ASYMPTOTIC PROPERTIES OF THE MLE IN HIDDEN MARKOV MODELS
服从指数分布的极大似然估计的实际例子
服从指数分布的极大似然估计的实际例子1.统计学家使用极大似然估计来估计指数分布的参数。
Statisticians use maximum likelihood estimation toestimate the parameters of the exponential distribution.2.通过估计参数λ,我们可以更好地了解指数分布中事件发生的方式。
By estimating the parameter λ, we can gain a better understanding of how events occur in an exponential distribution.3.极大似然估计是一种常用的统计方法,可用于估计各种类型的分布。
Maximum likelihood estimation is a commonly usedstatistical method that can be used to estimate various types of distributions.4.我们可以使用极大似然估计来估计指数分布的中位数或平均值。
We can use maximum likelihood estimation to estimate the median or mean of the exponential distribution.5.估计出的参数可以用于预测未来事件的发生情况。
The estimated parameters can be used to predict the occurrence of future events.6.极大似然估计需要收集一定数量的数据来进行计算。
Maximum likelihood estimation requires collecting a sufficient amount of data for computation.7.通过比较不同参数值下的似然函数,我们可以找到最可能的参数值。
英语修辞隐含比较定义
英语修辞隐含比较定义In the realm of English rhetoric, implicit comparison is a subtle yet powerful device that enhances the expressiveness of language. It allows writers and speakers to convey complex ideas and emotional nuances without explicitly stating them, thus adding depth and richness to communication. The art of implicit comparison lies in the ability to draw parallels between seemingly unrelated concepts, creating a connection that is both insightful and engaging.One of the most striking examples of implicit comparison in English is the use of analogies. Analogies work by comparing two different things or concepts to illustrate a similarity between them. By doing so, they help readers or listeners better understand a complex concept by relating it to something more familiar. For instance, in describing the vastness of the universe, an author might compare it to an ocean, noting that both are vast, unending, and full of mysteries waiting to be discovered.Another common form of implicit comparison is the use of hyperbole. Hyperbole involves exaggerating a statement for the purpose of emphasis or to evoke a strong emotional response. By pushing the boundaries of realism, hyperbole allows speakers and writers to convey a sense of urgency or importance that might be difficult to achieve with aliteral statement. For example, when someone says, "I'm starving to death!" they are not literally on the brink of death, but they are emphasizing their extreme hunger through exaggeration.The power of implicit comparison lies in its ability to engage the reader or listener on a deeper level. By making connections between seemingly unrelated ideas, it encourages them to think beyond the literal meaning of words and consider the underlying connections and meanings. This type of rhetorical device is particularly effective in persuasive writing, as it allows the author to subtly guide the reader's thinking without overtly stating their arguments.Implicit comparison also adds a layer of aesthetic pleasure to language. By comparing disparate elements in acreative and unexpected way, it generates a sense of surprise and delight that makes language more enjoyable to read or hear. This is particularly evident in poetry, where poets often use implicit comparison to create images and evoke emotions that are both beautiful and profound.In conclusion, the implicit comparison is a vital tool in the English rhetorician's toolbox. It allows writers and speakers to convey complex ideas and emotional nuances with precision and elegance, engaging their audience on a deeper level. By drawing parallels between seemingly unrelated concepts and using creative language to evoke strong emotional responses, implicit comparison adds a unique and powerful dimension to English rhetoric.**修辞之力:英语中隐含比较的修辞魅力**在英语修辞的世界里,隐含比较是一种微妙而强大的手法,能够增强语言的表达力。
英语作文我马雷什比知识
英语作文我马雷什比知识In the vast expanse of human knowledge, there lies arealm that is as fascinating as it is enigmatic: the world of Maresh. This term, though not widely recognized, encapsulates a concept that has intrigued scholars, philosophers, and adventurers alike for centuries. The purpose of this essay is to delve into the intricacies of Maresh, exploring its origins, its significance, and the impact it has had on our understanding of the world.The Origins of MareshThe etymology of the term "Maresh" is shrouded in mystery. Some linguists suggest it is derived from an ancient language, possibly pre-Sumerian, indicating a place of profound wisdomor a hidden knowledge. Others argue that it is a modern concoction, a neologism created to describe a contemporary phenomenon. Regardless of its origin, the concept of Maresh has captured the imagination of those who seek to understand the depths of human potential and the universe's secrets.The Essence of MareshAt its core, Maresh represents the pursuit of knowledge that transcends the ordinary. It is the quest for understanding the unexplained, the mastery of the arcane, and the exploration of the esoteric. Maresh is not merely about accumulating facts; it is about the synthesis of knowledgeinto a profound wisdom that can guide humanity towards a greater destiny.The Significance of Maresh in HistoryThroughout history, figures who have been attributed with a deep understanding of Maresh have often been regarded as visionaries. From the alchemists of the Middle Ages, who sought to transmute base metals into gold and in the process uncovered the principles of modern chemistry, to the astronomers of the Renaissance, who charted the stars and expanded our understanding of the cosmos, these individuals have pushed the boundaries of what was known and possible.The Impact of Maresh on Modern SocietyIn contemporary society, the influence of Maresh can be seen in various fields. In technology, the relentless pursuit of innovation is driven by a Maresh-like desire to unlock new potentials and solve complex problems. In environmental science, the study of ecosystems and the search for sustainable practices are fueled by a similar quest for knowledge that can lead to a harmonious coexistence with our planet.The Role of Maresh in Personal DevelopmentOn an individual level, the concept of Maresh encourages a lifelong commitment to learning and self-improvement. It is the drive to never be satisfied with the status quo, to always question, to explore, and to grow. Embracing Maresh inone's personal journey can lead to a richer, more fulfilling life experience.The Challenges of MareshThe path of Maresh is not without its challenges. The pursuit of such profound knowledge often requires a level of dedication and sacrifice that many are not prepared to make. Moreover, the nature of Maresh itself can lead to isolation, as those who delve too deeply into its mysteries may find it difficult to communicate their insights to others.The Future of MareshAs we look to the future, the role of Maresh in shaping human knowledge and understanding will likely continue to evolve. With the advent of new technologies and the increasing interconnectedness of the global community, the potential for discovering and sharing knowledge on a scale previously unimaginable is within our grasp.ConclusionThe world of Maresh is a testament to the indomitable human spirit and its unceasing quest for knowledge. It is a reminder that the pursuit of wisdom is not just a journeyinto the unknown, but a voyage into the very essence of what it means to be human. As we continue to explore the depths of Maresh, we contribute to the collective understanding that has the power to transform not only ourselves but also the world around us.In conclusion, Maresh is more than a mere concept; it is a call to action, an invitation to embark on a journey of discovery that has the potential to unlock the greatest mysteries of our existence. It is a challenge to the curious, a beacon to the seekers, and a promise of a future where the limits of knowledge are continually expanded.。
研究生公共英语教材阅读B第3、4、10、11、14课文原文及翻译
