Reducing surgical mortality in Scotland by use of the WHO Surgical Safety Checklist.

BACKGROUND: The WHO Surgical Safety Checklist has been implemented widely since its launch in 2008. It was introduced in Scotland as part of the Scottish Patient Safety Programme (SPSP) between 2008 and 2010, and is now integral to surgical practice. Its influence on outcomes, when analysed at a population level, remains unclear. METHODS: This was a population cohort study. All admissions to any acute hospital in Scotland between 2000 and 2014 were included. Standardized differences were used to estimate the balance of demographics over time, after which interrupted time-series (segmented regression) analyses were performed. Data were obtained from the Information Services Division, Scotland. RESULTS: There were 12 667 926 hospital admissions, of which 6 839 736 had a surgical procedure. Amongst the surgical cohort, the inpatient mortality rate in 2000 was 0·76 (95 per cent c.i. 0·68 to 0·84) per cent, and in 2014 it was 0·46 (0·42 to 0·50) per cent. The checklist was associated with a 36·6 (95 per cent c.i. -55·2 to -17·9) per cent relative reduction in mortality (P < 0·001). Mortality rates before implementation were decreasing by 0·003 (95 per cent c.i. -0·017 to +0·012) per cent per year; annual decreases of 0·069 (-0·092 to -0·046) per cent were seen during, and 0·019 (-0·038 to +0·001) per cent after, implementation. No such improvement trends were seen in the non-surgical cohort over this time frame. CONCLUSION: Since the implementation of the checklist, as part of an overall national safety strategy, there has been a reduction in perioperative mortality.

Minimally invasive surgery and its impact on 30-day postoperative complications, unplanned readmissions and mortality.

BACKGROUND: A critical appraisal of the benefits of minimally invasive surgery (MIS) is needed, but is lacking. This study examined the associations between MIS and 30-day postoperative outcomes including complications graded according to the Clavien-Dindo classification, unplanned readmissions, hospital stay and mortality for five common surgical procedures. METHODS: Patients undergoing appendicectomy, colectomy, inguinal hernia repair, hysterectomy and prostatectomy were identified in the American College of Surgeons National Surgical Quality Improvement Program database. Non-parsimonious propensity score methods were used to construct procedure-specific matched-pair cohorts that reduced baseline differences between patients who underwent MIS and those who did not. Bonferroni correction for multiple comparisons was applied and P < 0·006 was considered significant. RESULTS: Of the 532 287 patients identified, 53·8 per cent underwent MIS. Propensity score matching yielded an overall sample of 327 736 patients (appendicectomy 46 688, colectomy 152 114, inguinal hernia repair 59 066, hysterectomy 59 066, prostatectomy 10 802). Within the procedure-specific matched pairs, MIS was associated with significantly lower odds of Clavien-Dindo grade I-II, III and IV complications (P ≤ 0·004), unplanned readmissions (P < 0·001) and reduced hospital stay (P < 0·001) in four of the five procedures studied, with the exception of inguinal hernia repair. The odds of death were lower in patients undergoing MIS colectomy (P < 0·001), hysterectomy (P = 0·002) and appendicectomy (P = 0·002). CONCLUSION: MIS was associated with significantly fewer 30-day postoperative complications, unplanned readmissions and deaths, as well as shorter hospital stay, in patients undergoing colectomy, prostatectomy, hysterectomy or appendicectomy. No benefits were noted for inguinal hernia repair.

Mortality and drug exposure in a 5-year cohort of patients with chronic liver disease.

