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Clinical limitations of risk assessment models.

Appropriate thromboprophylaxis in hospital patients is effective in preventing clinically important venous thromboembolic events, including deep vein thrombosis (DVT) and fatal pulmonary embolism. Due to the risk of bleeding associated with pharmacological prophylaxis and the cost of administering prophylactic drugs, the clinical benefit and cost-effectiveness of thromboprophylaxis may be optimized by providing prophylaxis only to patients at risk of thrombosis, and tailoring the intensity of prophylaxis to the level of risk. Accurate assessment of patients' thromboembolic risk is therefore highly necessary. Thromboembolic risk is influenced by numerous factors. Several risk factor indices based on clinical risk factors and laboratory variables have been proposed since the 1970s, but these have not been widely adopted due to their complexity and lack of prospective validation. The method of deriving risk data on which these indices are based is questioned, and older prognostic indices excluded recently identified risk factors, particularly molecular factors such as the clotting factor V Leiden mutation, further undermining their clinical value. A number of much simpler risk assessment models (RAMs) have now been developed which stratify patients into low-, moderate- and high-risk categories. However, no RAM currently available provides comprehensive guidance for all patient groups. Use of poorly designed RAMs may fail to identify some patients at risk, leading to omission of prophylaxis and preventable thrombotic events. Certain patient groups develop DVT despite prophylaxis. Current RAMs are not validated to identify these patients. Well-designed and well-validated RAMs, incorporated into standard practice guidelines in hospitals, should contribute to improved clinical outcomes and economic benefits of prophylaxis.

Disease Management↗

Evaluation of BRCA1 and BRCA2 mutation prevalence, risk prediction models and a multistep testing approach in French-Canadian families with high risk of breast and ovarian cancer.

BACKGROUND AND OBJECTIVE: In clinical settings with fixed resources allocated to predictive genetic testing for high-risk cancer predisposition genes, optimal strategies for mutation screening programmes are critically important. These depend on the mutation spectrum found in the population under consideration and the frequency of mutations detected as a function of the personal and family history of cancer, which are both affected by the presence of founder mutations and demographic characteristics of the underlying population. The results of multistep genetic testing for mutations in BRCA1 or BRCA2 in a large series of families with breast cancer in the French-Canadian population of Quebec, Canada are reported. METHODS: A total of 256 high-risk families were ascertained from regional familial cancer clinics throughout the province of Quebec. Initially, families were tested for a panel of specific mutations known to occur in this population. Families in which no mutation was identified were then comprehensively tested. Three algorithms to predict the presence of mutations were evaluated, including the prevalence tables provided by Myriad Genetics Laboratories, the Manchester Scoring System and a logistic regression approach based on the data from this study. RESULTS: 8 of the 15 distinct mutations found in 62 BRCA1/BRCA2-positive families had never been previously reported in this population, whereas 82% carried 1 of the 4 mutations currently observed in > or =2 families. In the subset of 191 families in which at least 1 affected individual was tested, 29% carried a mutation. Of these 27 BRCA1-positive and 29 BRCA2-positive families, 48 (86%) were found to harbour a mutation detected by the initial test. Among the remaining 143 inconclusive families, all 8 families found to have a mutation after complete sequencing had Manchester Scores > or =18. The logistic regression and Manchester Scores provided equal predictive power, and both were significantly better than the Myriad Genetics Laboratories prevalence tables (p<0.001). A threshold of Manchester Score > or =18 provided an overall sensitivity of 86% and a specificity of 82%, with a positive predictive value of 66% in this population. CONCLUSION: In this population, a testing strategy with an initial test using a panel of reported recurrent mutations, followed by full sequencing in families with Manchester Scores > or =18, represents an efficient test in terms of overall cost and sensitivity.

Adolescent↗

Curvature in the cancer mortality dose response in Japanese atomic bomb survivors: absence of evidence of threshold.