Unite 3 Doctor’s Dilemma: Treat or Let Die?Abigail Trafford1. Medical advances in wonder drugs, daring surgical procedures, radiation therapies, and intensive-care units have brought new life to thousands of people. Yet to many of them, modern medicine has become a double-edged sword.2. Doctor’s power to treat with an array of space-age techniques has outstripped the body’s capacity to heal. More medical problems can be treated, but for many patients, there is little hope of recovery. Even the fundamental distinction between life and death has been blurred.3. Many Americans are caught in medical limbo, as was the South Korean boxer Duk Koo Kim, who was kept alive by artificial means after he had been knocked unconscious in a fight and his brain ceased to function. With the permission of his family, doctors in Las Vegas disconnected the life-support machines and death quickly followed.4. In the wake of technology’s advances in medicine, a heated debate is taking place in hospitals and nursing homes across the country --- over whether survival or quality of life is the paramount goal of medicine.5. “It gets down to what medicine is all about, ” says Daniel Callahan, director of the Institute of Society, Ethics, and the Life Sciences in Hastings-on-Hudson, New York. “Is it really to save a life? Or is the larger goal the welfare of the patient?”6. Doctors, patients, relatives, and often the courts are being forced to make hard choices in medicine. Most often it is at the two extremes of life that these difficultyethical questions arise --- at the beginning for the very sick newborn and at the end for the dying patient.7. The dilemma posed by modern medical technology has created the growing new discipline or bioethics. Many of the country’s 127 medical s chools now offer courses in medical ethics, a field virtually ignored only a decade ago. Many hospitals have chaplains, philosophers, psychiatrists, and social workers on the staff to help patients make crucial decisions, and one in twenty institutions has a special ethics committee to resolve difficult cases.Death and Dying8. Of all the patients in intensive-care units who are at risk of dying, some 20 percent present difficult ethical choices --- whether to keep trying to save the life or to pull back and let the patient die. In many units, decisions regarding life-sustaining care are made about three times a week.9. Even the definition of death has been changed. Now that the heart-lung machine can take over the functions of breathing and pumping blood, death no longer always comes with the patient’s “last gasp” or when the heart stops beating. Thirty-one states and the District of Columbia have passed brain-death statutes that identify death as when the whole brain ceases to function.10. More than a do zen states recognize “living wills” in which the patients leave instructions to doctors not to prolong life by feeding them intravenously or by other methods if their illness becomes hopeless. A survey of California doctors showed that 20 to 30 percent were following instructions of such wills. Meanwhile, the hospicemovement, which its emphasis on providing comfort --- not cure --- to the dying patient, has gained momentum in many areas.11. Despite progress in society’s understanding of death and dying, t heory issues remain. Example: A woman, 87, afflicted by the nervous-system disorder of Parkinson’s disease, has a massive stroke and is found unconscious by her family. Their choices are to put her in a nursing home until she dies or to send her to a medical center for diagnosis and possible treatment. The family opts for a teaching hospital in New York city. Tests show the woman’s stroke resulted from a blood clot that is curable with surgery. After the operation, she says to her family: “Why did you bring me back to this agony?” Her health continues to worsen, and two years later she dies.12. On the other hand, doctors say prognosis is often uncertain and that patients, just because they are old and disabled, should not be denied life-saving therapy. Ethicists also fear that under the guise of medical decision not to treat certain patients, death may become too easy, pushing the country toward the acceptance of euthanasia.13. For some people, the agony of watching high-technology dying is too great. Earlier this year, Woodrow Wilson Collums, a retired dairyman from Poteet, Texas, was put on probation for the mercy killing of his older brother Jim, who lay hopeless in his bed at a nursing home, a victim of severe senility resul ting from Alzheimer’s disease. After the killing, the victim’s widow said: “I think God, Jim’s out of his misery. I hate to think it had to be done the way it was done, but I understand it. ”Crisis in Newborn Care14. At the other end of the life span, technology has so revolutionized newborn carethat it is no longer clear when human life is viable outside the womb. Newborn care has got huge progress, so it is absolutely clear that human being can survive independently outside the womb. Twenty-five years ago, infants weighting less than three and one-half pounds rarely survived. The current survival rate is 70 percent, and doctors are “salvaging” some babies that weigh only one and one-half pounds. Tremendous progress has been made in treating birth deformities such as spina bifida. Just ten years ago, only 5 percent of infants with transposition of the great arteries --- the congenital heart defect most commonly found in newborns --- survived. Today, 50 percent live.15. Yet, for many infants who owe their lives to new medical advances, survival has come at a price. A significant number emerge with permanent physical and mental handicaps.16. “The question of treatment and nontreatment of seriously ill newborns is not a single one,”says Thomas Murray of the Hastings Center. “But I feel strongly that retardation or the fact that someone is going to be less than perfect is not good grounds for allowing an infant to die.”17. For many parents, however, the experience of having a sick newborn becomes a lingering nightmare. Two years ago, an Atlanta mother gave birth to a baby suffering from Down’s Syndrome, a form of mental retardation; the child also had blocked intestines. The doctors rejected the parents’ plea not to operate, and today the child, severely retarded, still suffers intestinal problems.18. “Every time Melanie has a bowel movement, she cries,” explains her mother.“She’s not able to take care of herself, and we won’t live forever. I wanted to save her from sorrow, pain, and suffering. I don’t understand the emphasis on life at all costs, and I’m very angry at the doctors and the hospital. Who will take care of Melanie after we’re gone? Where will you doctors be then?”Changing Standards19. The choices posed by modern technology have profoundly changed the practice of medicine. Until now, most doctors have been activists, trained to use all the tools in their medical arsenals to treat disease. The current trend is toward nontreatment as doctors grapple with questions not just of who should get care but when to take therapy away.20. Always in the background is the threat of legal action. In August, two California doctors were charged with murdering a comatose patient by allegedly disconnecting the respirator and cutting off food and water. In 1981, a Massachusetts nurse was charged with murdering a cancer patient with massive doses of morphine but was subsequently acquitted.21. Between lawsuits, government regulations, and patients’ rights, many doctors feel they are under siege. Modern technology actually has limited their ability to make choices. More recently, these actions are resolved by committees.Public Policy22. In recent years, the debate on medical ethics has moved to the level of national policy. “It’s just beginning to hit us that we don’t have unlimited resources,” says Washington Hospital Center’s Dr. Lynch. “You can’t talk about ethics without talkingethics without talking about money.”23. Since 1972. Americans have enjoyed unlimited access to a taxpayer-supported, kidney dialysis program that offers life-prolonging therapy to all patients with kidney failure. To a number of police analysts, the program has grown out of control --- to a $1.4billion operation supporting 61,000 patients. The majority are over 50, and about a quarter have other illness, such as cancer or heart disease, conditions that could exclude them from dialysis in other countries.24. Some hospitals are pulling back from certain lifesaving treatment. Massachusetts General Hospital, for example, has decided not perform heart transplants on the ground that the high costs of providing such surgery help too few patients. Burn units --- through extremely effective --- also provide very expensive therapy for very few patients.25. As medical scientists push back the frontiers of therapy, the moral dilemma will continue to grow for doctors and patients alike, making the choice of to treat the basic question in modern medicine.1. 在特效药、风险性手术进程、放疗法以及特护病房方面的医学进展已为数千人带来新生。