BACKGROUND: Chronic liver diseases are common in the general population. Drug treatment in this group may be challenging, as many drugs are hepatically metabolised and hepatotoxic. OBJECTIVES: We aimed to assess the mortality of patients with chronic liver disease according to specific drug exposures and the three laboratory parameters creatinine, bilirubin and International Normalised Ratio (INR). METHODS: We conducted a multicentre, 5-year retrospective cohort study in two tertiary university referral hospitals and a secondary referral hospital, using a research database to evaluate the crude and adjusted mortality. RESULTS: Of 1159362 individual patients 1.7% (n = 20158) had chronic liver disease and in this group 36.8% had unspecified chronic non-alcoholic liver disease, 30.1% chronic hepatitis C and 11.9% cirrhosis of the liver. 8.4% of patients presented a diagnosis associated with alcohol. The 4-year survival rates were significantly higher in the group with the most normal laboratory values (94.3%) versus 34.5% in the group with elevated parameters (p <0.001). Overall, drug exposure was not associated with higher mortality; in adjusted multivariate analysis the hazard ratio for anti-cancer drugs was 2.69 (95% CI 1.32-5.46). Of individual drugs, mortality hazard ratios for amiodarone, morphine oral, acetazolamide, sirolimus and lamivudine were 2.46 (95% CI 1.68-3.61), 2.26 (95% CI 1.78-2.86), 2.10 (95% CI 1.19-3.70), 1.81 (95% CI 1.02-3.21) and 1.72 (95% CI 1.17-2.53) respectively. CONCLUSIONS: Drug exposure in general was not associated with higher mortality except for a few categories. Mortality in patients with chronic liver disease was high and is associated with simple laboratory values.

Non-invasive assessment of rejection in pediatric transplant patients: serologic and echocardiographic prediction of biopsy-proven myocardial rejection.

BACKGROUND: Cardiac allograft rejection is a multifocal immune process that is currently assessed using biopsy-guided histologic classification systems (International Society for Heart and Lung Transplantation). Cardiac troponin T and I are established serologic markers of global myocyte damage. The use of load-independent measures of contractility have also been shown to accurately assess the presence of ventricular dysfunction. Little is known about their utility in accurately predicting rejection in the pediatric age group. We undertook the present study to compare rejection grade with echocardiographic and serologic estimates of transplant rejection-related myocardial damage. METHODS: We compared histologic rejection grades (0 to 4) with patient characteristics, echocardiographic measurements, catheterization measurements, and biochemical markers for 86 evaluations in 37 transplant recipients at Children's Hospital. RESULTS: In univariate analyses, biopsy scores correlated (p < 0.05) inversely with left ventricular systolic function (shortening fraction) and contractility (stress velocity index, SVI), and directly with mitral E-wave amplitude. In multivariate analyses, lower contractility and higher mitral E-wave amplitude remained significantly (p < or = 0.01) associated with rejection (SVI, p = 0.002, odds ratio = 0.393; E wave, p = 0.0002, odds ratio = 228). Most rejection episodes were associated with elevation of biochemical markers of myocardial injury. Although troponin I was weakly associated with differences between rejection grades (p = 0.034), troponin T, creatine kinase-MB fraction, and C-reactive protein did not differ with biopsy-rejection scores. Serum markers had a poor predictive capacity for biopsy-detected rejection. Troponin T and I did correlate with increased left ventricular wall thickness and mass. CONCLUSION: Progressively depressed left ventricular contractility and diastolic function are found with worsening pediatric heart transplant rejection-biopsy score; however, sensitive and specific serum markers do not correspond to the degree of active myocardial injury. The use of echocardiographic measures of contractility is associated with a specificity of 91.8% but low sensitivity of 66.7%. Overall we found poor concordance between serum markers and grade of rejection. It is unclear whether myocardial injury as assessed by serum markers, echocardiography, or histologic scoring is more important for assessment of acute rejection or long-term outcome, but it does not appear that serum and tissue markers of rejection can be used interchangeably.

Non-ignorable missing covariates in generalized linear models.

We propose a likelihood method for estimating parameters in generalized linear models with missing covariates and a non-ignorable missing data mechanism. In this paper, we focus on one missing covariate. We use a logistic model for the probability that the covariate is missing, and allow this probability to depend on the incomplete covariate. We allow the covariates, including the incomplete covariate, to be either categorical or continuous. We propose an EM algorithm in this case. For a missing categorical covariate, we derive a closed form expression for the E- and M-steps of the EM algorithm for obtaining the maximum likelihood estimates (MLEs). For a missing continuous covariate, we use a Monte Carlo version of the EM algorithm to obtain the MLEs via the Gibbs sampler. The methodology is illustrated using an example from a breast cancer clinical trial in which time to disease progression is the outcome, and the incomplete covariate is a quality of life physical well-being score taken after the start of therapy. This score may be missing because the patients are sicker, so this covariate could be non-ignorably missing.

