Andrew Titman

Disease-specific survival benefit of lung transplantation in adults: a national cohort study.

The lung transplantation candidate population is heterogeneous and survival benefit has not been established for all patient groups. UK data from a cohort of 1997 adult (aged ≥ 16), first lung transplant candidates (listed July 1995 to July 2006, follow‐up to December 2007) were analyzed by diagnosis, to assess mortality relative to continued listing. Donor lungs were primarily allocated according to local criteria. Diagnosis groups studied were cystic fibrosis (430), bronchiectasis (123), pulmonary hypertension (74), diffuse parenchymal lung disease (564), chronic obstructive pulmonary disease (COPD, 647) and other (159). The proportion of patients in each group who died while listed varied significantly (respectively 37%, 48%, 41%, 49%, 19%, 38%). All groups had an increased risk of death at transplant, which fell below waiting list risk of death within 4.3 months. Thereafter, the hazard ratio for death relative to listing ranged from 0.34 for cystic fibrosis to 0.64 for COPD (p < 0.05 all groups except pulmonary hypertension). Mortality reduction was greater after bilateral lung transplantation in pulmonary fibrosis patients (p = 0.049), but not in COPD patients. Transplantation appeared to improve survival for all groups. Differential waiting list and posttransplant mortality by diagnosis suggest further use and development of algorithms to inform lung allocation.

Model diagnostics for multi-state models.

Multi-state models are a popular method of describing medical processes that can be represented as discrete states or stages. They have particular use when the data are panel-observed, meaning they consist of discrete snapshots of disease status at irregular time points which may be unique to each patient. However, due to the difficulty of inference in more complicated cases, strong assumptions such as the Markov property, patient homogeneity and time homogeneity are applied. It is important that the validity of these assumptions is tested. A review of methods for diagnosing model fit for panel-observed continuous-time Markov and misclassification-type hidden Markov models is given, with illustrative application to a dataset on cardiac allograft vasculopathy progression in post-heart transplant patients.

Semi-Markov Models with Phase-Type Sojourn Distributions

Continuous-time multistate models are widely used for categorical response data, particularly in the modeling of chronic diseases. However, inference is difficult when the process is only observed at discrete time points, with no information about the times or types of events between observation times, unless a Markov assumption is made. This assumption can be limiting as rates of transition between disease states might instead depend on the time since entry into the current state. Such a formulation results in a semi-Markov model. We show that the computational problems associated with fitting semi-Markov models to panel-observed data can be alleviated by considering a class of semi-Markov models with phase-type sojourn distributions. This allows methods for hidden Markov models to be applied. In addition, extensions to models where observed states are subject to classification error are given. The methodology is demonstrated on a dataset relating to development of bronchiolitis obliterans syndrome in post-lung-transplantation patients.

Long-term Follow-up Reveals Low Incidence of Colorectal Cancer, but Frequent Need for Resection, Among Australian Patients With Inflammatory Bowel Disease

BACKGROUND & AIMS Inflammatory bowel disease can require surgical resection and also lead to colorectal cancer (CRC). We investigated the cumulative incidence of resection surgeries and CRC among patients with ulcerative colitis (UC) or Crohns disease (CD). METHODS We analyzed data from a cohort of patients who participated in an inflammatory bowel disease study (504 with UC and 377 with CD) at 2 academic medical centers in Sydney, Australia from 1977 to 1992 (before the development of biologic therapies). We collected follow-up data on surgeries and development of CRC from hospital and community medical records or via direct contact with patients during a median time period of 14 years. Cumulative incidences of resection surgeries and CRC were calculated by competing risk survival analysis. RESULTS Among patients with UC, CRC developed in 24, for a cumulative incidence of 1% at 10 years (95% confidence interval [CI], 0%-2%), 3% at 20 years (95% CI, 1%-5%), and 7% at 30 years (95% CI, 4%-10%). Their cumulative incidence of colectomy was 15% at 10 years (95% CI, 11%-19%), 26% at 20 years (95% CI, 21%-30%), and 31% at 30 years (95% CI, 25%-36%). Among patients with CD, 5 of 327 with colon disease developed CRC, with a cumulative incidence of CRC of 1% at 10 years (95% CI, 0%-2%), 1% at 20 years (95% CI, 0%-2%), and 2% at 30 years (95% CI, 0%-4%). Among all patients with CD, the cumulative incidence of resection was 32% at 5 years (95% CI, 27%-37%), 43% at 10 years (95% CI, 37%-49%), and 53% at 15 years (95% CI, 46%-58%). Of these 168 subjects, 42% required a second resection within 15 years of the first surgery (95% CI, 33%-50%). CONCLUSIONS Patients with UC have a low incidence of CRC during a 30-year period (7% or less); the incidence among patients with CD is even lower. However, almost one-third of patients with UC and about 50% of those with CD will require surgery.