Functional-coefficient regression models for nonlinear time series
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transpose of a matrix or vector. The idea to model time series in such a form is not new; see,
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一类非光滑优化问题的邻近交替方向法
一类非光滑优化问题的邻近交替方向法钱伟懿;杨岩【摘要】非光滑优化问题在现实生活中有着广泛应用.针对一类带有结构特征为两个连续凸函数与具有Lipschitz梯度的二次可微函数的和的无约束非光滑非凸优化问题,给出了一种邻近交替方向法,称之为二次上界逼近算法.该算法结合交替方向法与邻近点算法的思想,将上述优化问题转化为平行的子问题.在求解子问题的过程中,对目标函数中的光滑部分线性化,此时子问题被转化为凸优化问题.然后分别对两个凸优化子问题交替利用邻近点算法求解.基于以上思想,首先我们给出算法的伪代码,然后建立了算法收敛性的充分条件,最后证明在该条件下,算法产生迭代序列的每个极限点是原问题的临界点.【期刊名称】《渤海大学学报(自然科学版)》【年(卷),期】2018(039)002【总页数】5页(P134-138)【关键词】非光滑优化;交替方向法;邻近点算法;收敛性分析;临界点【作者】钱伟懿;杨岩【作者单位】渤海大学数理学院, 辽宁锦州121013;渤海大学数理学院, 辽宁锦州121013【正文语种】中文【中图分类】O2210 引言考虑下列非凸非光滑的极小化问题(P) min{φ(x,y):=f(x)+g(y)+h(x,y)|x∈Rn,y∈Rm}其中函数φ有下界→(-∞,+∞),g: Rm→(-∞,+∞)都是正常的连续凸函数,h:Rn×Rm→R是具有Lipschitz梯度的二次可微函数,即存在常数L∈(0,∞),使得‖▽h(x,y)-▽h(x′,y′)‖≤L‖(x,y)-(x′,y′)‖Attouch等人〔1〕最先对问题(P)进行研究,将常规的Gauss-Seidel迭代引入算法中,给定初始点(x0,y0),由下列公式产生迭代序列{(xk,yk)}k∈N该方法被称为交替极小化方法. Gauss-Seidel方法的收敛性分析在很多文献中可见〔2-4〕,证明其收敛性的必要假设条件之一是每步迭代得到唯一最小解〔5〕,否则算法可能无限循环没有收敛性〔6〕 . 当一个变量固定,假设连续可微函数φ关于另一个变量是严格凸的,按照以上的方法迭代产生的迭代序列{(xk,yk)}k∈N 的极限点极小化目标函数φ〔3〕. 对凸光滑约束最小化问题,Beck和Tetruashvili〔7〕提出了块坐标梯度投影算法,并讨论了其全局收敛速率.去掉严格凸的假设,考虑邻近正则化Gauss-Seidel迭代其中αk,βk是正实数.该方法最先是Auslender〔8〕提出的,并进一步研究了含有非二次邻近项的线性约束凸问题〔9〕. 以上结果只是得到子序列的收敛性.当φ非凸非光滑情况下,收敛性分析是一个值得研究的课题.当φ是非凸非光滑的条件下,Attouch等人〔1,10〕证明了由邻近Gauss-Seidel 迭代〔10〕产生的序列是收敛的. 在文献〔10〕中,Attouch用熟知的proximal-forward-backward (PFB)算法求解非凸非光滑最小化问题,也得到了相似的结论. Bolte〔11〕和Daniilidis〔12〕等人在假设目标函数φ满足Kurdyka-Lojasiewicz(KL)性质的条件下,研究了一类非光滑最优化问题.交替方向法(Alternating direction method,简称ADM)最初是由Gabay和Mercier〔13〕提出. 该方法与Douglas-Rachford算子分裂算法紧密相关〔14-16〕. Eckstein〔17〕将邻近点算法(Proximal point algorithm,简称PPA)与ADM方法相结合得到了邻近交替方向法(PADM). 基于ADM方法,Beck〔18〕对凸最小化问题提出了次线性收敛速度的迭代再加权最小二乘法. Bolte和Sabach 等人〔19〕在强Kurdyka-ojasiewicz性质下对非光滑非凸优化问题提出了邻近交替线性化算法,该方法是对优化问题中光滑部分向前一个梯度步,非光滑部分向后一个邻近步,非精确求解每个线性化的子问题,迭代产生序列收敛到一个临界点. Fazel等人〔20〕提出了带半正定邻近项的交替方法,是在一定的条件下将邻近项中的正定算子扩展到半正定算子.1 预备知识本节,我们陈述一些基本概念和性质〔21〕,方便之后的证明.定义1.1 设S⊂Rn,如果对∀x1,x2∈S,0≤λ≤1,有λx1+(1-λ)x2∈S,则称S为凸集.定义1.2 设S为Rn上的凸集,如果对任意x,y ∈S,0≤λ≤1,有f(λx+(1-λ)y)≤λf(x)+(1-λ)f(y),∀x,y∈S,λ∈[0,1]则称f(x)为S上的凸函数.定理1.1 对于定义在一个开凸集O⊂Rn上的可微函数f,下面条件等价:(a)f在O上是凸函数;(b)<x1-x0,▽f(x1)-▽f(x0)>≥0对于任意的x0和x1在O上成立;(c)f(y)≥f(x)+<▽f(x),y-x>对于任意的x和y在O上成立;(d)▽2f(x)是半正定对任意的x在O上.定义1.3 函数f的次微分∂f:Rn→Rn,定义为∂f(x)={w∈Rn:f(x)-f(v)≤<w,x-v>,∀v∈Rn}若那么点称为函数f:Rn→R的临界点.定义1.4 设S⊆Rn为非空闭凸集,若f:S→R可微,其满足对任意的x,y∈S,μ>0总有f(y)≥f(x)+<▽则称f在非空闭凸集C上是μ强凸的.2 算法及收敛性分析设(1)(2)其中s∈Rn,x∈Rn,y∈Rm,t∈Rm,x∈Rn,y∈Rm. 式子(1)和(2)是将问题(P)用交替方向法产生的逼近子问题,因而称为二次上界逼近算法(Quadratic Upper-bound Approximation algorithm,简称QUA算法.QUA算法的伪代码:1. 给定初始点x0∈Rn,y0∈Rm,正实数选择正实数αk↘↘令k=0,2. k=k+13. xk+1∈arg min{ux(x,xk,yk,αk):x∈Rn}(3)4. yk+1∈arg min{uy(y,xk+1,yk,βk):y∈Rm}(4)回到第二步,直到满足某一终止条件.引理2.1 设(xk,yk)是由QUA算法迭代产生的序列,那么(5)且无穷级数和是可和的,从而有‖xk+1-xk‖→0和‖yk+1-yk‖→0.证明由二阶梯度的定义得‖▽2h(x,y)‖≤L, ∀x,y∈Rn函数h分别对x和y泰勒展开,可得下列不等式(6)(7)由αK>L ,βk>L 得f(xk+1)+g(yk)+h(xk+1,yk)≤ux(xk+1,xk,yk,αk)(8)f(xk+1)+g(yk+1)+h(xk+1,yk+1)≤uy(yk+1,xk+1,yk,βk)(9)因为在xk+1和yk+1取得极小,所以有ux(xk+1,xk,yk,αk)≤ux(xk,xk,yk,αk)=f(xk)+g(yk)+h(xk,yk)(10)uy(yk+1,xk+1,yk,βk)≤uy(yk,xk+1,yk,βk)=f(xk+1)+g(yk)+h(xk+1,yk) (11)▽xh(xk,yk)>-f(xk+1)▽yh(xk+1,yk)>-g(yk+1)应用不等式(6)和(7)得(12)(13)将不等式(12)和(13)相加得不等式(5).进一步,由不等式(5)得因此,无穷级数是可和的. 证毕.定理2.1 QUA算法迭代序列(xk,yk)的每个极限点(x*,y*)是问题(P)的临界点. 证明对迭代序列(xk,yk)的每个极限点(x*,y*)总是存在一个子序列,使得(xkj,ykj)→(x*,y*). 因为xkj+1∈arg min{ux(x,xkj,ykj,αkj):x∈Rn}(14)ykj+1∈arg min{uy(y,xkj+1,ykj,βkj):y∈Rm}(15)可得ux(xkj+1,xkj,ykj,αkj)≤ux(x,xkj,ykj,αkj), ∀x∈Rn(16)uy(ykj+1,xkj+1,ykj,βkj)≤uy(y,xkj+1,ykj,βkj), ∀y∈Rm(17)由引理2.1知‖xkj+1-xkj‖→0,‖ykj+1-ykj‖→0,从而(xkj+1,ykj+1)→(x*,y*).令j→∞得∀x∈Rn(18)∀y∈Rm(19)由最优性条件得-▽xh(x*,y*)∈∂f(x*)-▽yh(x*,y*)∈∂g(y*)极限点(x*,y*)是问题(P)的临界点.证毕.参考文献:【相关文献】〔1〕ATTOUCH H, BOLTE J, REDONT P, et al. Proximal alternating minimization and projection methods for nonconvex problems: an approach based on the Kurdyka-ojasiewicz inequality〔J〕. Mathematics of Operations Research, 2010, 35(2): 438-457. 〔2〕AUSLENDER A. Méthodes numériques pour la décomposition et la minimisation de functions non différentiables〔J〕. Numerische Mathematik, 1971, 18: 213-223.〔3〕BERTSEKAS D P, TSITSIKLIS J N. Parallel and distributed computation: numerical methods, prentice-hall〔M〕. New Jersey, 1989.〔4〕TSENG P. Convergence of block coordinate descent method for nondifferentiable minimization〔J〕. Journal of Optimization Theory and Applications, 2001, 109(3): 475-494.〔5〕ZANGWILL W L. Nonlinear programming: a unified approach〔M〕. Prentice Hall, 1971.〔6〕POWELL M. On search directions for minimization algorithms〔J〕. Mathematical Programming, 1973, 4: 193-201.〔7〕BECK A, TETRUASHVILI L. On the convergence of block coordinate descent type methods〔M〕. Preprint, 2011.〔8〕AUSLENDER A. Asymptotic properties of the fenchel dual functional and applications to decomposition problems〔J〕. Journal of Optimization Theory & Applications, 1992,73(3): 427-449.〔9〕AUSLENDER A, TEBOULLE M, BEN-TIBA S. Coupling the logarithmic-quadratic proximal method and the block nonlinear Gauss-Seidel algorithm for linearly constrained convex minimization〔J〕. 1999, 477: 35-47.〔10〕ATTOUCH H, BOLTE J, SVAITER B F. Convergence of descent methods for semi-algebraic and tame problems: proximal algorithms, forward-backward splitting, and regularized Gauss-Seidel methods〔J〕. Mathematical Programming, 2013, 137(1-2): 91-129.〔11〕BOLTE J, DANIILIDIS A, LEWIS A A. The ojasiewicz inequality for nonsmooth subanalytic functions with applications to subgradient dynamical systems〔J〕. Siam Journal on Optimization, 2007, 17(4): 1205-1223.〔12〕DANIILIDIS A, LEWIS A A, SHIOTAH M. Clarke subgradients of stratifiable functions 〔J〕. Siam Journal on Optimization, 2007, 18(2): 556-572.〔13〕GABAY D, B MERCIER. A dual algorithm for the solution of nonlinear variational problems via finite element approximations〔J〕. Computers & Mathematics with Applications, 1976, 2(1): 17-40.〔14〕DOUGLAS J, RACHFORD H. On the numerical solution of heat conduction problems in two and three space variables〔M〕. Transactions of the American Mathematical Society, 1956, 82(2): 421-439.〔15〕SVAITER B. On weak convergence of the Douglas-Rachford method〔M〕. Society for Industrial and Applied Mathematics, 2011.〔16〕BOT R, HENDRICH C. A Douglas-Rachford type primal-dual method for solving inclusions with mixtures of composite and parallel-sum type monotone operators〔J〕. Siam Journal on Optimization, 2012, 23(4): 2541-2565.〔17〕ECKSTEIN J. Some saddle-function splitting methods for convex programming〔J〕. Optimization Methods & Software, 1994, 4(1): 75-83.〔18〕BECK A. On the convergence of alternating minimization for convex programming with applications to Iteratively reweighted least squares and decomposition schemes〔J〕. Siam Journal on Optimization, 2013, 25(1): 185-209.〔19〕BOLTE J, SABACH S, TEBOULLE M. Proximal alternating linearized minimization for nonconvex and nonsmooth problems〔J〕. Mathematical Programming, 2014, 146(1-2): 459-494.〔20〕FAZEL M, PONG T K, SUN D, et al. Hankel matrix rank minimization with applications to system identification and realization〔J〕. Siam Journal on Matrix Analysis & Applications, 2012, 34(3): 946-977.〔21〕ROCKAFELLAR R T. Convex analysis〔M〕. Princeton University Press, 1970.。
浅谈BLUP方法及其三种形式的应用
浅谈BLUP方法及其三种形式的应用摘要:blup(best linear unbiased prediction,最佳线性无偏预测)方法是目前进行育种值估计最好的方法,它已经在各个国家得到了广泛应用,有利于各国畜牧业的发展。
本文主要介绍blup 的基本原理、特点、基本步骤;并简述目前常用的blup三种形式(e-blup、r-blup、m-blup)的模型、原理以及blup的应用和未来的发展前景。
关键词:blup; 家畜育种; 模型中图分类号:s8-0 文献标识码:a 文章编号:1674-0432(2012)-07-0139-21949年,美国数量遗传学家c.r.汉特逊(henderson)在研究对于不平衡资料应用混和模型方程组的原理估计固定效应和预测随机效应时,提出了blup(best linear unbiased prediction,最佳线性无偏预测)方法[1],于1973年在纪念勒什(lush)的学术讨论会上他又对该法的理论和应用进行了系统阐述,同时随着计算机技术的迅速发展和普及,blup法才得到了广泛的应用,普遍认为blup法是最好的畜禽遗传评定方法。
1 blup法的概述1.1 基本原理blup是一种数理统计方法,基本原理是线性统计模型方法论与数量遗传学相结合。
blup模型中包括固定效应和除了残差效应以外的随机效应,所以是一个混合模型。
blup混合模型的一般形式:yijk =μ+hi+sj+eijk (1)式中yijk:观察值向量,μ:总体均值,hi:第i个畜禽的固定效应值,sij:第i个畜群中第j个公畜的随机遗传效应,eijk:随机剩余效应。
以矩阵形式表示为:y=xβ+zn+e (2)式中y:观察值向量,x:固定因子结构矩阵,β:固定效应向量,z:随机因子的结构矩阵,u:随机效应向量,e:随机残差向量,并有e~n(0,r),e(y)=xβ,e(u)=0, e(e’)=0,var(u)=g,var (e)=r, cov(u,e,)=0, var(y)=v=zgz’+r当u和e服从正态分布,即u~n(0,g), e~n(0,r)时y和u的联合密度函数:f(y,u)=f1(y∣u)f2(u)f1(y∣u)=c1exp{-1/2(y- xβ-zu)’r-1(y- xβ-zu)}f2(u)= c2exp{-1/2u’g-1u}f(y,u)=cexp{-1/2(y- xβ-zu)’r-1(y-xβ-zu)-1/2u’g-1u} 其中:c=c2*c1,为一常数。
高级计量经济学习题及解答4
find this? ) is n−1 nx f (x|θ) = θn 0 0<x<θ otherwise .