PURPOSES: To investigate the evidence for a threshold in the cancer dose-response curve. MATERIALS AND METHODS: Japanese atomic bomb survivor cancer mortality data, based on follow-up to 1990, was used, taking account of random errors in DS86 dose estimates. RESULTS: For all solid cancers analysed together, there is a significant positive dose response (two-sided p<0.05) if all survivors who received <0.5 Sv are considered, but the significance vanishes if doses of <0.2 Sv are considered; the same is also true for leukaemia. For solid cancer mortality there is no indication of curvilinearity in the dose response: no statistically significant improvement in fit to a linear relative risk model is provided by addition of quadratic or threshold dose terms. If a relative risk model with a threshold (the dose response is assumed linear above the threshold) is fitted to solid cancer mortality data, the best estimate of the threshold is < 0.00 Sv (95% CI <0.00-0.13). If a linear-quadratic-threshold model is used the best estimate of the threshold is < 0.00 Sv (95% CI < 0.00-0.15). For leukaemia mortality there is highly statistically significant upward curvature in the dose response. In particular, if a relative risk model with a threshold (the dose response is assumed linear above the threshold) is fitted to the leukaemia data, the best estimate of the threshold is 0.16 Sv (95% CI 0.05-0.40) (two-sided p=0.001 for test of departure of threshold from 0). However, there is no evidence for a threshold effect (two-sided p = 0.16) when a quadratic term is included in the dose response: the best estimate of threshold in this case is 0.09Sv (95% CI <0.00-0.29). Moreover, addition of a quadratic term improves the fit of a linear-threshold model at borderline levels of statistical significance (two-sided p = 0.07). Therefore, the most parsimonious description of the leukaemia dose response is provided by a linear-quadratic function of dose. CONCLUSIONS: There is no evidence of threshold-type departures from the linear-quadratic dose response either for solid tumours or for leukaemia in the Japanese atomic bomb survivor mortality data.

Dose-Response Relationship, Radiation↗

Model comparison for risk assessment: a case study of contaminated groundwater.

Many environmental multimedia risk assessment models have been developed and widely used along with increasing sophistication of the risk assessment method. Despite of the considerable improvement, uncertainty remains a primary threat to the credibility of and users' confidence in the model-based risk assessments. In particular, it has been indicated that scenario and model uncertainty may affect significantly the assessment outcome. Furthermore, the uncertainty resulting from choosing different models has been shown more important than that caused by parameter uncertainty. Based on the relationship between exposure pathways and estimated risk results, this study develops a screening procedure to compare the relative suitability between potential multimedia models, which would facilitate the reduction of uncertainty due to model selection. MEPAS, MMSOILS, and CalTOX models, combined with Monte Carlo simulation, are applied to a realistic groundwater-contaminated site to demonstrate the process. It is also shown that the identification of important parameters and exposure pathways, and implicitly, the subsequent design of uncertainty reduction and risk management measures, would be better-formed.

Animals↗

Ki-67 index enhances the prognostic accuracy of the urothelial superficial bladder carcinoma risk group classification.

Approximately 80% of bladder tumors are urothelial superficial papillary carcinomas (USPC). Despite a generally good prognosis, these tumors have a strong propensity to recur and about 1/3 of them compared to disease progression. Histological assessment of these superficial tumors is not sufficiently discriminator in predicting prognosis; therefore, we decided to evaluate the prognostic significance of p53 and Ki-67 immunoexpression in low-grade (GI-II) USPC in order to predict the potential outcome of these tumors. P53 and Ki-67 immunoexpression were studied in function of recurrence-free and progression-free survival in 159 primary superficial bladder tumors. A prognostic risk model based on grade, stage and multifocality was also evaluated. P53 accumulation was significantly related to tumor progression (p=0.006). High Ki-67 index (>/=18%) and multifocality were significantly related to recurrence (both p=0.0001) and progression-free survival (both p=0.0001) and were independent prognostic factors in the multivariate analysis. The prognostic risk model based on grade, stage and multifocality was not an efficient discriminator of outcome. Adding the Ki-67 index into the risk model, single pTa/T1-GI Ki-67 positive tumors, usually classified as low risk, were reclassified as of intermediate risk. After this reclassification, the risk group model identified a subgroup of pTa/T1-G1 with a high risk of recurrence and progression. Ki-67 index is a reliable prognostic marker in urothelial superficial bladder carcinoma and, when included into a risk profile classification of the low-grade USPC, the accuracy of the prognostic discrimination is enhanced.

