ICDs at higher age and clinical risk factors

Background

The implantable cardioverter defibrillator (ICD) is effective in preventing sudden cardiac death. However, in elderly patients (aged 75 years or older) the role of ICDs is still not well-defined and controversial.

Methods

We retrospectively analysed all clinical and survival data of all ICD patients who were ≥75 years at the date of implantation in the Erasmus MC, Rotterdam, the Netherlands and the University Hospital, Basel, Switzerland. Kaplan-Meier survival analysis was performed, and mortality predictors were identified. Mortality of the cohort was compared with a random sample of patients aged 60–70 years originating from the same database and to an age- and sex-matched cohort of Dutch persons.

Results

The study cohort consisted of 179 patients aged 75 years or older who were implanted between February 1999 and July 2008. The median follow-up time was 2.0 (IQR 2.8) years. Survival rates after 1, 2 and 3 years were 87, 82, 75 %, respectively. Survival was similar for primary and secondary prevention. Mortality in this study population could be predicted by combining four clinical risk factors: QRS duration >120 ms, NYHA class > II, renal failure and atrial fibrillation (AF). Survival was worse compared with the group of ICD patients aged 60–70 years and to the age- and sex-matched group of elderly persons. However, survival was not significantly worse when comparing elderly ICD patients without additional risk factors to the general population.

Conclusions

Elderly patients still have an acceptable survival probability independent of prevention indication, certainly if there are no additional clinical risk factors. The presence or absence of additional clinical risk factors should be taken into account when making the decision for implantation, since they strongly correlate with survival.     

HIV international clinical research: exploitation and risk

This paper aims to show that to reduce the level of exploitation present in (some) international clinical trials, research sponsors must aim to provide both an ex-ante expected gain in utility and a fair ex-post distribution of benefits for research subjects. I suggest the following principles of fair risk distribution in international research as the basis of a normative definition of fairness: (a) Persons should not be forced (by circumstance) to gamble in order to achieve or protect basic goods; (b) In cases where one party is gambling with basic goods and the other party is not, the distribution of benefits and burdens must be arranged so that they are of greatest benefit to the worst off; (c) In relationships where one party is gambling for basic goods and the other party is not, the party gambling for basic goods must be assured of some guaranteed benefits in addition to the chance of getting some practical benefits. These principles are applied to the case of HIV international research. I conclude that the research (as described) is mutually advantageous but still exploitative because the distribution of surplus benefits is unfair. It is unfair because research subjects are gambling with and for basic goods but they are not assured of a fair ex-post distribution of benefits. Principles (b) and (c) are not satisfied. Research participants are not accorded enough guaranteed benefits to outweigh the risks they undertake.     

The consumer's risk in clinical trials

In any formal statistical test of the null hypothesis (the statement that a population parameter is equal to a specific value), there are two possible types of error. Type 1 or alpha error has occurred if the investigator rejects the null hypothesis when it is true. For example, an experimental treatment is declared an advance over standard treatment when it is not. Type 2 or beta error has occurred if the null hypothesis is not rejected when it is false. In this case, the investigator concludes that the experimental treatment is no different than the standard when it actually is. The two types of error can be conceptualized, respectively, as the consumer's risk and the producer's risk. In many reports of clinical trial methodology, it is the producer's risk that is emphasized. It is understandable why producer's risk would be of concern to authors of clinical studies. There are, however, numerous potential sources of consumer's risk. It is the latter type of risk that is the primary subject of this report.     

A variable risk clinical prognostic compartmental model

A model for predicting the occurrence of disease endpoints from a knowledge of baseline variables and intermediate events is described and illustrated with numerical examples. Maximum likelihood equations are developed and maximum likelihood estimates of coefficients in risk functions of variables included in a stepwise upward procedure are applied to a small set of data for illustrative purposes.     

Type 2 diabetes in children: clinical aspects and risk factors

In the past, type 2 diabetes mellitus was considered a disease of adults and older individuals, not a paediatric condition. Over the last decade, however, in the USA and the rest of the world there has been a disturbing trend of increasing cases of type 2 diabetes in children, mirroring increasing rates of obesity. The risk factors for paediatric type 2 diabetes are: (1) obesity and increased body mass index; (2) family history of type 2 diabetes; (3) membership of ethnic minority; (4) puberty (mean age of diagnosis is approximately 13.5 years); (5) female gender; and (6) features of 'syndrome X'. The common link among these risk factors is insulin resistance, which plays a pivotal role in the pathophysiology of type 2 diabetes. Both insulin resistance and beta-cell failure are present in the fully established diabetes state. Data will be presented on how these risk factors impact on insulin sensitivity and insulin secretion in childhood, ultimately leading to type 2 diabetes. The clinical presentation of type 2 diabetes in children and its distinction from type 1 diabetes will be discussed.     