Calculate the mean and variance of the mle. Compare the variance, the bias, and the mean squared error to those of the method of moments estimate. (c) Find a modification of the mle that renders it unbiased. 2
argument as in (a), we have E[Y ] = ρ(n − 1)E[s2 ] = ρ(n − 1)σ 2 , and Var[Y ] = (ρ(n − 1)) Var[s2 ] = ρ2 (n − 1)2 Thus MSE(Y ) = Var[Y ] + b(Y )2 = 2ρ2 (n − 1)σ 4 + ρ(n − 1)σ 2 − σ 2 = σ 4 [2ρ2 (n − 1) + (ρn − ρ − 1)2 ] ≡ f (ρ). Since f (ρ) = σ 4 [4ρ(n − 1) + 2(ρn − ρ − 1)(n − 1)] = σ 4 [4ρ + 2(ρn − ρ − 1)](n − 1) = 2(n − 1)σ 4 (ρn + ρ − 1), and f (ρ) = 2(n − 1)(n + 1)σ 4 > 0, 1 we see that f (ρ) achieve its minimum at ρ = . (f (n + 1)−1 = n+1 0.)
n i=1 (Xi
算法导论习题答案 (1)
Introduction to Algorithms September 24, 2004Massachusetts Institute of Technology 6.046J/18.410J Professors Piotr Indyk and Charles E. Leiserson Handout 7Problem Set 1 SolutionsExercise 1-1. Do Exercise 2.3-7 on page 37 in CLRS.Solution:The following algorithm solves the problem:1.Sort the elements in S using mergesort.2.Remove the last element from S. Let y be the value of the removed element.3.If S is nonempty, look for z=x−y in S using binary search.4.If S contains such an element z, then STOP, since we have found y and z such that x=y+z.Otherwise, repeat Step 2.5.If S is empty, then no two elements in S sum to x.Notice that when we consider an element y i of S during i th iteration, we don’t need to look at the elements that have already been considered in previous iterations. Suppose there exists y j∗S, such that x=y i+y j. If j<i, i.e. if y j has been reached prior to y i, then we would have found y i when we were searching for x−y j during j th iteration and the algorithm would have terminated then.Step 1 takes �(n lg n)time. Step 2 takes O(1)time. Step 3 requires at most lg n time. Steps 2–4 are repeated at most n times. Thus, the total running time of this algorithm is �(n lg n). We can do a more precise analysis if we notice that Step 3 actually requires �(lg(n−i))time at i th iteration.However, if we evaluate �n−1lg(n−i), we get lg(n−1)!, which is �(n lg n). So the total runningi=1time is still �(n lg n).Exercise 1-2. Do Exercise 3.1-3 on page 50 in CLRS.Exercise 1-3. Do Exercise 3.2-6 on page 57 in CLRS.Exercise 1-4. Do Problem 3-2 on page 58 of CLRS.Problem 1-1. Properties of Asymptotic NotationProve or disprove each of the following properties related to asymptotic notation. In each of the following assume that f, g, and h are asymptotically nonnegative functions.� (a) f (n ) = O (g (n )) and g (n ) = O (f (n )) implies that f (n ) = �(g (n )).Solution:This Statement is True.Since f (n ) = O (g (n )), then there exists an n 0 and a c such that for all n √ n 0, f (n ) ←Similarly, since g (n )= O (f (n )), there exists an n � 0 and a c such that for allcg (n ). �f (n ). Therefore, for all n √ max(n 0,n Hence, f (n ) = �(g (n )).�()g n ,0← �),0c 1 � g (n ) ← f (n ) ← cg (n ).n √ n c � 0 (b) f (n ) + g (n ) = �(max(f (n ),g (n ))).Solution:This Statement is True.For all n √ 1, f (n ) ← max(f (n ),g (n )) and g (n ) ← max(f (n ),g (n )). Therefore:f (n ) +g (n ) ← max(f (n ),g (n )) + max(f (n ),g (n )) ← 2 max(f (n ),g (n ))and so f (n ) + g (n )= O (max(f (n ),g (n ))). Additionally, for each n , either f (n ) √max(f (n ),g (n )) or else g (n ) √ max(f (n ),g (n )). Therefore, for all n √ 1, f (n ) + g (n ) √ max(f (n ),g (n )) and so f (n ) + g (n ) = �(max(f (n ),g (n ))). Thus, f (n ) + g (n ) = �(max(f (n ),g (n ))).(c) Transitivity: f (n ) = O (g (n )) and g (n ) = O (h (n )) implies that f (n ) = O (h (n )).Solution:This Statement is True.Since f (n )= O (g (n )), then there exists an n 0 and a c such that for all n √ n 0, �)f ()n ,0← �()g n ,0← f (n ) ← cg (n ). Similarly, since g (n ) = O (h (n )), there exists an n �h (n ). Therefore, for all n √ max(n 0,n and a c � such thatfor all n √ n Hence, f (n ) = O (h (n )).cc�h (n ).c (d) f (n ) = O (g (n )) implies that h (f (n )) = O (h (g (n )).Solution:This Statement is False.We disprove this statement by giving a counter-example. Let f (n ) = n and g (n ) = 3n and h (n )=2n . Then h (f (n )) = 2n and h (g (n )) = 8n . Since 2n is not O (8n ), this choice of f , g and h is a counter-example which disproves the theorem.(e) f(n)+o(f(n))=�(f(n)).Solution:This Statement is True.Let h(n)=o(f(n)). We prove that f(n)+o(f(n))=�(f(n)). Since for all n√1, f(n)+h(n)√f(n), then f(n)+h(n)=�(f(n)).Since h(n)=o(f(n)), then there exists an n0such that for all n>n0, h(n)←f(n).Therefore, for all n>n0, f(n)+h(n)←2f(n)and so f(n)+h(n)=O(f(n)).Thus, f(n)+h(n)=�(f(n)).(f) f(n)=o(g(n))and g(n)=o(f(n))implies f(n)=�(g(n)).Solution:This Statement is False.We disprove this statement by giving a counter-example. Consider f(n)=1+cos(�≈n)and g(n)=1−cos(�≈n).For all even values of n, f(n)=2and g(n)=0, and there does not exist a c1for which f(n)←c1g(n). Thus, f(n)is not o(g(n)), because if there does not exist a c1 for which f(n)←c1g(n), then it cannot be the case that for any c1>0and sufficiently large n, f(n)<c1g(n).For all odd values of n, f(n)=0and g(n)=2, and there does not exist a c for which g(n)←cf(n). By the above reasoning, it follows that g(n)is not o(f(n)). Also, there cannot exist c2>0for which c2g(n)←f(n), because we could set c=1/c2if sucha c2existed.We have shown that there do not exist constants c1>0and c2>0such that c2g(n)←f(n)←c1g(n). Thus, f(n)is not �(g(n)).Problem 1-2. Computing Fibonacci NumbersThe Fibonacci numbers are defined on page 56 of CLRS asF0=0,F1=1,F n=F n−1+F n−2for n√2.In Exercise 1-3, of this problem set, you showed that the n th Fibonacci number isF n=�n−� n,�5where �is the golden ratio and �is its conjugate.A fellow 6.046 student comes to you with the following simple recursive algorithm for computing the n th Fibonacci number.F IB(n)1 if n=02 then return 03 elseif n=14 then return 15 return F IB(n−1)+F IB(n−2)This algorithm is correct, since it directly implements the definition of the Fibonacci numbers. Let’s analyze its running time. Let T(n)be the worst-case running time of F IB(n).1(a) Give a recurrence for T(n), and use the substitution method to show that T(n)=O(F n).Solution: The recurrence is: T(n)=T(n−1)+T(n−2)+1.We use the substitution method, inducting on n. Our Induction Hypothesis is: T(n)←cF n−b.To prove the inductive step:T(n)←cF n−1+cF n−2−b−b+1← cF n−2b+1Therefore, T(n)←cF n−b+1provided that b√1. We choose b=2and c=10.∗{For the base case consider n0,1}and note the running time is no more than10−2=8.(b) Similarly, show that T(n)=�(F n), and hence, that T(n)=�(F n).Solution: Again the recurrence is: T(n)=T(n−1)+T(n−2)+1.We use the substitution method, inducting on n. Our Induction Hypothesis is: T(n)√F n.To prove the inductive step:T(n)√F n−1+F n−2+1√F n+1Therefore, T(n)←F n. For the base case consider n∗{0,1}and note the runningtime is no less than 1.1In this problem, please assume that all operations take unit time. In reality, the time it takes to add two numbers depends on the number of bits in the numbers being added (more precisely, on the number of memory words). However, for the purpose of this problem, the approximation of unit time addition will suffice.Professor Grigori Potemkin has recently published an improved algorithm for computing the n th Fibonacci number which uses a cleverly constructed loop to get rid of one of the recursive calls. Professor Potemkin has staked his reputation on this new algorithm, and his tenure committee has asked you to review his algorithm.F IB�(n)1 if n=02 then return 03 elseif n=14 then return 15 6 7 8 sum �1for k�1to n−2do sum �sum +F IB�(k) return sumSince it is not at all clear that this algorithm actually computes the n th Fibonacci number, let’s prove that the algorithm is correct. We’ll prove this by induction over n, using a loop invariant in the inductive step of the proof.(c) State the induction hypothesis and the base case of your correctness proof.Solution: To prove the algorithm is correct, we are inducting on n. Our inductionhypothesis is that for all n<m, Fib�(n)returns F n, the n th Fibonacci number.Our base case is m=2. We observe that the first four lines of Potemkin guaranteethat Fib�(n)returns the correct value when n<2.(d) State a loop invariant for the loop in lines 6-7. Prove, using induction over k, that your“invariant” is indeed invariant.Solution: Our loop invariant is that after the k=i iteration of the loop,sum=F i+2.We prove this induction using induction over k. We assume that after the k=(i−1)iteration of the loop, sum=F i+1. Our base case is i=1. We observe that after thefirst pass through the loop, sum=2which is the 3rd Fibonacci number.To complete the induction step we observe that if sum=F i+1after the k=(i−1)andif the call to F ib�(i)on Line 7 correctly returns F i(by the induction hypothesis of ourcorrectness proof in the previous part of the problem) then after the k=i iteration ofthe loop sum=F i+2. This follows immediately form the fact that F i+F i+1=F i+2.(e) Use your loop invariant to complete the inductive step of your correctness proof.Solution: To complete the inductive step of our correctness proof, we must show thatif F ib�(n)returns F n for all n<m then F ib�(m)returns m. From the previous partwe know that if F ib�(n)returns F n for all n<m, then at the end of the k=i iterationof the loop sum=F i+2. We can thus conclude that after the k=m−2iteration ofthe loop, sum=F m which completes our correctness proof.(f) What is the asymptotic running time, T�(n), of F IB�(n)? Would you recommendtenure for Professor Potemkin?Solution: We will argue that T�(n)=�(F n)and thus that Potemkin’s algorithm,F ib�does not improve upon the assymptotic performance of the simple recurrsivealgorithm, F ib. Therefore we would not recommend tenure for Professor Potemkin.One way to see that T�(n)=�(F n)is to observe that the only constant in the programis the 1 (in lines 5 and 4). That is, in order for the program to return F n lines 5 and 4must be executed a total of F n times.Another way to see that T�(n)=�(F n)is to use the substitution method with thehypothesis T�(n)√F n and the recurrence T�(n)=cn+�n−2T�(k).k=1Problem 1-3. Polynomial multiplicationOne can represent a polynomial, in a symbolic variable x, with degree-bound n as an array P[0..n] of coefficients. Consider two linear polynomials, A(x)=a1x+a0and B(x)=b1x+b0, where a1, a0, b1, and b0are numerical coefficients, which can be represented by the arrays [a0,a1]and [b0,b1], respectively. We can multiply A and B using the four coefficient multiplicationsm1=a1·b1,m2=a1·b0,m3=a0·b1,m4=a0·b0,as well as one numerical addition, to form the polynomialC(x)=m1x2+(m2+m3)x+m4,which can be represented by the array[c0,c1,c2]=[m4,m3+m2,m1].