Biomarkers, Tumor↗

Tooth retention as an indicator of quality dental care: development of a risk adjustment model.

BACKGROUND: Retaining teeth improves oral health and quality of life. Thus, receipt of a root canal (vs. a tooth extraction) is a useful indicator of the quality of dental care. However, use of this quality measure without adjusting for the severity of oral disease could lead to spurious conclusions. OBJECTIVES: This paper describes the development of a dental severity adjustment methodology. RESEARCH DESIGN: Retrospective study. SUBJECTS: 54,423 users of Department of Veterans Affairs (VA) dental care who had either root canal therapy or a tooth extraction at a VA facility in Fiscal year 1998. MEASURES: International Classification of Disease Clinical Modification codes for dental diagnoses and comorbid medical conditions. We modeled the effects of dental disease severity in logistic regression models of the probability of receiving a root canal, using both conceptual and Modified Delphi-Panel derived models, adjusting for age, and medical comorbidities. RESULTS: Conceptual and Modified Delphi models performed similarly. The dental disease severity adjustments increased the fit in models of the probability of receiving a root canal (C-statistic = 0.822 for the conceptual model and 0.804 for the Modified Delphi Panel model) compared with the model including comorbid medical conditions alone (C-statistic = 0.561). CONCLUSIONS: Risk adjustment for dental disease severity improves the fit of models of the probability of receiving a root canal. Studies of the quality of dental care should consider employing risk-adjusted models.

Alcoholism↗

Adverse cardiac events after surgery: assessing risk in a veteran population.

OBJECTIVE: To establish rates of and risk factors for cardiac complications after noncardiac surgery in veterans. DESIGN: Prospective cohort study. SETTING: A large urban veterans affairs hospital. PARTICIPANTS: One thousand patients with known or suspected cardiac problems undergoing 1,121 noncardiac procedures. MEASUREMENTS: Patients were assessed preoperatively for important clinical variables. Postoperative evaluation was done by an assessor blinded to preoperative status with a daily physical examination, electrocardiogram, and creatine kinase with MB fraction until postoperative day 6, day of discharge, death, or reoperation (whichever occurred earliest). Serial electrocardiograms, enzymes, and chest radiographs were obtained as indicated. Severe cardiac complications included cardiac death, cardiac arrest, myocardial infarction, ventricular tachycardia, and fibrillation and pulmonary edema. Serious cardiac complications included the above, heart failure, and unstable angina. MAIN RESULTS: Severe and serious complications were seen in 24% and 32% of aortic, 8.3% and 10% of carotid, 11.8% and 14.7% of peripheral vascular, 9.0% and 13.1% of intraabdominal/intrathoracic, 2.9% and 3.3% of intermediate-risk (head and neck and major orthopedic procedures), and 0.27% and 1.1% of low-risk procedures respectively. The five associated patient-specific risk factors identified by logistic regression are: myocardial infarction < 6 months (odds ratio [OR], 4.5; 95% confidence interval [CI], 1.9 to 12.9), emergency surgery (OR, 2.6; 95% CI, 1.2 to 5.6), myocardial infarction > 6 months (OR, 2.2; 95% CI, 1.4 to 3.5), heart failure ever (OR, 1.9; 95% CI, 1.2 to 3.0), and rhythm other than sinus (OR, 1.7; 95% CI, 0.9 to 3.2). Inclusion of the planned operative procedure significantly improves the predictive ability of our risk model. CONCLUSIONS: Five patient-specific risk factors are associated with high risk for cardiac complications in the perioperative period of noncardiac surgery in veterans. Inclusion of the operative procedure significantly improves the predictive ability of the risk model. Overall cardiac complication rates (pretest probabilities) are established for these patients. A simple nomogram is presented for calculation of post-test probabilities by incorporating the operative procedure.

Adult↗

[Methods of designing a prognostic system, regression models and risk scale in the surgical treatment of cholelithiasis].

An automated assessment of the results of treatment and prediction of a course of the postoperative period was performed in 218 patients with cholelithiasis by means of ES computer according to 100 parameters. Five statistic packs of the application programs (VMDR-75 version) were used. Cluster-analysis, factor analysis and a method of the main components were employed. Four most essential risk factors were distinguished, the regressive models of a postoperative period obtained. This permitted to choose the most rational method for treatment.