Assessing and managing breast cancer risk: clinical tools for advising patients

Using breast cancer risk assessment tools and going through the process of assessing breast cancer risk can answer many women's questions about what puts them at relatively higher or lower risk. This effectively engages both the clinician and the patient in a discussion about breast cancer, the chances of getting it, and the family's involvement--making the process as important as the actual tools. Examples of selected case histories demonstrate risk assessment using available tools such as the Gail-NCI and the Claus models. For some women, such as those considering tamoxifen or prophylactic surgeries, it may be desirable to prescreen for the inheritance of hereditary mutations and to follow with genetic testing, if indicated. Testing for mutations of breast cancer susceptibility genes or for their diminished expression adds to our ability to assess breast cancer risk at an individual level. The literature contains general interventions that are widely accepted to reduce the severity and the burden of breast cancer, and these are brought together here. The risk assessment process is an important part of a risk reduction program and can help motivate women to engage in prevention activities. This paper uses 2 hypothetical but fact-based and typical case histories to discuss the utility of risk assessment tools for informing women about their options.     

Association of VEGF genetic polymorphisms with prostate carcinoma risk and clinical outcome

OBJECTIVES: Vascular endothelial growth factor (VEGF) is a potent stimulus of angiogenesis that has an important role in many human malignancies including prostate carcinoma (PCa). We evaluated the role of the functional VEGF polymorphisms as genetic markers for PCa susceptibility and prognosis. METHODS: The study included 101 patients with PCa and [corrected] 100 age-matched healthy men. The VEGF genotypes -1154G>A were identified by allele-specific polymerase chain reaction (AS-PCR) and the genotypes -634G>C and 936C>T were identified by restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR). RESULTS: A negative association was found between VEGF -1154AA genotype and PCa risk (OR=0.27; P=0.009). Furthermore, the presence of the VEGF -1154A allele appeared to be associated with a decreased [corrected] risk of higher tumor grade (OR=0.37; P=0.01). A significant increased risk of prostate cancer was associated with the VEGF -634 (GC+CC) combined genotype (OR=1.95; P=0.02). The VEGF -634C allele was associated with the aggressive phenotype of prostate cancer as defined by the high histological grade (OR=3.48; P=0.007). The VEGF -1154A/-634G haplotype was negatively associated with PCa risk (OR=0.48; P=0.005) and high tumor grade compared to low grade (OR=0.37; P=0.02). CONCLUSIONS: Genetic variations in the VEGF may predict not only PCa risk but also tumor aggressiveness.     

A clinical method of estimating risk of drug induced delirium

A clinical research method for estimating risk of drug induced acute organic mental syndromes or delirium is described. The method was tested on two patient populations where delirium is expected to occur, and one population where mild organic mental syndromes occur. In two populations, post-cardiotomy and post-cataractectomy states, the drug risk number separated delirium from non-delirium subjects. Subjects with mild acute organic mental syndrome after electroconvulsive therapy also had a higher average drug risk number than comparison subjects.     

Hepatitis B vaccine antibody response and the risk of clinical AIDS or death

Background

Whether seroresponse to a vaccine such as hepatitis B virus (HBV) vaccine can provide a measure of the functional immune status of HIV-infected persons is unknown.This study evaluated the relationship between HBV vaccine seroresponses and progression to clinical AIDS or death.

Methods and Findings

From a large HIV cohort, we evaluated those who received HBV vaccine only after HIV diagnosis and had anti-HBs determination 1–12 months after the last vaccine dose. Non-response and positive response were defined as anti-HBs <10 and ≥10 IU/L, respectively. Participants were followed from date of last vaccination to clinical AIDS, death, or last visit. Univariate and multivariable risk of progression to clinical AIDS or death were evaluated with Cox regression models. A total of 795 participants vaccinated from 1986–2010 were included, of which 41% were responders. During 3,872 person-years of observation, 122 AIDS or death events occurred (53% after 1995). Twenty-two percent of non-responders experienced clinical AIDS or death compared with 5% of responders (p<0.001). Non-response to HBV vaccine was associated with a greater than 2-fold increased risk of clinical AIDS or death (HR 2.47; 95% CI, 1.38–4.43) compared with a positive response, after adjusting for CD4 count, HIV viral load, HAART use, and delayed type hypersensitivity skin test responses (an in vivo marker of cell-mediated immunity). This association remained evident among those with CD4 count ≥500 cells/mm³ (HR 3.40; 95% CI, 1.39–8.32).

Conclusions

HBV vaccine responses may have utility in assessing functional immune status and risk stratificating HIV-infected individuals, including those with CD4 count ≥500 cells/mm³.     