Using missing data methods in genetic studies with missing mutation status.

Because of current techniques of determining gene mutation, investigators are now interested in estimating the odds ratio between genetic status (mutation, no mutation) and an outcome variable such as disease cell type (A, B). In this paper we consider the mutation of the RAS genetic family. To determine if the genes have mutated, investigators look at five specific locations on the RAS gene. RAS mutated is a mutation in at least one of the five gene locations and RAS non-mutated is no mutation in any of the five locations. Owing to limited time and financial resources, one cannot obtain a complete genetic evaluation of all five locations on the gene for all patients. We propose the use of maximum likelihood (ML) with a 2(6) multinomial distribution formed by cross-classifying the binary mutation status at five locations by binary disease cell type. This ML method includes all patients regardless of completeness of data, treats the locations not evaluated as missing data, and uses the EM algorithm to estimate the odds ratio between genetic mutation status and the disease type. We compare the ML method to complete case estimates, and a method used by clinical investigators, which excludes patients with data on less than five locations who have no mutations on these sites.

Likelihood methods for incomplete longitudinal binary responses with incomplete categorical covariates.

We consider longitudinal studies in which the outcome observed over time is binary and the covariates of interest are categorical. With no missing responses or covariates, one specifies a multinomial model for the responses given the covariates and uses maximum likelihood to estimate the parameters. Unfortunately, incomplete data in the responses and covariates are a common occurrence in longitudinal studies. Here we assume the missing data are missing at random (Rubin, 1976, Biometrika 63, 581-592). Since all of the missing data (responses and covariates) are categorical, a useful technique for obtaining maximum likelihood parameter estimates is the EM algorithm by the method of weights proposed in Ibrahim (1990, Journal of the American Statistical Association 85, 765-769). In using the EM algorithm with missing responses and covariates, one specifies the joint distribution of the responses and covariates. Here we consider the parameters of the covariate distribution as a nuisance. In data sets where the percentage of missing data is high, the estimates of the nuisance parameters can lead to highly unstable estimates of the parameters of interest. We propose a conditional model for the covariate distribution that has several modeling advantages for the EM algorithm and provides a reduction in the number of nuisance parameters, thus providing more stable estimates in finite samples.

Monte Carlo EM for missing covariates in parametric regression models.

We propose a method for estimating parameters for general parametric regression models with an arbitrary number of missing covariates. We allow any pattern of missing data and assume that the missing data mechanism is ignorable throughout. When the missing covariates are categorical, a useful technique for obtaining parameter estimates is the EM algorithm by the method of weights proposed in Ibrahim (1990, Journal of the American Statistical Association 85, 765-769). We extend this method to continuous or mixed categorical and continuous covariates, and for arbitrary parametric regression models, by adapting a Monte Carlo version of the EM algorithm as discussed by Wei and Tanner (1990, Journal of the American Statistical Association 85, 699-704). In addition, we discuss the Gibbs sampler for sampling from the conditional distribution of the missing covariates given the observed data and show that the appropriate complete conditionals are log-concave. The log-concavity property of the conditional distributions will facilitate a straightforward implementation of the Gibbs sampler via the adaptive rejection algorithm of Gilks and Wild (1992, Applied Statistics 41, 337-348). We assume the model for the response given the covariates is an arbitrary parametric regression model, such as a generalized linear model, a parametric survival model, or a nonlinear model. We model the marginal distribution of the covariates as a product of one-dimensional conditional distributions. This allows us a great deal of flexibility in modeling the distribution of the covariates and reduces the number of nuisance parameters that are introduced in the E-step. We present examples involving both simulated and real data.

Using ecological data to estimate a regression model for individual data: the association between arsenic in drinking water and incidence of skin cancer.