Cholelithiasis↗

Mechanistic modelling and risk assessment.

Risk Assessment in the United States has been rapidly changing over the last few years. The historical methods and endpoints by which risk estimates were derived are gradually being replaced by newer methods and a broader spectrum of endpoints. For carcinogenic risk assessment, there is movement from the routinely used "linearized multistage model" for low dose risk estimation to methodology which is more deeply rooted in carcinogenic mechanisms and which allows the incorporation of additional data into the estimation of risks in a direct, quantitative fashion. There is also a determined effort under way to develop methods for assessing risks from exposure based on other endpoints such as effects on the immune system and the reproductive system. This paper briefly discusses some of the statistical and mathematical issues which will play important roles in determining the utility and precision of these new methods for estimating risks from environmental exposures.

Animals↗

A risk-based model to establish threshold planning quantities of hazardous substances.

The Threshold Planning Quantity (TPQ) is the minimum quantity of any hazardous substance stored or processed at an industry that can pose a defined level of risk up to a certain distance from the industrial premises should an accidental release occur. These are recommended by the concerned government departments of the respective countries. Often, concerned regulatory authorities focus on simple screening tools to prescribe TPQs of hazardous chemicals rather than on more detailed technical aspects. This is illustrated with the help of TPQs presently administered in India, which are followed based on Control of Industrial Major Accident Hazard regulations of the United Kingdom. In this paper, the risk ranking matrix (RRM) approach is described to evaluate the recommended TPQs and prescribe these for some extremely hazardous chemicals (EHS) commonly used in industries. The RRM presented here is unique in the sense that various acceptable risk criteria are reviewed to appropriately rank the risk potential and provide suitability criteria in terms of individual risk factors and geosocietal risk factors (GSRF). Based on this concept, an attempt has been made to develop a risk-based model to determine the TPQs of various EHS (acrolein, ammonia, chlorine, hydrogen fluoride, and phosgene).

Air Pollutants↗

Use of risk projection models to estimate mortality and incidence from radiation-induced breast cancer in screening programs.

The authors report on a method to calculate radiological risks, applicable to breast screening programs and other controlled medical exposures to ionizing radiation. In particular, it has been applied to make a risk assessment in the Valencian Breast Cancer Early Detection Program (VBCEDP) in Spain. This method is based on a parametric approach, through Markov processes, of hazard functions for radio-induced breast cancer incidence and mortality, with mean glandular breast dose, attained age and age-at-exposure as covariates. Excess relative risk functions of breast cancer mortality have been obtained from two different case-control studies exposed to ionizing radiation, with different follow-up time: the Canadian Fluoroscopy Cohort Study (1950--1987) and the Life Span Study (1950--1985 and 1950--1990), whereas relative risk functions for incidence have been obtained from the Life Span Study (1958--1993), the Massachusetts tuberculosis cohorts (1926--1985 and 1970--1985), the New York post-partum mastitis patients (1930--1981) and the Swedish benign breast disease cohort (1958--1987). Relative risks from these cohorts have been transported to the target population undergoing screening in the Valencian Community, a region in Spain with about four and a half million inhabitants. The SCREENRISK software has been developed to estimate radiological detriments in breast screening. Some hypotheses corresponding to different screening conditions have been considered in order to estimate the total risk associated with a woman who takes part in all screening rounds. In the case of the VBCEDP, the total radio-induced risk probability for fatal breast cancer is in a range between [5 x 10(-6), 6 x 10(-4)] versus the natural rate of dying from breast cancer in the Valencian Community which is 9.2 x 10(-3). The results show that these indicators could be included in quality control tests and could be adequate for making comparisons between several screening programs.

Adult↗

Mesothelioma: risk apportionment among asbestos exposure sources.

