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斯特勒-米尔德万相关性是冈珀茨拟合的一个退化流形。

Strehler-Mildvan correlation is a degenerate manifold of Gompertz fit.

作者信息

Tarkhov Andrei E, Menshikov Leonid I, Fedichev Peter O

机构信息

Gero LLC, Novokuznetskaya street 24/2, Moscow 119017, Russia; Skolkovo Institute of Science and Technology, Skolkovo Innovation Center, Novaya street 100, Skolkovo 143025, Russia.

Gero LLC, Novokuznetskaya street 24/2, Moscow 119017, Russia; National Research Center "Kurchatov Institute", 1, Akademika Kurchatova pl., Moscow 123182, Russia.

出版信息

J Theor Biol. 2017 Mar 7;416:180-189. doi: 10.1016/j.jtbi.2017.01.017. Epub 2017 Jan 16.

Abstract

Gompertz empirical law of mortality is often used in practical research to parametrize survival fraction as a function of age with the help of just two quantities: the Initial Mortality Rate (IMR) and the Gompertz exponent, inversely proportional to the Mortality Rate Doubling Time (MRDT). The IMR is often found to be inversely related to the Gompertz exponent, which is the dependence commonly referred to as Strehler-Mildvan (SM) correlation. In this paper, we address fundamental uncertainties of the Gompertz parameters inference from experimental Kaplan-Meier plots and show, that a least squares fit often leads to an ill-defined non-linear optimization problem, which is extremely sensitive to sampling errors and the smallest systematic demographic variations. Therefore, an analysis of consequent repeats of the same experiments in the same biological conditions yields the whole degenerate manifold of possible Gompertz parameters. We find that whenever the average lifespan of species greatly exceeds MRDT, small random variations in the survival records produce large deviations in the identified Gompertz parameters along the line, corresponding to the set of all possible IMR and MRDT values, roughly compatible with the properly determined value of average lifespan in experiment. The best fit parameters in this case turn out to be related by a form of SM correlation. Therefore, we have to conclude that the combined property, such as the average lifespan in the group, rather than IMR and MRDT values separately, may often only be reliably determined via experiments, even in a perfectly homogeneous animal cohort due to its finite size and/or low age-sampling frequency, typical for modern high-throughput settings. We support our findings with careful analysis of experimental survival records obtained in cohorts of C. elegans of different sizes, in control groups and under the influence of experimental therapies or environmental conditions. We argue that since, SM correlation may show up as a consequence of the fitting degeneracy, its appearance is not limited to homogeneous cohorts. In fact, the problem persists even beyond the simple Gompertz mortality law. We show that the same degeneracy occurs exactly in the same way, if a more advanced Gompertz-Makeham aging model is employed to improve the modeling. We explain how SM type of relation between the demographic parameters may still be observed even in extremely large cohorts with immense statistical power, such as in human census datasets, provided that systematic historical changes are weak in nature and lead to a gradual change in the mean lifespan.

摘要

冈珀茨死亡率经验定律在实际研究中经常被用于借助两个量来将存活分数参数化为年龄的函数

初始死亡率(IMR)和冈珀茨指数,该指数与死亡率加倍时间(MRDT)成反比。人们经常发现IMR与冈珀茨指数呈负相关,这种依赖性通常被称为斯特勒 - 米尔德万(SM)相关性。在本文中,我们探讨了从实验性的卡普兰 - 迈耶图推断冈珀茨参数时的基本不确定性,并表明最小二乘法拟合常常会导致一个定义不明确的非线性优化问题,该问题对抽样误差和最小的系统人口统计学变化极其敏感。因此,对在相同生物学条件下重复进行的相同实验进行分析,会得出可能的冈珀茨参数的整个退化流形。我们发现,只要物种的平均寿命大大超过MRDT,存活记录中的小随机变化就会使确定的冈珀茨参数沿线产生大的偏差,这些偏差对应于所有可能的IMR和MRDT值的集合,大致与实验中正确确定的平均寿命值相符。在这种情况下,最佳拟合参数结果呈现出一种SM相关性形式。因此,我们不得不得出结论,即使在一个完全同质的动物群体中,由于其有限的规模和/或低年龄抽样频率(这在现代高通量设置中很典型),通常可能只能通过实验可靠地确定诸如群体平均寿命这样的综合属性,而不是分别确定IMR和MRDT值。我们通过仔细分析在不同大小的秀丽隐杆线虫群体中、对照组以及在实验性疗法或环境条件影响下获得的实验存活记录来支持我们的发现。我们认为,由于SM相关性可能是拟合退化的结果,其出现并不局限于同质群体。事实上,即使超出简单的冈珀茨死亡率定律,这个问题仍然存在。我们表明,如果采用更先进的冈珀茨 - 马凯姆衰老模型来改进建模,同样的退化会以完全相同的方式出现。我们解释了即使在具有巨大统计能力的极大群体中,比如在人口普查数据集中,只要系统性的历史变化本质上很微弱并导致平均寿命逐渐变化,人口统计学参数之间仍可能观察到SM类型的关系。

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