In ecologic studies, participants are studied by groups, and the exposure status of each group is usually represented by a single indicator, mostly the mean exposure. In this paper, we propose using multiple variables derived from dummy variables at the individual level to describe the exposure. An analysis of the association between arsenic in drinking water and skin cancer was used as an example. Well water arsenic levels and skin cancer incidence from 1980 to 1987 were assessed for 243 townships in Taiwan. We first analyzed the data using the mean arsenic concentration in each township as the only exposure variable. The second analysis used multiple variables to describe arsenic exposure; each variable denoted the percentage of wells with arsenic levels within a specific range in each township. Although the first approach did not identify associations between arsenic levels and skin cancer, the multiple-variable approach identifies a positive association at the highest arsenic exposure category (>0.64 mg/L) in both men and women. Therefore, using multiple variables to describe an exposure in ecologic studies may facilitate a better description of the exposure status and thereby lead to more accurate risk assessment, especially when the dose-response relationship is not linear.

Estimating equations with incomplete categorical covariates in the Cox model.

Incomplete covariate data is a common occurrence in many studies in which the outcome is survival time. When a full likelihood is specified, a useful technique for obtaining parameter estimates is the EM algorithm. We propose a set of estimating equations to estimate the parameters of Cox's proportional hazards model when some covariate values are missing. These estimating equations can be solved by an algorithm similar to the EM algorithm. Because of the computational burden of finding a solution to these estimating equations, we propose obtaining parameter estimates via Monte Carlo methods. Asymptotic variances of the parameter estimates are also derived. We present a clinical trials example with three covariates, two of which have some missing values.

Tests for homogeneity of the risk difference when data are sparse.

Test statistics for the homogeneity of the risk difference for a series of 2 x 2 tables when the data are sparse is proposed. A weighted least squares statistic is commonly used to test for equality of the risk difference over the tables; however, when the data are sparse, this statistic can have anticonservative Type I error rates. Simulation is used to compare the proposed test statistics to the weighted least squares statistic. The weighted least squares statistic has the most anticonservative Type I error rates of all the statistics compared. We suggest the use of one of our proposed test statistics instead of the weighted least squares statistic.

Inference using conditional logistic regression with missing covariates.

When there are many nuisance parameters in a logistic regression model, a popular method for eliminating these nuisance parameters is conditional logistic regression. Unfortunately, another common problem in a logistic regression analysis is missing covariate data. With many nuisance parameters to eliminate and missing covariates, many investigators exclude any subject with missing covariates and then use conditional logistic regression, often called a complete-case analysis. In this article, we derive a modified conditional logistic regression that is appropriate with covariates that are missing at random. Performing a conditional logistic regression with only the complete cases is convenient with existing statistical packages, but it may give bias if missingness is not completely at random.

Relationship between cumulative anthracycline dose and late cardiotoxicity in childhood acute lymphoblastic leukemia.

PURPOSE: Late anthrocycline cardiotoxicity after treatment for childhood cancer is common and often progressive. A safe anthracycline dose that will not result in late cardiac abnormalities has not been established due to the limited dose ranges used in existing studies. PATIENTS AND METHODS: To determine the relationship between cumulative anthracycline dose and late cardiotoxicity, we performed echocardiograms on 189 survivors of childhood acute lymphoblastic leukemia a median of 8.1 years (range, 2.0 to 23.4) after completion of anthracycline therapy. Patients were treated according to protocols that used widely varying cumulative anthracycline doses, but comparable nonanthracycline chemotherapy. Patients were divided into four groups based on the city of treatment and cumulative anthracycline dose: Copenhagen, 0 to 23 mg/m2 (n = 32); Boston, 45 mg/m2 (n = 17); Copenhagen, 73 to 301 mg/m2 (n = 53); and Boston, 244 to 550 mg/m2 (n = 87). Left ventricular dimension and fractional shortening were adjusted for sex and age or body-surface area through use of a control population (n = 296), and then compared among the four groups. RESULTS: Mean left ventricular dimension was significantly increased in the high-dose Boston group (observed:predicted value, 4.57 cm:4.45 cm; P = .002) and significantly higher than in the two Copenhagen groups. In the three lower-dose groups, there was no significant increase in mean left ventricular dimension, and the groups were not significantly different from each other. Similarly, the mean left ventricular fractional shortening was significantly depressed in the high-dose Boston group (observed:predicted value, 29.0%:33.8%; P = .0001) and significantly lower than in the three lower-dose groups. CONCLUSION: Depressed left ventricular fractional shortening and left ventricular dilatation were uncommon years after treatment of childhood leukemia when cumulative anthracycline doses were < or = 300 mg/m2.