(a) Give a divide-and-conquer algorithm for multiplying two polynomials of degree-bound n,represented as coefficient arrays, based on this formula.Solution:We can use this idea to recursively multiply polynomials of degree n−1, where n isa power of 2, as follows:Let p(x)and q(x)be polynomials of degree n−1, and divide each into the upper n/2 and lower n/2terms:p(x)=a(x)x n/2+b(x),q(x)=c(x)x n/2+d(x),where a(x), b(x), c(x), and d(x)are polynomials of degree n/2−1. The polynomial product is thenp(x)q(x)=(a(x)x n/2+b(x))(c(x)x n/2+d(x))=a(x)c(x)x n+(a(x)d(x)+b(x)c(x))x n/2+b(x)d(x).The four polynomial products a(x)c(x), a(x)d(x), b(x)c(x), and b(x)d(x)are computed recursively.(b) Give and solve a recurrence for the worst-case running time of your algorithm.Solution:Since we can perform the dividing and combining of polynomials in time �(n), recursive polynomial multiplication gives us a running time ofT(n)=4T(n/2)+�(n)=�(n2).(c) Show how to multiply two linear polynomials A(x)=a1x+a0and B(x)=b1x+b0using only three coefficient multiplications.Solution:We can use the following 3 multiplications:m1=(a+b)(c+d)=ac+ad+bc+bd,m2=ac,m3=bd,so the polynomial product is(ax+b)(cx+d)=m2x2+(m1−m2−m3)x+m3.� (d) Give a divide-and-conquer algorithm for multiplying two polynomials of degree-bound nbased on your formula from part (c).Solution:The algorithm is the same as in part (a), except for the fact that we need only compute three products of polynomials of degree n/2 to get the polynomial product.(e) Give and solve a recurrence for the worst-case running time of your algorithm.Solution:Similar to part (b):T (n )=3T (n/2) + �(n )lg 3)= �(n �(n 1.585)Alternative solution Instead of breaking a polynomial p (x ) into two smaller polynomials a (x ) and b (x ) such that p (x )= a (x ) + x n/2b (x ), as we did above, we could do the following:Collect all the even powers of p (x ) and substitute y = x 2 to create the polynomial a (y ). Then collect all the odd powers of p (x ), factor out x and substitute y = x 2 to create the second polynomial b (y ). Then we can see thatp (x ) = a (y ) + x b (y )· Both a (y ) and b (y ) are polynomials of (roughly) half the original size and degree, and we can proceed with our multiplications in a way analogous to what was done above.Notice that, at each level k , we need to compute y k = y 2 (where y 0 = x ), whichk −1 takes time �(1) per level and does not affect the asymptotic running time.。
美丽的景色夸克作文英语
美丽的景色夸克作文英语Title: The Enchanting Beauty of Quarks。
In the vast tapestry of the cosmos, there exists arealm of subatomic particles where the very fabric ofreality dances in intricately woven patterns. Among these minuscule entities, there exists a class of particles known as quarks, which, despite their diminutive size, possess an awe-inspiring beauty that captivates the imagination of physicists and enthusiasts alike.Quarks, fundamental constituents of matter, exist in a state of perpetual motion within the atomic nucleus. Their interactions give rise to the rich diversity of particles that form the universe we inhabit. Yet, it is not merely their functional significance that renders quarks beautiful; it is their profound essence and the elegance with which they contribute to the cosmic symphony.At the heart of quark beauty lies their intrinsicproperties. Quarks possess electric charge, color charge, and mass, each contributing to their dynamic nature. These properties intertwine in a delicate balance, governed bythe fundamental forces of nature, to form the basis of all matter. From the simplest hydrogen atom to the most complex structures in the universe, quarks play an indispensablerole in shaping the cosmos.Furthermore, the interactions between quarks give riseto mesmerizing phenomena, such as confinement andasymptotic freedom. Confinement, a manifestation of the strong nuclear force, binds quarks together within the confines of protons and neutrons, creating a stable nucleus. On the other hand, asymptotic freedom describes theintriguing behavior of quarks at high energies, where they appear to move almost independently, revealing theintricate dynamics of the strong force.The beauty of quarks transcends their physicalproperties and extends into the realm of theoretical abstraction. In the framework of quantum chromodynamics (QCD), physicists unravel the intricate tapestry of quarkinteractions through elegant mathematical formalism. The symmetries and patterns that emerge from this theoretical framework elucidate the underlying unity of nature,offering glimpses into the profound beauty that permeates the cosmos.Moreover, quarks embody the essence of symmetry and harmony in the universe. In the symphony of particle physics, quarks dance in perfect accord, exchanging energy and information through the exchange of force carriers. This symphony, orchestrated by the fundamental forces of nature, unfolds in a mesmerizing display of coherence and unity, reflecting the underlying orderliness of the cosmos.In the pursuit of understanding quarks, physicists embark on a journey of discovery that transcends the boundaries of empirical observation. Through ingenious experiments and theoretical insights, they unravel the mysteries of quark confinement, explore the nature ofquark-gluon plasma, and probe the fundamental symmetries of the universe. Each revelation brings us closer to unraveling the enigma of quark beauty, unveiling theprofound mysteries that lie at the heart of existence.In conclusion, the beauty of quarks transcends the confines of empirical observation, manifesting in their intrinsic properties, dynamic interactions, and theoretical elegance. As we delve deeper into the fabric of reality, we uncover the profound mysteries that lie at the heart of quark beauty, offering glimpses into the underlying unity and harmony of the cosmos. In the intricate dance of subatomic particles, quarks emerge as celestial artisans, sculpting the very essence of existence with their ethereal beauty.。
Contribution of the Intestinal Microbiota to Human Health
Contribution of the Intestinal Microbiotato Human Health:From Birthto100Years of AgeJing Cheng,Airi M.Palva,Willem M.de Vos and Reetta Satokari Abstract Our intestinal tract is colonized since birth by multiple microbial species that show a characteristic succession in time.Notably the establishment of the microbiota in early life is important as it appears to impact later health.While apparently stable in healthy adults,the intestinal microbiota is changing signifi-cantly during aging.After100years of symbiosis marked changes have been observed that may relate to an increased level of intestinal inflammation.There is considerable interest in the microbiota in health and disease as it may provide functional biomarkers,the possibility to differentiate subjects,and avenues for interventions.This chapter reviews the present state of the art on the research to investigate the contribution of the intestinal microbiota to human health.SpecificJ.ChengÁA.M.PalvaÁW.M.de VosÁR.Satokari(&)Department of Veterinary Biosciences,University of Helsinki,P.O.Box66FIN-00014,Helsinki,Finlande-mail:reetta.satokari@helsinki.fiJ.Chenge-mail:jing.cheng@helsinki.fiA.M.Palvae-mail:airi.palva@helsinki.fiW.M.de Vose-mail:willem.devos@helsinki.fiW.M.de VosLaboratory,Department of Bacteriology and Immunology,Haartman Institute,University of Helsinki,Helsinki,FinlandW.M.de VosLaboratory of Microbiology,Wageningen University,6703HB,Wageningen,NetherlandsCurrent Topics in Microbiology and Immunology(2013)358:323–346323 DOI:10.1007/82_2011_189ÓSpringer-Verlag Berlin Heidelberg2011Published Online:19November2011324J.Cheng et al. attention will be given to the healthy microbiota and aberrations due to distur-bances such as celiac disease,irritable bowel syndrome,inflammatory bowel disease,obesity and diabetes,and non-alcoholic fatty liver disease.Contents1Microbiota Succession From Birth to Hundred Years of Age (325)1.1Establishment of Microbiota in Early Life (325)1.2The Normal Microbiota in Adults (326)1.3Microbiota in the Old Age (328)2Microbial Disbalance and Health (329)2.1Celiac Disease (331)2.2Irritable Bowel Syndrome (332)2.3Inflammatory Bowel Disease (334)2.4Obesity (335)2.5Type2Diabetes (337)2.6Type1Diabetes (338)2.7Non-Alcoholic Fatty Liver Disease (338)3Concluding Remarks (339)References (340)AbbreviationsBF Breast feedingFF Formula feedingCeD Celiac diseaseTLRs Toll-like receptorsNOD Nucleotide-binding oligomerization domain containingIBS Irritable bowel syndromeHCs Healthy controlsIBD Inflammatory bowel dieaseUC Ulcerative colitisCD Crohn’s diseaseTNBS2,4,6-trinitrobenzenesulphonic acidSCFA Short chain fatty acidBMI Body mass indexFIAF Fasting-induced adipose factorLPS LipopolysaccharideT1D Type1diabetesT2D Type2diabetesDGGE Denaturing gradient gel electrophoresisNAFLD Non-alcoholic fatty liver diseaseNASH Non-alcoholic steatohepatitisSIBO Small intestinal bacterial overgrowthLGG Lactobacillus rhamnosus GGContribution of the Intestinal Microbiota to Human Health325 1Microbiota Succession From Birth to Hundred Years of Age 1.1Establishment of Microbiota in Early LifeThe prevailing assumption is that the human fetus is microbiologically sterile and the bacterial colonization starts during and after birth when the newborn comes into contact with the microbes in the birth canal and the surrounding environment. The detection of bacteria in the amnioticfluid bacterial is generally linked to the pathogenesis of preterm birth(DiGiulio et al.2008,2010;Zhou et al.2010). However,the recent discoveries of bacterial DNA signatures from placenta and live bacteria in the umbilical cord blood and meconium of healthy neonates born by cesarean section suggest that exposure to low levels of microbes in utero may also occur during normal course of pregnancy and without pathologic conse-quences(Jiménez et al.2005,2008;Satokari et al.2009).While in utero exposure to microbes may prime the infant’s immune system already during fetal life,the major microbial colonization of the infant gut starts after delivery.The bacterial colonization of the infant gut after birth is a gradual process. Typically thefirst colonizers are facultative anaerobic bacteria followed by strictly anaerobic genera such as Bifidobacterium,Bacteroides,Clostridium and Eubacterium(Favier et al.2002;Palmer et al.2007).A number of factors including the mode of delivery,gestational age,infant hospitalization,antibiotic therapy,mother’s microbiota and mode of feeding during early life have an impact on the development of infant microbiota(Penders et al.2006;Palmer et al.2007; Collado et al.2010;Dominguez-Bello et al.2010).Also a significant