The mesothelioma epidemic in the United States, which peaked during the 2000-2004 period, can be traced to high-level asbestos exposures experienced by males in occupational settings prior to the full recognition of the disease-causing potential of asbestos and the establishment of enforceable asbestos exposure limits by the Occupational Safety and Health Administration (OSHA) in 1971. Many individuals diagnosed with mesothelioma where asbestos has been identified as a contributing cause of the disease have filed claims seeking compensation from asbestos settlement trusts or through the court system. An individual with mesothelioma typically has been exposed to asbestos in more than one setting and from more than one asbestos product. Apportioning risk for mesothelioma among contributing factors is an ongoing problem faced by occupational disease compensation boards, juries, parties responsible for paying damages, and currently by the U.S. Senate in its efforts to formulate a bill establishing an asbestos settlement trust. In this article we address the following question: If an individual with mesothelioma where asbestos has been identified as a contributing cause were to be compensated for his or her disease, how should that compensation be apportioned among those responsible for the asbestos exposures? For the purposes of apportionment, we assume that asbestos is the only cause of mesothelioma and that every asbestos exposure contributes, albeit differentially, to the risk. We use an extension of the mesothelioma risk model initially proposed in the early 1980s to quantify the contribution to risk of each exposure as a percentage of the total risk. The percentage for each specific discrete asbestos exposure depends on the start and end dates, the intensity, and the asbestos fiber type for the exposure. We provide justification for the use of the mesothelioma risk model for apportioning risk and discuss how to assess uncertainty associated with its application.

Asbestos↗

[A rapid model of risk assessment of the biomechanical overload to the whole skeletal system].

A tool easy to apply is presented that can be used in ergonomic analysis of 1st level to identify the risk factors of biomechanical overload of the skeletal structures. The model is an evolution of a previous proposal, published in 2001, which was aimed at evaluation of the only upper arms: the present model also permits the evaluation of the spine (cervical and torso-lumbar tract) and of the inferior arms. A red flag judgement criterion has been maintained and, if an item is marked, there is the possibility to recognise the cause of the ergonomic criticality and to plan the correction according to a scale of ergonomic priority. The aim of this communication is to stimulate a wide participation in the project to develop a model for the risk assessment of biomechanical overload to the whole skeletal system.

Arm↗

Use of a Bayesian statistical model for risk assessment in coronary artery surgery.

A computerized statistical model based on the theorem of Bayes was developed to predict mortality after coronary artery bypass grafting. From January, 1984, to April, 1987, at our hospital, 700 patients underwent isolated coronary artery bypass grafting. The presence or absence of 20 risk factors was determined for each patient. The first 300 patients formed the initial database of the Bayesian predictive model, and the remaining 400 patients were prospectively evaluated in four groups of 100 each. Each group was prospectively evaluated and then incorporated into the database to update the model. There was good agreement between predicted and observed results. Bayesian theory is particularly suited to this task because it (1) accommodates multiple risk factors, (2) is tailored to one's specific practice, (3) determines individual, rather than group, prognosis, and (4) can be updated with time to compensate for a changing patient population. These flexible attributes are especially valuable in light of recent changes in the coronary artery bypass graft patient profile.

Aged↗

Applying risk assessment models in general surgery: overview of our clinical experience.

Venous thromboembolism (VTE) is an important complication of general surgery. Epidemiological data demonstrate that the incidence of VTE may exceed 50% in some patient groups in the absence of prophylaxis, but the risk varies widely in different types of general surgery. A large number of concomitant risk factors for VTE have now been identified, including intrinsic patient factors such as older age and a previous history of VTE. Over recent years, several consensus conferences have defined categories for different levels of thromboembolic risk in general surgery based on clinical criteria, and have made prophylaxis recommendations according to the degree of risk. Existing physical and pharmacological methods of prophylaxis, particularly low-molecular-weight heparins, have been shown to be safe and effective in reducing thromboembolic risk to very low levels in the majority of patients undergoing general surgical procedures. However, these measures are currently underused, due both to underestimation of thromboembolic risk and fear of haemorrhage. Furthermore, some patient groups, such as those undergoing neurosurgery or with malignancy, remain at significant risk of VTE despite conventional prophylaxis. More accurate stratification of patients for thromboembolic risk, using evidence-based prophylaxis recommendations may lead to improved thrombosis prevention. Validation of independent thromboembolic risk factors and risk assessment models will assist in patient stratification, and allow identification of very-high-risk patients. Novel anticoagulant therapies currently under development may offer a superior antithrombotic:haemorrhagic ratio, providing improved protection in very-high-risk patients.