Learning-based biomarker-assisted rules for optimized clinical benefit under a risk constraint

Novel biomarkers, in combination with currently available clinical information, have been sought to improve clinical decision making in many branches of medicine, including screening, surveillance, and prognosis. Statistical methods are needed to integrate such diverse information to develop targeted interventions that balance benefit and harm. In the specific setting of disease detection, we propose novel approaches to construct a multiple-marker-based decision rule by directly optimizing a benefit function, while controlling harm at a maximally tolerable level. These new approaches include plug-in and direct-optimization-based algorithms, and they allow for the construction of both nonparametric and parametric rules. A study of asymptotic properties of the proposed estimators is provided. Simulation results demonstrate good clinical utilities for the resulting decision rules under various scenarios. The methods are applied to a biomarker study in prostate cancer surveillance.     

Molecular signatures of cardiovascular disease risk: potential for test development and clinical application

Most cardiovascular diseases are multifactorial by etiology. As an example, the development of myocardial infarction is promoted by numerous risk factors, ranging from rather modifiable lifestyle habits (e.g. smoking, physical activity) to genetic predisposition. With respect to the latter, 15 years of candidate gene analyses have failed to explain the molecular basis for the genetic predisposition to myocardial infarction. By contrast, recent genome-wide association studies have identified chromosomal loci that reproducibly displayed some association with myocardial infarction risk. When molecular genetic studies of coronary artery disease were first begun, it was assumed that genetic factors would soon be routinely incorporated into risk prediction scores. A number of biomarkers have been identified and tested in combination with the classical risk factors for refined risk prediction. However, the strategy for individualized risk prediction by incorporation of new biomarkers in established scores has so far proven to be more difficult than at first hoped.     

Predicting progression of IgA nephropathy: new clinical progression risk score

IgA nephropathy (IgAN) is a common cause of end-stage renal disease (ESRD) in Asia. In this study, based on a large cohort of Chinese patients with IgAN, we aim to identify independent predictive factors associated with disease progression to ESRD. We collected retrospective clinical data and renal outcomes on 619 biopsy-diagnosed IgAN patients with a mean follow-up time of 41.3 months. In total, 67 individuals reached the study endpoint defined by occurrence of ESRD necessitating renal replacement therapy. In the fully adjusted Cox proportional hazards model, there were four baseline variables with a significant independent effect on the risk of ESRD. These included: eGFR [HR = 0.96(0.95-0.97)], serum albumin [HR = 0.47(0.32-0.68)], hemoglobin [HR = 0.79(0.72-0.88)], and SBP [HR = 1.02(1.00-1.03)]. Based on these observations, we developed a 4-variable equation of a clinical risk score for disease progression. Our risk score explained nearly 22% of the total variance in the primary outcome. Survival ROC curves revealed that the risk score provided improved prediction of ESRD at 24th, 60th and 120th month of follow-up compared to the three previously proposed risk scores. In summary, our data indicate that IgAN patients with higher systolic blood pressure, lower eGFR, hemoglobin, and albumin levels at baseline are at a greatest risk of progression to ESRD. The new progression risk score calculated based on these four baseline variables offers a simple clinical tool for risk stratification.     

Three-tiered risk stratification model to predict progression in Barrett's esophagus using epigenetic and clinical features

Background

Barrett''s esophagus predisposes to esophageal adenocarcinoma. However, the value of endoscopic surveillance in Barrett''s esophagus has been debated because of the low incidence of esophageal adenocarcinoma in Barrett''s esophagus. Moreover, high inter-observer and sampling-dependent variation in the histologic staging of dysplasia make clinical risk assessment problematic. In this study, we developed a 3-tiered risk stratification strategy, based on systematically selected epigenetic and clinical parameters, to improve Barrett''s esophagus surveillance efficiency.

Methods and Findings

We defined high-grade dysplasia as endpoint of progression, and Barrett''s esophagus progressor patients as Barrett''s esophagus patients with either no dysplasia or low-grade dysplasia who later developed high-grade dysplasia or esophageal adenocarcinoma. We analyzed 4 epigenetic and 3 clinical parameters in 118 Barrett''s esophagus tissues obtained from 35 progressor and 27 non-progressor Barrett''s esophagus patients from Baltimore Veterans Affairs Maryland Health Care Systems and Mayo Clinic. Based on 2-year and 4-year prediction models using linear discriminant analysis (area under the receiver-operator characteristic (ROC) curve: 0.8386 and 0.7910, respectively), Barrett''s esophagus specimens were stratified into high-risk (HR), intermediate-risk (IR), or low-risk (LR) groups. This 3-tiered stratification method retained both the high specificity of the 2-year model and the high sensitivity of the 4-year model. Progression-free survivals differed significantly among the 3 risk groups, with p = 0.0022 (HR vs. IR) and p<0.0001 (HR or IR vs. LR). Incremental value analyses demonstrated that the number of methylated genes contributed most influentially to prediction accuracy.

Conclusions

This 3-tiered risk stratification strategy has the potential to exert a profound impact on Barrett''s esophagus surveillance accuracy and efficiency.