive Care unit (ICU) level, were generated from the Australia and New Zealand Intensive Care Society adult patient database.

A review of statistical estimators for risk-adjusted length of stay: analysis of the Australian and new Zealand Intensive Care Adult Patient Data-Base, 2008-2009.

Background: For the analysis of length-of-stay (LOS) data, which is characteristically right-skewed, a number of statistical estimators have been proposed as alternatives to the traditional ordinary least squares (OLS) regression with log dependent variable.

Methods: Using a cohort of patients identified in the Australian and New Zealand Intensive Care Society Adult Patient Database, 2008-2009, 12 different methods were used for estimation of intensive care (ICU) length of stay. These encompassed risk-adjusted regression analysis of firstly: log LOS using OLS, linear mixed model [LMM], treatment effects, skew-normal and skew-t models; and secondly: unmodified (raw) LOS via OLS, generalised linear models [GLMs] with log-link and 4 different distributions [Poisson, gamma, negative binomial and inverse-Gaussian], extended estimating equations [EEE] and a finite mixture model including a gamma distribution.

Mortality and intensive care volume in ventilated patients from 1995 to 2009 in the Australian and New Zealand binational adult patient intensive care database*.

Objectives: The mortality outcome of mechanical ventilation, a key intervention in the critically ill, has been variously reported to be determined by intensive care patient volume. We determined the volume-(mortality)-outcome relationship of mechanically ventilated patients whose records were contributed to the Australian and New Zealand Intensive Care Society Adult Patient Database.

Design, Setting, And Participants: Retrospective cohort study of 208,810 index patient admissions from 136 Australian and New Zealand intensive care units in the same number of hospitals over the course of 1995-2009.

Conventional and advanced time series estimation: application to the Australian and New Zealand Intensive Care Society (ANZICS) adult patient database, 1993-2006.

Rationale: Time series analysis has seen limited application in the biomedical Literature. The utility of conventional and advanced time series estimators was explored for intensive care unit (ICU) outcome series.

Methods: Monthly mean time series, 1993-2006, for hospital mortality, severity-of-illness score (APACHE III), ventilation fraction and patient type (medical and surgical), were generated from the Australia and New Zealand Intensive Care Society adult patient database.

Global quantitative indices reflecting provider process-of-care: data-base derivation.

Background: Controversy has attended the relationship between risk-adjusted mortality and process-of-care. There would be advantage in the establishment, at the data-base level, of global quantitative indices subsuming the diversity of process-of-care.

Methods: A retrospective, cohort study of patients identified in the Australian and New Zealand Intensive Care Society Adult Patient Database, 1993-2003, at the level of geographic and ICU-level descriptors (n = 35), for both hospital survivors and non-survivors.

Some statistics in bioinformatics: the fifth Armitage Lecture.

The spirit and content of the 2007 Armitage Lecture are presented in this paper. To begin, two areas of Peter Armitage's early work are distinguished: his pioneering research on sequential methods intended for use in medical trials and the comparison of survival curves. Their influence on much later work is highlighted, and motivate the proposal of several statistical 'truths' that are presented in the paper.

Modelling survival in acute severe illness: Cox versus accelerated failure time models.

Background: The Cox model has been the mainstay of survival analysis in the critically ill and time-dependent covariates have infrequently been incorporated into survival analysis.

Objectives: To model 28-day survival of patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), and compare the utility of Cox and accelerated failure time (AFT) models.

Methods: Prospective cohort study of 168 adult patients enrolled at diagnosis of ALI in 21 adult ICUs in three Australian States with measurement of survival time, censored at 28 days.

Mortality and length-of-stay outcomes, 1993-2003, in the binational Australian and New Zealand intensive care adult patient database.

Objective: Intensive care unit (ICU) outcomes have been the subject of controversy. The objective was to model hospital mortality and ICU length-of-stay time-change of patients recorded in the Australian and New Zealand Intensive Care Society adult patient database.

Design: Retrospective, cohort study of prospectively collected data on index patient admissions.

Statistics in review. Part 2: generalised linear models, time-to-event and time-series analysis, evidence synthesis and clinical trials.

In Part I, we reviewed graphical display and data summary, followed by a consideration of linear regression models. Generalised linear models, structured in terms of an exponential response distribution and link function, are now introduced, subsuming logistic and Poisson regression. Time-to-event ("survival") analysis is developed from basic principles of hazard rate, and survival, cumulative distribution and density functions.

New models for old questions: generalized linear models for cost prediction.

Background: Generalized linear models (GLMs) have recently been introduced into cost data analysis. GLMs, transformations of the linear regression model, are characterized by a particular response distribution from one of the exponential family of distributions and monotonic link function which relates the response mean to a scale on which additive model effects operate.

Objectives: This study compared GLMs and ordinary least squares regression (OLS) in predicting individual patient costs in adult intensive care units (ICUs) and sought to define the utility of the inverse Gaussian distribution family within GLMs.

Statistics in review Part I: graphics, data summary and linear models.

Statistics and biomedical literature have historically had an uneasy alliance. A critical approach to the application of statistics is developed. Initially, we survey graphical data display and trace the historical development of the "testing" statistical paradigm, and the contributions of A R Fisher and J Neyman and E Pearson.

Tympanic temperature measurements: are they reliable in the critically ill? A clinical study of measures of agreement.

Objective: Accurate measurement of temperature is vital in the intensive care setting. A prospective trial was performed to compare the accuracy of tympanic, urinary, and axillary temperatures with that of pulmonary artery (PA) core temperature measurements.

Design: A total of 110 patients were enrolled in a prospective observational cohort study.

Meta-analysis of controlled trials of ventilator therapy in acute lung injury and acute respiratory distress syndrome: an alternative perspective.

Objective: The role of protective ventilation in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is controversial. Evidence was sought from published randomised trials for a consistent treatment effect of protective ventilation and any covariate modification.

Design: Meta-analysis of protective ventilation trials in ALI/ARDS and meta-regression of covariates on treatment effect (log odds ratio), with respect to 28-day mortality.