impact of geographic location(country)on the microbiota of infants was revealed in a recent cross-European study(Fallani et al.2010).It seems that vaginally born full term infants who are consequently exclusively breast-fed during thefirst months of life have the most favorable microbiota.Cesarean delivered infants may have gener-ally delayed colonization and lower counts of Bacteroides and bifidobacteria and be more frequently colonized and have higher counts of Clostridium sp.as com-pared to vaginally delivered infants(Grönlund et al.1999;Adlerberth et al.2007; Palmer et al.2007;Kuitunen et al.2009).The differences in microbiota between these two groups of infants may persist up to one year of age(Grönlund et al. 1999;Adlerberth et al.2006;Penders et al.2006).The mode of feeding,either breast-feeding(BF)or formula-feeding(FF)has a profound effect on the infant microbiota.Human breast milk contains3–16g/l of complex oligosaccharides,whereas cow’s milk contains only0.03–0.06g/l(Kunz and Rudloff1993).These oligosaccharides stimulate the growth of bifidobacteria and recent genomic analysis of a number of B.longum strains has revealed their specialization in the utilization of this source on nutrients and high level of adaptation to the infant gut(Schell et al.2002;Sela et al.2008;Zivkovic et al. 2011).The traditional view that the microbiota of breast-fed infants is predomi-nated by bifidobactera still seems valid.Although some studies have not found significant differences in the bifidobacterial counts between BF and FF infants,the326J.Cheng et al. latter seem to be more frequently colonized also with other bacterial groups and harbor them in higher numbers(Adlerberth and Wold2009;Fallani et al.2010). Thus,the FF infants generally have a more mixed-type microbiota.The product development of infant formulas has improved their composition and subsequently narrowed the microbiota differences between BF and FF infants(Rinne et al.2005; Penders et al.2006;van der Aa et al.2010).However,a recent study showed that BF infants have a more complex Bifidobacterium microbiota in terms of species and strain diversity as compared to FF infants(Roger et al.2010).While breast milk stimulates the growth of bifidobacteria it also serves as a source of living bacteria,including bifidobacteria,to the infant gut(Martín et al.2003,2009; Grönlund et al.2007;Perez et al.2007).The common infant species of bifido-bacteria include B.breve,B.bifidum,B.longum and B.longum subsp.infantis (Satokari et al.2002).Further,BF is recognized to reduce the risk of not only GI tract infections(diarrhea,necrotizing enterocolitis)but also other infections such as otitis media and respiratory and urinary tract infections in infants(Hanson et al. 2002).The action of human breast milk is mediated via several mechanisms, which include providing support to the infant0s immune system,stimulation of potentially protective gut microbes(bifidobacteria)and binding of milk oligo-saccharides to pathogens and thus preventing infections i.e.acting as receptor analogs(Hanson et al.2002).During thefirst months and year of life individual-specific temporal patterns of bacterial colonization can be seen(Palmer et al.2007).After weaning and intro-duction of solid foods the infantile microbial population gradually starts to diversify and convert to an adult-type microbiota(Palmer et al.2007).It has been generally considered that by the age of1–2years of age the microbiota starts to resemble that of an adult(Mackie et al.1999),but the actual age of microbiota stabilization has not been addressed adequately in long-term studies.Shkoporov et al.investigated fecal bifidobacteria in eight children when they were1and 6years old and demonstrated a shift in the Bifidobacterium population from an infantile species profile to an adult-type species profile,but the actual turning point remained unspecified(Shkoporov et al.2008).Our high-throughput microbiota profiling studies of infant microbiota by using the bacterial phylogenetic micro-array HITChip(Rajilic´-Stojanovic´et al.2009)have shown that at the age of 1.5years the microbiota diversity is still much lower than in adults,although all major bacterial groups are already present(Nylund et al.in preparation).1.2The Normal Microbiota in AdultsThe complex microbial community of an adult individual typically consists of hundreds of species,but in some individuals the species richness may account in thousands(Eckburg et al.2005;Tap et al.2009).The estimates of the full microbial richness in the human population vary from several thousands up to40,000spe-cies or phylotypes(Eckburg et al.2005;Frank et al.2007;Tap et al.2009).However,only approximately 1,000can be considered as abundantly present species (Qin et al.2010).In contrast to the enormous species diversity,the mic-robiota is dominated by very few phyla,the major ones being Firmicutes and Bacteroidetes,which typically constitute 60–80and 15–30%of the total bacteria,respectively (Eckburg et al.2005;Ley et al.2006;Frank et al.2007;Andersson et al.2008;Tap et al.2009).The phylum Actinobacteria have a share of 2–10%or even as high as 25%,while Proteobacteria and Verrumicrobia typically represent only 1–2%or less of the total microbiota (Andersson et al.2008;Krogius-Kurikka et al.2009;Tap et al.2009;Jalanka-Tuovinen et al.2011).According to a cross-European cohort study of 91individuals the major bacterial groups or genera in the gut are Eubacterium rectale -Clostridium coccoides (28%),Clostridium leptum (25.2%),Bacteroides (8.5%),Bifidobacterium (4.4%),Atopobium (3.1%)and Lactobacillus -Enterococcus (1.3%)(Lay et al.2005).The measurement was based on fluorescent in situ hybridization with specific 16S rRNA probes and flow cytometric counting of cells and thus,the quantification can be considered highly reliable.In this study,only a limited impact of the geographic location (country)on the microbiota composition was observed (Lay et al.2005).The phyla to which these groups belong to are presented in Fig.1.There have been attempts to define a common core microbiota among people i.e.microbial phylotypes that we all share.In a recent metagenomic microbiota • Ruminococcus torques and R. gnavus• Clostridium cluster IV (includes the group C. leptum):• Faecalibacterium prausnitzii• Bacilli: Lactobacillus-EnterococcusBacteroidetes (15-30%)• Bacteroides• PrevotellaProteobacteria (1-2 %)• EnterobacteriaceaeFusobacteriaEukarya• FungiVerrucomicrobia (1-2 %)• Akkermanciamuciniphila Actinobacteria (2-25%)• Bifidobacterium (up to 60-90% in BF infants)•AtopobiumSpirochaetesArchaea• methanogensContribution of the Intestinal Microbiota to Human Health 327328J.Cheng et al. analysis of142individuals from Europe it was constituted that each individual carries at least160phylotypes(species),which are largely shared with other people and that57phylotypes can be found in more than90%of individuals(Qin et al.2010).The number of detected phylotypes is strongly dependent on the analysis depth and therefore the estimates on the phylogenic core still vary con-siderably(Tap et al.2009;Turnbaugh et al.2009;Qin et al.2010;Jalanka-Tuovinen et al.2011).Thus,the more detailed composition of the normal mic-robiota still remains undefined,but nevertheless several important features of the so-called normal microbiota have been established.In healthy adults the bacterial profiles of the total gut microbiota are characterized by individual-specificity and relative temporal stability(Zoetendal et al.1998;Rajilic´-Stojanovic´et al.2009; Jalanka-Tuovinen et al.2011).Further,different bacterial groups such as Actinobacteria,including bifidobacteria and Clostridium cluster XIVa,and the Eubacterium rectale-Clostridium coccoides group have also shown remarkable stability in healthy adults(Satokari et al.2001a,b;Maukonen et al.2006;Rajilic´-Stojanovic´et al.2009),but there may be large variation in the temporal behavior of different bacterial groups between individuals(Jalanka-Tuovinen et al.2011).1.3Microbiota in the Old AgeWhen we age,our microbiota also‘‘ages’’i.e.age-related changes of microbiota occur.Naturally,the basis for the microbiota in old age is the individual-specific microbiota during adulthood and it has been demonstrated that among the elderly each individual has a unique microbial profile(Claesson et al.2010).Despite the interindividual variation in microbiota composition,some general trends of the age-related changes of microbiota can be seen,although the age-related changes may be partly country-and population-specific.Recent high-throughput microbiota analysis studies have shown an increase in the ratio of Bacteroidetes to Firmicutes related to aging.However,while Biagi et al.(2010)reported the relative decrease in Firmicutes and no change in the Bacteroidetes,Claesson et al.(2010)noticed also a significant increase in Bacteroidetes.Earlier culture-based and lower-resolution molecular studies have shown discrepancy in the results concerning the genus Bacteroides(Woodmansey et al.2004;Zwielehner et al.2009).Within the Firmicutes phylum Clostridium cluster XIVa has been found to decrease in the elderly(Biagi et al.2010;Claesson et al.2010)and the proportion of Clostridium cluster IV of the total microbiota either to increase,decrease or remain unaltered (Zwielehner et al.2009;Biagi et al.2010;Claesson et al.2010).Interestingly, Biagi et al.