A simple, rapid, interpretable, actionable and implementable digital PCR based mortality index.

Mortality assessments are conducted for both civil and commercial purposes. Recent advances in epigenetics have resulted in DNA methylation tools to assess risk and aid in this task. However, widely available array-based algorithms are not readily translatable into clinical tools and do not provide a good foundation for clinical recommendations. Further, recent work shows evidence of heritability and possible racial bias in these indices. Using a publicly available array data set, the Framingham Heart Study (FHS), we develop and test a five-locus mortality-risk algorithm using only previously validated methylation biomarkers that have been shown to be free of racial bias, and that provide specific assessments of smoking, alcohol consumption, diabetes and heart disease. We show that a model using age, sex and methylation measurements at these five loci outperforms the 513 probe Levine index and approximates the predictive power of the 1030 probe GrimAge index. We then show each of the five loci in our algorithm can be assessed using a more powerful, reference-free digital PCR approach, further demonstrating that it is readily clinically translatable. Finally, we show the loci do not reflect ethnically specific variation. We conclude that this algorithm is a simple, yet powerful tool for assessing mortality risk. We further suggest that the output from this or similarly derived algorithms using either array or digital PCR can be used to provide powerful feedback to patients, guide recommendations for additional medical assessments, and help monitor the effect of public health prevention interventions.

Mortality study of policies on insured lives with diabetes mellitus known at time of issue.

BACKGROUND: This is an Impairment Study Capture System (ISCS) study of contemporary diabetes mellitus mortality among insured lives. Because the diagnosis and treatment of diabetes has changed during the last 15 years, many applicants may be expected to exhibit more favorable outcomes than in the past. The study covers policy-years durational experience extending to only 10 years. METHODS: We analyzed the total mortality experience of 41,972 insurance policies. The policies were issued at standard or substandard premium rates between 1989 and 2002 policy anniversaries. The number of policies terminated by death (actual deaths) is compared with expected deaths using the 2001 Valuation Basic Table (2001 VBT). Main outcome measures are expressed as mortality ratios (MR %) and excess death rates/1000 (EDR/M). Poisson confidence intervals are used to test the statistical significance of mortality ratios at the 95% confidence limit. RESULTS: The total experience is based on 103,104 policy-years exposure: males 57,888 policy-years (56%) and females 45,216 policy-years (44%). There were 495 policy-deaths 284 male and 211 female. Substandard risks represented the majority of the total exposure, 76,658 policy-years in both sexes combined (male 56%, female 44%). The mean duration of substandard exposure was 2.3 years. Total mortality for all insured age-groups and risk categories combined was 187%. The mortality ratios for policies rated standard had confidence intervals that were consistent with 100% of the 2001 VBT. The mortality ratios for policies rated substandard had confidence intervals that were above 100% of the 2001 VBT. Mortality ratios varied with the type of treatment. They were lowest in those treated with diet alone and highest in individuals treated with diet plus insulin. CONCLUSION: A clinical diagnosis of diabetes continues to demonstrate evidence of increased, but improving, mortality in insured individuals. The underwriting risk appraisal process effectively categorizes the risk, especially for the substandard classes where the ratings assigned to policies were consistent with the mortality results. The lack of significant differences in the mortality ratios between males and females as well as between nonsmokers and smokers indicate that the early duration variations by gender and smoking status in the 2001 VBT account for these differences in early duration diabetes mortality. Subsequent follow-up studies containing longer durations may show these differences emerging. Results must be interpreted with caution because of the small data set, limited number of ISCS participating companies, and durational experience extending to only 10 policy years.

Study of policies on insured lives with elevated blood pressure known at time of issue.

BACKGROUND: The mortality results of policies on insured lives with elevated blood pressure have been the subject of several studies since the early 20th century. This study, which began with issues of 1989, utilizes data from the Impairment Study Capture System (ISCS). Data are also compiled for impairments other than elevated blood pressure in the ISCS for the same study period. A comparison of these 2 sets of data shows the relative severity of elevated blood pressure compared to all other impairments combined. The determination of elevated blood pressure was made on the basis of risk classification due to lack of specific blood pressure readings. METHODS: Mortality results are actual to expected ratios based on the SOA 1990-95 Select Basic Table. The companies participating in this study have completed 3 steps: (1) agreement to have individual reports to the MIB included in the ISCS file; (2) submission of additional policy information, not on the MIB report; and (3) update of in-force status annually. Reports do not include personal identifying information. RESULTS: Based on the limited amount of data contributed by relatively few companies, there has been considerable improvement since earlier studies in mortality among insureds with elevated blood pressure. Some possible reasons for this include: (1) fewer smokers--there were fewer smokers in the population and hence applying for insurance during the period covered by this study as compared to earlier studies; (2) improved treatment, patient awareness and adherence to regimen--a wider variety of medications and current treatment practices compared to treatment in the 1970s and early 1980s may have influenced results. Compared to prior studies, it is likely that more insureds with elevated blood pressure first noted on the insurance examination subsequently have received treatment. In addition, those with elevated blood pressure have become more aware of the importance of adhering to their medication regimen and improving other adverse risk factors; (3) improvement in the treatment of related medical conditions. CONCLUSION: The results of this study must be interpreted with caution. The volume of data is not substantial, and the results may not be representative of non-contributing companies. Going forward, it is hoped that more companies will agree to participate such that future studies will produce data and results of greater utility.