Error catastrophe in mutant mitochondria

The error catastrophe theory of aging, proposed by Orgel in 1963, predicted a decrease in the fidelity of information transfer that accelerated as aging progressed, until properly functioning macromolecules could no longer be reliably made. The theory was extensively tested by comparing DNA polymerases, transfer RNAs, and proteins derived from aging versus young animals, but it did not prove to have general applicability to the process of aging. Recently, the heritable eye disorder progressive external ophthalmoplegia has been found to result from mutation of the gene encoding DNA polymerase gamma, which replicates mitochondrial DNA. The mutant form of the polymerase replicates DNA less accurately than the wild-type enzyme, providing an explanation for the accumulation of mutations in the mitochondrial DNA of patients with this disorder. The affected mitochondria appear to exhibit an age-dependent error catastrophe. It is possible that other genetic diseases might result in error catastrophes in mitochondria as well.     

Choice of Parametric Accelerated Life and Proportional Hazards Models for Survival Data: Asymptotic Results

We discuss the impact of misspecifying fully parametric proportional hazards and accelerated life models. For the uncensored case, misspecified accelerated life models give asymptotically unbiased estimates of covariate effect, but the shape and scale parameters depend on the misspecification. The covariate, shape and scale parameters differ in the censored case. Parametric proportional hazards models do not have a sound justification for general use: estimates from misspecified models can be very biased, and misleading results for the shape of the hazard function can arise. Misspecified survival functions are more biased at the extremes than the centre. Asymptotic and first order results are compared. If a model is misspecified, the size of Wald tests will be underestimated. Use of the sandwich estimator of standard error gives tests of the correct size, but misspecification leads to a loss of power. Accelerated life models are more robust to misspecification because of their log-linear form. In preliminary data analysis, practitioners should investigate proportional hazards and accelerated life models; software is readily available for several such models.     

Calculating the density and distribution function for the singly and doubly noncentral F

Simple, closed form saddlepoint approximations for the distribution and density of the singly and doubly noncentral F distributions are presented. Their overwhelming accuracy is demonstrated numerically using a variety of parameter values. The approximations are shown to be uniform in the right tail and the associated limitating relative error is derived. Difficulties associated with some algorithms used for exact computation of the singly noncentral F are noted.     

Measurement error, skewness, and risk analysis: coping with the long tail of the distribution.

Probabilistic risk analyses often construct multistage chance trees to estimate the joint probability of compound events. If random measurement error is associated with some or all of the estimates, we show that resulting estimates of joint probability may be highly skewed. Joint probability estimates based on the analysis of multistage chance trees are more likely than not to be below the true probability of adverse events, but will sometimes substantially overestimate them. In contexts such as insurance markets for environmental risks, skewed distributions of risk estimates amplify the "winner's curse" so that the estimated risk premium for low-probability events is likely to be lower than the normative value. Skewness may result even in unbiased estimators of expected value from simple lotteries, if measurement error is associated with both the probability and pay-off terms. Further, skewness may occur even if the error associated with these two estimates is symmetrically distributed. Under certain circumstances, skewed estimates of expected value may result in risk-neutral decisionmakers exhibiting a tendency to choose a certainty equivalent over a lottery of equal expected value, or vice versa. We show that when distributions of estimates of expected value are, positively skewed, under certain circumstances it will be optimal to choose lotteries with nominal values lower than the value of apparently superior certainty equivalents. Extending the previous work of Goodman (1960), we provide an exact formula for the skewness of products.     

Leading beyond the bottom line, Part 4. The questions it has raised

The Leading Beyond the Bottom Line article series has received an overwhelming response from ACPE members, mostly in enthusiastic support of this new leadership concept. Some of the important questions raised by members are presented with answers from the authors. This article also explores the moral challenge of leadership and why health care is more than a business. In recent years, there's been confusion about the role of the health care enterprise, its leadership and its management. We have lost our way about the "moral" thing, the "right" thing, because we have no philosophy to guide us. To manage or lead in this "business" of health care, a philosophy is required that recognizes the multiple elements to which the leader has responsibility and obligations: the customers, community, employees, and, certainly, the financial assets.     

Customized clinical case management for chronically ill patients. Health system sees remarkable results with teams of case managers,physicians, patients

Securing excellent care and positive outcomes for seriously ill, high-risk patients requires extraordinary measures. A health system in Georgia is experiencing strong results by taking a team approach to health care with case managers, physicians and patients working together.     

Index of Authors Volume 55, 2001

Authors Index

Index of Authors Volume 55, 2001     

Quality of Life Indexes for National Policy: Review and Agenda for Research

A number of governments and public policy institutes have developed Quality of Life Indexes – statistics that attempt to measure the quality of life for entire states or regions. We develop 14 criteria for determining the validity and usefulness of such QOL indexes to public policy. We then review 22 of the most-used QOL indexes from around the world. We conclude that many of the indexes are successful in that they are reliable, have established time series measures, and can be disaggregated to study subpopulations. However, many fall short in four areas: (1) indexes vary greatly in their coverage and definitions of domains of QOL, (2) none of the indexes distinguish among the concepts of input, throughput, and output that are used by public policy analysts, (3) they fail to show how QOL outputs are sensitive to public policy inputs, and (4) none have examined convergent validity against each other. We conclude that many of these indexes are potentially very useful for public policy and recommend research to further improve them.     

A chronology of the study of older women's health: data, discoveries, and future directions

Women have been traditionally ignored in health and medical research. Some reasons for this mentality include a fear of harming a woman's reproductive ability, fear that variations in the menstrual cycle could confound results, fear that a woman's body could not withstand the rigors of clinical research, and an assumption that male and female body chemistry is similar. Thankfully, these fears and assumptions are being challenged and several major data-bases, designed specifically to study women's health, have emerged. The purpose of this paper is to: (1) characterize the major longitudinal studies on women's health, (2) summarize the major discoveries from these studies that are relevant to older women, and (3) pose several future directions for research throughout the paper.