Humans↗

The importance of limited exposure to ultraviolet radiation and dietary factors in the aetiology of Asian rickets: a risk-factor model.

Regional variation in the prevalence of Asian rickets was examined in Coventry, Bradford and Glasgow. Records of 152 weeks of daylight outdoor exposure were obtained from 104 Glasgow Asian children, 53 of whom had been treated for rickets. Records of seven-day weighed dietary intake were obtained from 84 Asian children, 43 of whom had been treated for rickets. There was a marked north-south gradient in the prevalence of Asian rickets. In all cases of severe rickets with deformity the child was vegetarian. Severe rickets was associated with lower intake of meat, higher intake of chapati and lower daylight outdoor exposure values than in normal children. Multivariate analysis employing a combination of these variables provided good separation between rachitic and normal groups. A risk-factor model is proposed which suggests that regional variation in the prevalence of rickets among Asian communities in Britain is mainly determined by the effects of latitude and the nature of the urban environment on available ultraviolet radiation. Where UV radiation is restricted, individual propensity to rickets within a given Asian community is mainly determined by dietary factors.

Adolescent↗

Quasi-likelihood estimation for relative risk regression models.

For a prospective randomized clinical trial with two groups, the relative risk can be used as a measure of treatment effect and is directly interpretable as the ratio of success probabilities in the new treatment group versus the placebo group. For a prospective study with many covariates and a binary outcome (success or failure), relative risk regression may be of interest. If we model the log of the success probability as a linear function of covariates, the regression coefficients are log-relative risks. However, using such a log-linear model with a Bernoulli likelihood can lead to convergence problems in the Newton-Raphson algorithm. This is likely to occur when the success probabilities are close to one. A constrained likelihood method proposed by Wacholder (1986, American Journal of Epidemiology 123, 174-184), also has convergence problems. We propose a quasi-likelihood method of moments technique in which we naively assume the Bernoulli outcome is Poisson, with the mean (success probability) following a log-linear model. We use the Poisson maximum likelihood equations to estimate the regression coefficients without constraints. Using method of moment ideas, one can show that the estimates using the Poisson likelihood will be consistent and asymptotically normal. We apply these methods to a double-blinded randomized trial in primary biliary cirrhosis of the liver (Markus et al., 1989, New England Journal of Medicine 320, 1709-1713).

Antibiotics, Antineoplastic↗

Competing risks analysis of lamb mortality in a terminal sire composite population.

Mortality records from birth to weaning of 8,301 lambs from a composite population at the U.S. Meat Animal Research Center were analyzed using a competing risks model. The advantage of the competing risks model over traditional survival analyses is that different hazards of mortality can be assigned to different causes, such as disease, dystocia, and starvation. In this study, specific causes of mortality were grouped into dam-related (DAMR; e.g., dystocia and starvation), pneumonia (PNEU), disease (DIS; excluding pneumonia), and other (OTHER) categories. The hazard of mortality was analyzed using a competing risk approach, where each mortality category was assumed to be independent. Continuous- and discrete-time survival analyses were implemented using sire, animal, and maternal effects mixed models. The continuous-time survival analysis used the Weibull model to describe the hazard of mortality for each category of mortality. Under the discrete-time survival analysis, a complementary log-log link function was used to analyze animal-time data sets using weekly intervals for each category of mortality. Explanatory variables were sex, type of birth, contemporary group, and age of dam. The significant influences of type of birth and age of dam effects were consistent across category of mortality, and the sex effect was significant for all categories except the OTHER category. Estimates of variance components indicated strong maternal effects for all categories except for PNEU. Estimates of additive genetic heritabilities from the discrete maternal effects models were 0.08+/-0.04, 0.09+/-0.18, 0.16+/-0.12, 0.19+/-0.09, and 0.14+/-0.10 for OVERALL (all causes combined), DIS, DAMR, PNEU, and OTHER categories, respectively. Ignoring the cause of the defining event in mortality and longevity studies may hide important genetic differences. Therefore, the effectiveness of breeding programs relying on models that ignore multiple causes of an event in time-to-event data, such as mortality and longevity, could be affected.

Animals↗