Predictive value of cardiac troponin T in pediatric patients at risk for myocardial injury.

BACKGROUND: Biochemical markers have not been routinely used in children at risk for myocardial damage. Yet, because of somatic growth and the duration of survival, a low level of myocardial damage may ultimately be of more consequence in children than in adults. METHODS AND RESULTS: We investigated the utility of cardiac troponin T (cTnT) blood levels (CARDIAC T ELISA Troponin T, Boehringer Mannheim Corp) in 51 consecutively sampled patients from 1 day to 34 years of age (median=5.7 years) undergoing cardiovascular (n=19) or noncardiovascular (n=17) surgery or who received doxorubicin for acute lymphoblastic leukemia (ALL) (n=15). Minimum detectable cTnT elevations were 0.03 ng/mL. cTnT was measurable in children of all ages with myocyte damage. In patients who underwent cardiovascular surgery, a correlation was noted between a score of increasing surgical severity and the mean level of postoperative cTnT (r=.79, P<.0001). Postoperative cTnT levels were elevated in children who completed cardiovascular surgery with an open chest compared with those with a closed chest (P=.0083). In addition, cTnT levels before cardiovascular surgery predicted postoperative survival (P=.007). cTnT elevations were observed after initial doxorubicin therapy for ALL. The magnitude of elevation predicted left ventricular dilatation (r=.80 when variables were treated as continuous, P=.003) and wall thinning (r=.61, P=.044) 9 months later. CONCLUSIONS: Elevations of blood cTnT in children relate to the severity of myocardial damage and predict subsequent subclinical and clinical cardiac morbidity and mortality.

Arsenic in drinking water and incidence of urinary cancers.

The associations between arsenic ingestion and cancers of the bladder and kidney have been documented in Taiwan. To evaluate further such associations for urinary cancers of various cell types, we conducted an ecologic study encompassing 243 townships using cancer registry data of patients diagnosed between 1980 and 1987. We used the proportions of wells with various specified arsenic levels in each township as indicators of exposure and evaluated the effects of urbanization and smoking by an urbanization index and the number of cigarettes sold per capita. In both genders, we observed associations of high arsenic levels in drinking water with transitional cell carcinomas of the bladder, kidney, and ureter and all urethral cancers combined. We also observed such associations in adenocarcinomas of the bladder in males, but not in squamous cell carcinomas of the bladder or renal cell carcinomas or nephroblastomas of the kidney. There was also a positive association between the urbanization index and transitional cell carcinomas of the ureter in males. The number of cigarettes sold per capita was not a good predictor for urinary cancers. The results indicate that the carcinogenicity of arsenic may be cell type specific.

Parameter estimation from incomplete data in binomial regression when the missing data mechanism is nonignorable.

We propose a method for estimating parameters in binomial regression models when the response variable is missing and the missing data mechanism is nonignorable. We assume throughout that the covariates are fully observed. Using a logit model for the missing data mechanism, we show how parameter estimation can be accomplished using the EM algorithm by the method of weights proposed in Ibrahim (1990, Journal of the American Statistical Association 85, 765-769). An example from the Six Cities Study (Ware et al., 1984, American Review of Respiratory Diseases 129, 366-374) is presented to illustrate the method.

Initial results of a phase II trial of high dose radiation therapy, 5-fluorouracil, and cisplatin for patients with anal cancer (E4292): an Eastern Cooperative Oncology Group study.