(2010)found that Clostridium cluster IV was subject to compositional rearrangement in the centenarians,although no quantitative cluster-level changes were observed.Within this group of bacteria a significant reduction was observed in Faecalibacterium prausnitzii,a species with anti-inflammatory properties in the centenarians(Biagi et al.2010).On the other hand,the centenarians had a more than tenfold increase in Eubacterium limosum(Clostridium cluster XV),Contribution of the Intestinal Microbiota to Human Health329 also a species with anti-inflammatory activity,which may have contributed as a balancing factor in the aged intestine(Biagi et al.2010).A constantfinding in the elderly is that the proportion of facultative anaerobic bacteria increases(Woodmansey et al.2004;Tiihonen et al.2008;Biagi et al.2010; Claesson et al.2010).Particularly the increase in Proteobacteria,a group containing many opportunistic pathogens,may affect the health significantly.In a recent study, the increased proportion of Proteobacteria was positively correlated with the increased inflammatory status in centenarians(Biagi et al.2010).In another study, numbers of Enterobacteriaceae,a family which belongs to Proteobacteria,were found to be higher in elderly with high frailty scores as compared to less frail elderly(van Tongeren et al.2005).The age-related microbiota alterations may either contribute to the inflammatory status or be a consequence of the compro-mised immunity in the old age.Another group of bacteria that seems to be con-sistently altered in the aged people in most human populations studied is bifidobacteria.Decreased counts of bifidobacteria in the elderly have been reported frequently from both cultivation-based and molecular studies(Woodmansey et al. 2004;Mueller et al.2006;Zwielehner et al.2009;Biagi et al.2010).Reduced diversity and compromised stability of the total bacterial population have been observed in the elderly and extremely old people(Rajilic´-Stojanovic´et al.2009; Zwielehner et al.2009;Biagi et al.2010).Also the compositional profiles of bifidobacteria appeared to be less stable in elderly subjects as compared to healthy adults(Rajilic´-Stojanovic´et al.2009;Claesson et al.2010).The reduced stability and decrease in bifidobacteria together with the use of antibiotics are considered as main factors of the increased susceptibility of elderly to GI tract infections.Taken together,while age-related microbiota changes are generally seen when elderly people are compared to young adults from the same country or region, there are significant country-specific differences in the bacterial groups that have found to differ and also at what age the microbiota changes start to take place (Mueller et al.2006;Biagi et al.2010).For example,in the recent study by Biagi et al.(2010)no microbiota changes were observed in an Italian population when young adults and old people with mean age of73years and no recent use of antibiotics were compared,but significant changes were found between cente-narians and these two groups.In contrast,in the Claesson et al.(2010)study the Irish elderly subjects who had an average age of77years and no recent use of antibiotics showed significant differences in their microbiota composition as compared to young controls.This emphasizes the need of baseline studies on the effect of aging on microbiota in defined populations and community settings.2Microbial Disbalance and HealthThere is considerable interest in the intestinal microbiota in health and disease as it may provide functional biomarkers,the possibility to differentiate subjects and avenues for interventions.The used approaches build on high-throughput and othermolecular approaches to determine the microbiota and its function that are used to compare and contrast intestinal samples from healthy and compromised subjects (Zoetendal et al.2008).One of the strongest disturbing factors for intestinal microbiota is the use of antibiotics.In healthy adults the microbiota composition may be restored in a relatively short period of time after the antibiotic treatment has been stopped (Dethlefsen et al.2008).This points to a certain resilience of the microbial ecosystem as it returns to its original composition (De La Cochetière et al.2005).As a consequence,this does not lead to permanent changes,such as in dysbiosis or imbalance (see below).However,repeated antibiotics treatments may result in incomplete recovery of the microbiota and subsequently permanent changes in its composition (Dethlefsen and Relman 2010).In infants and elderly with a less stable microbiota,the effects can be even more long-term,although they have not been studied systematically.In the elderly,antibiotics seem to fortify the age-related microbiota changes (Bartosch et al.2004;Woodmansey et al.2004;Claesson et al.2010)and increase the risk of GI tract infections including Clostridium difficile infection.When comparing the microbiota in healthy and compromised subjects,the concept of microbial dysbiosis or imbalance is often applied.This relates to the absence of resilience in the microbial ecosystem and results in permanent dis-turbances in the microbiota that contrast with the stability observed in healthy subjects (Zoetendal et al.2008;Jalanka-Tuovinen et al.2011).As the intestinal microbiota is highly subject-specific and complex,our databases are still limited and it is not yet possible to define the microbial imbalance in molecular terms.However,it is expected that the mining of large datasets will be instrumental in this approach,as has recently been shown for the analysis of the microbiota of over 1,000subjects that revealed the presence of networks of specific microbial taxa MicrobialimbalanceMucosal barrier MucosalinflammationGenetic predisposition& Triggering factors(Pathogens, Diet,Environmental changes)330J.Cheng et al.(Nikkiläand De Vos 2010).What has been observed so far is that the microbial imbalance is manifested in a decrease in protective bacteria and this results in a compromised mucosal barrier.This in turn may result in mucosal inflammation as potential pathogenic taxa are exposed that in a healthy intestine are prevented from interacting.This inflammation may in turn affect the microbial composition,leading to a vicious circle (see Fig.2).Support for this series of events,the actual order of which may vary,stems from the observation that in the intestinal microbiota of many compromised subjects there is an increased number of bacteria that are likely to induce inflammation whereas bacterial taxa that are associated with anti-inflammatory properties are reduced.However,the studies conducted so far have generated considerable insight into the role of the intestinal microbiota as will be summarized below for major aberrations such as celiac disease,irritable bowel syndrome,inflammatory bowel disease,obesity and diabetes,and non-alcoholic fatty liver disease (Table 1).2.1Celiac DiseaseCeliac disease (CeD)is a chronic immune-mediated inflammatory disease of the small intestine induced by intolerance to gluten.Active CeD is characterized by mucosal injury with villous atrophy affecting also the nutrient absorption and increased numbers of lymphocytes in the lamina propria (Green and Jabri 2006).CeD occurs in genetically predisposed of all ages with the initial symptoms appearing from infancy (after introduction of gluten-containing food)to old age.Typical symptoms of CeD include malabsorption or even malnutrion in severe cases as well as other gastrointestinal disorders.Moreover,extra-intestinal symptoms such as dermatitis herpetiformis (skin rash)may also occur.Individuals who carry the alleles HLA-DQ2or HLA-DQ8have a heightened risk of devel-oping the disease,but only part of them eventually get CeD indicating that yet unknown genetic factors and/or environmental factors are important in the path-ogenesis (Trynka et al.2010).Table 1Potential biomarkers of GI microbiota in health and diseaseDisease Association with disease Association with health Irritable bowel syndromeR .torque like species Bifidobacteria Inflammatory bowel diseaseR .gnavus ,R .torque F .prausnitzii ,A .muciniphila Celiac disease–Bifidobacteria Metabolic syndrome-related diseases a Bacteroidetes/Firmicutes ratioR =RuminococcusF =FaecelibacteriumA =Akkermansia-indicates that no clear association has been reported a Obesity,T1D,T2D and NAFLDContribution of the Intestinal Microbiota to Human Health331332J.Cheng et al.Commensal microbiota is considered to be an important factor affecting the homeostasis of the gut epithelium and therefore,it has been suggested that altera-tions in the intestinal microbiota could play a role in the onset of celiac disease. Herein we discuss the possible role of intestinal microbiota in the onset of celiac disease in the light of results from pediatric CeD patients.Several research groups have addressed this question by comparing the microbiota composition of pediatric CeD patients and healthy controls by using both fecal and biopsy samples.While increased bacterial diversity and changes in several bacterial groups in the micro-biota of Spanish pediatric CeD patients have been reported in several studies(Nadal et al.2007;Sanz et al.2007;Collado et al.2009;De Palma et al.2010),recent Scandinavian studies have failed to show major microbiota differences between children with and without CeD(Ou et al.2009;Kalliomäki et al.2011).However, duodenal biopsies from CeD patients born during the Swedish CeD epidemic were enriched with rod-shaped bacteria(Ou et al.2009)and in the Finnish subjects different duodenal expression of Toll-like receptors(TLRs)and their inhibitor was found(Kalliomäki et al.2011).Thus,these studies also indicated a possible asso-ciation of microbiota with the disease.Also Italian pediatric CeD patients showed increased bacterial diversity of duodenal biopsies(Schippa et al.2010).The found microbiota changes may be either primary and contribute to the pathology of CeD or be a consequence of the disease.It has to be taken into account that CeD profoundly affects the morphology,physiology and immunology of the small intestinal epithelium,which thereby represents a completely different eco-logical niche for bacteria as compared to the normal healthy mucosa.On the other hand,a recent study showed that carriers of another genetic risk factor of CeD,a risk allele of SH2B3,have stronger activation of the Nucleotide-binding oligo-merization domain containing2(NOD2)recognition pathway,which is important in bacterial pathogen recognition(Zhernakova et al.2010).The combination of enhanced response to bacterial ligands and certain microbiota composition may create an immunological environment that can trigger the development of this immune-mediated disease.In this respect viral agents should also be taken into consideration(Plot and Amital2009).Indirectly,the role of microbiota is supported by thefinding that CeD children are more likely to have been born by cesarean section(Decker et al.2010),which in turn is known to cause altered microbiota colonization process during infancy.The idea of microbes being involved in the etiology is also supported by the association found between infantile infections and the risk of developing celiac disease(Sandberg-Bennich et al.2002)and thus, further studies are warranted to study the role of microbiota in CeD.2.2Irritable Bowel SyndromeIrritable bowel syndrome(IBS)refers to a common disorder characterized by gastrointestinal(GI)dysfunction.It is not known exactly what causes IBS,but its incidence could be associated with visceral hypersensitivity,aberrant gut motilityand autonomous nervous system malfunction.The interactions of these etiological factors make bowel susceptible to some risk and other factors like GI microbiota, diet,infection,hormones,or stress.In general,IBS can occur at any age,but it often begins in adolescence or early adulthood.In addition,studies show that IBS is more