Measurement of flood peak effects as a result of soil and land management, with focus on experimental issues and scale

As a result of several serious flood events which have occurred since 2000, flooding across Europe is now receiving considerable public and media attention. The impact of land use on hydrology and flood response is significantly under-researched, and the links between land use change and flooding are still unclear. This study considers runoff data available from studies of arable in-field land use management options, applied with the aim of reducing diffuse pollution from arable land, in order to investigate whether these treatments also have potential to reduce downstream flooding. Intensive monitoring of 17 hillslope treatment areas produced a record of flood peak data covering different mitigation treatments for runoff which occurred in the winter of 2007-2008. We investigated event total runoff responses to rainfall, peak runoff, and timing of the runoff peaks from replicates of different treatments, in order to assess whether there is a significant difference in flood peak response between different mitigation options which could be used to mitigate downstream flood risk. A mixed-modelling approach was adopted in order to determine whether differences observed in runoff response were significant. The results of this study suggest that changes in land use management using arable in-field mitigation treatments can affect local-scale runoff generation, with differences observed in the size, duration and timing of flood peaks as a result of different management practices, but the study was unable to allow significant treatment effects to be determined. We suggest that further field studies of the effects of changes in land use and land use management need to upscale towards farm and catchment scale experiments which consider high quality before-and-after data over longer temporal timescales. This type of data collection is essential in order to allow appropriate land use management decisions to be made.

Flexible Nonhomogeneous Markov Models for Panel Observed Data

Methods for fitting nonhomogeneous Markov models to panel-observed data using direct numerical solution to the Kolmogorov Forward equations are developed. Nonhomogeneous Markov models occur most commonly when baseline transition intensities depend on calendar time, but may also occur with deterministic time-dependent covariates such as age. We propose transition intensities based on B-splines as a smooth alternative to piecewise constant intensities and also as a generalization of time transformation models. An expansion of the system of differential equations allows first derivatives of the likelihood to be obtained, which can be used in a Fisher scoring algorithm for maximum likelihood estimation. The method is evaluated through a small simulation study and demonstrated on data relating to the development of cardiac allograft vasculopathy in posttransplantation patients.

Early morning salivary cortisol and cortisone, and adrenal responses to a simplified low-dose short Synacthen test in children with asthma.

To examine serum cortisol responses to a simplified low‐dose short Synacthen test (LDSST) in children treated with inhaled corticosteroids (ICS) for asthma and to compare these to early morning salivary cortisol (EMSC) and cortisone (EMSCn) levels.

A retrospective study of seven-day consultant working: reductions in mortality and length of stay.

UNLABELLED Weekend admission is associated with higher in-hospital mortality than weekday admission. Whether providing enhanced weekend staffing for acute medical inpatient services reduces mortality or length of stay is unknown. METHODS This paper describes a retrospective analysis of in-hospital mortality and length of stay before and after introduction of an enhanced, consultant-led weekend service in acute medicine in November 2012. In-hospital mortality was compared for matching admission calendar months before and after introduction of the new service, adjusted for case volume. Length of stay and 30-day postdischarge mortality were also compared; illness severity of patients admitted was assessed by cross-sectional acuity audits. RESULTS Admission numbers increased from 6,304 (November 2011-July 2012) to 7,382 (November 2012-July 2013), with no change in acuity score in elderly medical patients but a small fall in younger patients. At the same time, however, a 57% increase in early-warning score triggered calls was seen in 2013 (410 calls vs 262 calls in 2012; p<0.01). Seven-day consultant working was associated with a reduction in in-hospital mortality from 11.4% to 8.8% (p<0.001). Mortality within 30 days of discharge fell from 2.4% to 2.0% (p=0.12). Length of stay fell by 1.9 days (95% CI 1.1-2.7; p=0.004) for elderly medicine wards and by 1.7 days (95% CI 0.8-2.6; p=0.008) for medical wards. Weekend discharges increased from general medical wards (from 13.6% to 18.8%, p<0.001) but did not increase from elderly medicine wards. CONCLUSIONS Introduction of an enhanced, consultant-led model of working at weekends was associated with reduced in-hospital and 30-day post discharge mortality rates as well as reduced length of stay. These results require confirmation in rigorously designed prospective studies.

Transition probability estimates for non-Markov multi-state models

Non-parametric estimation of the transition probabilities in multi-state models is considered for non-Markov processes. Firstly, a generalization of the estimator of Pepe et al., (1991) (Statistics in Medicine) is given for a class of progressive multi-state models based on the difference between Kaplan-Meier estimators. Secondly, a general estimator for progressive or non-progressive models is proposed based upon constructed univariate survival or competing risks processes which retain the Markov property. The properties of the estimators and their associated standard errors are investigated through simulation. The estimators are demonstrated on datasets relating to survival and recurrence in patients with colon cancer and prothrombin levels in liver cirrhosis patients.

Computation of the asymptotic null distribution of goodness-of-fit tests for multi-state models

We develop an improved approximation to the asymptotic null distribution of the goodness-of-fit tests for panel observed multi-state Markov models (Aguirre-Hernandez and Farewell, Stat Med 21:1899–1911, 2002) and hidden Markov models (Titman and Sharples, Stat Med 27:2177–2195, 2008). By considering the joint distribution of the grouped observed transition counts and the maximum likelihood estimate of the parameter vector it is shown that the distribution can be expressed as a weighted sum of independent