PURPOSE: A prospective clinical trial was performed to assess the response and toxicity associated with the use of high dose radiation therapy, 5-fluorouracil, and cisplatin in patients with anal cancer. METHODS AND MATERIALS: Patients with anal cancer without distant metastasis were eligible for this study. Radiation therapy consisted of 59.4 Gy in 33 fractions; a 2 week break in treatment was taken after 36 Gy had been given. A treatment of 5-fluorouracil, 1,000 mg/m2 per day intravenously, was given for the first 4 days of radiation therapy, and cisplatin, 75 mg/m2 intravenously, was given on day 1 of radiation therapy. A second course of 5-fluorouracil and cisplatin was given after 36 Gy of radiation, when the radiation therapy was resumed. RESULTS: Nineteen patients entered this study and received treatment. Thirteen (68%) had a complete response, 5 (26%) had a partial response, and 1 (5%) had stable disease. The patient with stable disease and one of the patients with a partial response had complete disappearance of tumor more than 8 weeks after completion of radiation therapy. Fifteen patients had toxicity of Grade 3 or higher: the worst toxicity was Grade 3 in eight patients, Grade 4 in six patients, and Grade 5 in one patient. The most common form of toxicity of Grade 3 or higher was hematologic. The one lethal toxicity was due to pseudomembranous colitis, which was a complication of antibiotic therapy for a urinary tract infection. CONCLUSION: Radiation therapy, cisplatin, and 5-fluorouracil resulted in an overall response rate of 95%. Significant toxicity occurred, an indication that this regimen is near the maximal tolerated dose. A Phase III clinical trial is planned in which radiation therapy, cisplatin, and 5-fluorouracil will be used as an experimental arm.

The score test for independence in R x C contingency tables with missing data.

In this paper, the score test statistic for testing independence in R x C contingency tables with missing data is proposed. Under the null hypothesis of independence, the statistic has an approximate chi-squared distribution with (R - 1)(C - 1) degrees of freedom. The proposed test statistic is quite similar to the Pearson chi-squared statistic with complete data and, unlike the likelihood ratio statistic for testing independence, its computation is simple and noniterative. In addition, a score test statistic is proposed for testing independence when the rows and columns of the R x C table are ordinal. Finally, extensions of the score statistics to test for conditional independence in a set of (R x C) contingency tables with missing data are described. This yields score test statistics that are natural extensions of the Mantel-Haenszel statistic. An example, using a subset of data from the Six Cities Study, is presented to illustrate the methods.

Using the EM-algorithm for survival data with incomplete categorical covariates.

Incomplete covariate data is a common occurrence in many studies in which the outcome is survival time. With generalized linear models, when the missing covariates are categorical, a useful technique for obtaining parameter estimates is the EM by the method of weights proposed in Ibrahim (1990). In this article, we extend the EM by the method of weights to survival outcomes whose distributions may not fall in the class of generalized linear models. This method requires the estimation of the parameters of the distribution of the covariates. We present a clinical trials example with five covariates, four of which have some missing values.

Results of combined modality therapy for patients with anal cancer (E7283). An Eastern Cooperative Oncology Group study.

BACKGROUND: This prospective study assessed combined modality therapy of patients with International Union Against Cancer classification T1-4 N0 M0 anal cancer. METHODS: Protocol therapy consisted of a dose of 4000 cGy to the pelvis, anus, and perineum, followed by a 1000-1300 cGy boost. Infusions of 5-fluorouracil and mitomycin-C were administered when radiation therapy began. A second infusion of 5-fluorouracil was administered 28 days later. Biopsy was performed 6-8 weeks after completion of treatment. Positive biopsy findings resulted in abdominal-perineal resection. RESULTS: Survival at 7 years for 50 eligible patients was 58%. White patients and those with favorable performance status had significantly better survival. Of the 46 patients evaluable for response, 34 had a complete response, 11 had a partial response, and 1 had no response. Seven-year survival for partial responders was 53%. Freedom from locoregional progression was 80% at 7 years. CONCLUSION: Treatment with a combination of chemotherapy and radiation therapy is effective for patients with anal cancer. The investigation of methods of improving therapy is warranted.