commonly developed in women and people who have a family history of this syndrome(Longstreth et al.2006;Talley2007).Generally,IBS is characterized by chronic abdominal pain,discomfort,bloating gas as well as changes in bowel movements.Moreover,IBS patients may have complication of constipation or diarrhea,or switch between both.The above-mentioned symptoms vary from person to person,ranging from mild to severe,but most patients have mild symptoms.Unlike more serious intestinal disease such as IBD,IBS does not cause changes in bowel tissue or increase risk of colorectal cancer,but low-level inflammation has also been observed in IBS subjects (Salonen et al.2010).According to the stool frequency,form and defaecatory symptoms,described in Rome II criteria(Drossman2000),IBS can be subdivided into several subtypes.They are diarrhea predominant(IBS-D),constipation pre-dominant(IBS-C)and mixed subtype(IBS-M).Recently,Rome III criteria have also been described(Longstreth et al.2006).Although the pathophysiology of IBS is not well determined,GI tract microbiota is suggested to be critical due to their factorial roles in IBS,as described in the following.First,with culture-based methods some species-level differences have been found in earlier studies.To date,with a variety of molecular methods alterations in the GI microbiota in IBS have also been described.For example, significant differences in the GI microbiota of the different IBS-subgroups and healthy controls(HCs)were recently described based on extensive sequencing of percentage of G+C profiled fecal bacterial DNA sample(Kassinen et al.2007). However,no uniform compositional microbiota alterations have been defined due to the differences in the analytical power and specificity of the study methods used.Salonen et pared eight recent cohort studies,in whichfive studies were done on the same Finnish population.In these studies,the majority of the observed changes in microbial compositions occurred in Firmicutes,which is the largest GI phylum.In addition,genera Streptococcus,Lactobacillus,Veillonella, Bifidobacterium,Clostridium and families Lachnospiraceae and Ruminococcaceae have been identified for accounting for the differences(Salonen et al.2010). Regarding the microbial diversity between each subtype of IBS patients and HCs,the most deviation was found in IBS-D patients,while IBS-C was the least (Rajilic´-Stojanovic´2007;Lyra et al.2009).Generally,the diversity and temporal stability of microbiota is the criteria for defining host-specific microbiota core.As a potential health-beneficial genus, bifidobacteria has been highlighted in several IBS studies.In IBS patients,reduced counts of bifidobacteria have been observed(Kerckhoffs et al.2009;Malinen et al. 2005).Interestingly,in healthy individuals low counts of bifidobacteria was reported in the subjects suffering from abdominal pain as compared to the ones without pain(Jalanka-Tuovinen et al.2011).。
Frequentist Interpretation of Probability
basis the data can then be used to select d so as to obtain a desirable balance between these two aspects. Criteria for selecting d(and making analogous choices within a family of proposed models in other problems) have been developed by Akaike,Mallows,Schwarz, and others(for more details,see,for example,Linhart and Zucchini1986):Bayesian solutions to this problem differ in a number of ways,reflecting whether we assume that the true model belongs to the hypothesized class of models (e.g.,is really a polynomial)or can merely be approxi-mated arbitrarily closely by such models.For more on this topic see Shao(1997).See also:Estimation:Point and Interval;Robustness in Statistics.BibliographyBickel P,Doksum K2000Mathematical Statistics,2nd edn. Prentice Hall,New York,Vol.1Blackwell D,Dubins L1962Merging of opinions with increasing information.Annals of Mathematical Statistics33:882–6 Ferguson T S1996A Course in Large Sample Theory.Chapman &Hall,LondonFisher R A1922On the mathematical foundations of theoretical statistics.Philosophical Transactions of the Royal Society of London,Series A222:309–68Fisher R A1973Statistical Methods and Scientific Inference,3rd edn.Hafner Press,New YorkGauss C F1809Theoria Motus Corporum Celestium.Perthes, Hamburg,GermanyGirshick M A,Savage L J1951Bayes and Minimax Estimates for Quadratic Loss Functions.Proceedings of the2nd Berkeley Symposium of Mathematics,Statistics,and Probability.Uni-versity of California Press,Berkeley,CAHampel F,Ronchetti E,Rousseeuw P,Stahel W1986Robust Statistics.Wiley,New YorkJeffreys H1939Theory of Probability.Clarendon Press,Oxford, UKKeynes J M1921A Treatise on Probability.Macmillan,London LeCam L1990Maximum likelihood:An introduction.Inter-national Statistical Re iew58:153–71Lehmann E L1986Testing Statistical Hypotheses,2nd edn. Springer,New YorkLehmann E L,Casella G1998Theory of Point Estimation,2nd edn.Springer,New YorkLinhart H,Zucchini W1986Model Selection.Wiley,New York Neyman J1937Outline of a theory of statistical estimation based on the classical theory of probability.Philosophical Transactions of the Royal Society Series A236:333–80 Neyman J1961Silver Jubilee of my dispute with Fisher.Journal of the Operations Research Society of Japan3:145–54 Neyman J,Pearson E S1933On the problem of the most efficient tests of statistical hypothesis.Philosophical Transac-tions of the Royal Society Series A231:289–337Shao J1997An asymptotic theory for linear model selection (with discussion).Statistica Sinica7:221–66Staudte R G,Sheather S J1990Robust Estimation and Testing. Wiley,New YorkStein C1956Inadmissibility of the usual estimator for the mean of a multivariate distribution.Proceedings of the3rd BerkeleySymposium of Mathematics,Statistics,and Probability.Uni-versity of California Press,Vol.1,pp.187–95Tukey J W1960Conclusions versus decisions.Technology2: 423–33von Mises R1928Wahrscheinlichkeit,Statistik and Wahrheit. Springer,Wien,AustriaWald A1950Statistical Decision Functions.Wiley,New York Wilson E B1952An Introduction to Scientific Research.McGraw Hill,New YorkP.J.Bickel and E.L.LehmannFrequentist Interpretation of ProbabilityIf the outcome of an event is observed in a large number of independent repetitions of the event under roughly the same conditions,then it is a fact of the real world that the frequency of the outcome stabilizes as the number of repetitions increases.If another long sequence of such events is observed,the frequency of the outcome will typically be approximately the same as it was in thefirst sequence.Unfortunately,the real world is not very tidy.For this reason it was necessary in the above statement to insert several weasel words.The use of‘roughly the same,’‘typically,’‘approximately,’and‘long sequence’make it clear that the stability phenomenon being described cannot be stated very precisely.A much clearer statement is possible within a mathematical model of this phenomenon.This discovery is due to Jacob Bernoulli who raised the following question. It is well known,Bernoulli says in Part IV of his book Ars Conjectandi(published posthumously in 1713),that the degree to which the frequency of an observed event varies about the probability of the event decreases as the number of events increases.He goes on to say that an important question that has never been asked before concerns the behavior of this variability as the number n of events increases indefi-nitely.He envisages two possibilities.(a)As n gets larger and larger,the variability eventually shrinks to zero,so that for sufficiently large n the frequency will essentially pinpoint the probability p of the outcome.(b)Alternatively,it is conceivable that there is a positive lower bound below which the vari ability can never fall so that p will always be surrounded by a cloud of uncertainty,no matter how large a number of events we observe.Bernoulli then proceeds to prove the law of large numbers,which shows that it is(a)rather than(b)that pertains.More precisely,he proves that for any a 0Pr)X n k p) a 1as n _(1)5796Frequentist Inferencewhere X\n is the frequency under consideration.It is easy to be misled into the belief that this theorem proves something about the behavior of frequencies in the real world.It does not.The result is only concerned with properties of the mathematical model.What it does show is that the behavior of frequencies in the model is mirrored in a way that is much neater and more precise,the very imprecise stability phenomenon stated in thefirst paragraph of this article.In fact,a result for the model much more precise than(1)was obtained by De Moivre(1733).It gives the normal approximationPr)X n k p) c\N n &c/N pq−c/N pq (x)d x(2)where denotes the standard normal density.This is again a theorem in the model.The approximate corresponding real-world phenomenon can be seen, for example,by observing a quincunx,a mechanical device using balls falling through‘random’paths to generate a histogram.De Moivre’s result was given a far reaching generali-zation by Laplace(1810)in the central limit theorem (CLT)concerning the behavior of the average X of n identically,independently distributed random variable X",…,X n with meanξandfinite varianceσ#.It shows thatPr Q X kξQ c\N n &c/σ−c/σ (x)d x.(3)This reduces to(2)when X takes on the values of1and 0with probabilities p and q,respectively.The CLT formed the basis of most frequentist inference throughout the nineteenth century.Thefirst systematic discussion of the frequentist approach was given by Venn(1866),and an axiomati-zation based on frequencies in infinite random se-quences(Kollecti es)was attempted by von Mises (1928).Because of technical difficulties his concept of a random sequence was modified by Solomonoff(1964),Martin-Lo f(1966),and Kolmogorov(1968), with the introduction of computational complexity. (An entirely different axiomatization based on events and their probabilities rather than random sequences was put forward by Kolmogorov in1933,and has successfully served as a basis for both frequentist and subjective interpretations of probability).For more details on these different approaches see Barnett (1982).The frequentist concept of probability described so far has met considerable criticism.One of the main objections is that it is not applicable to many situations to which one might want to apply probability assess-ments.To see this,consider the following three possibilities.(a)An actual sequence of repetitions may be available;for example,a sequence of coin tosses or a sequence of independent measurements of the same quantity.(b)A sequence of repetitions may be available in principle but not likely to be carried out in practice;for example,the polio experiment of1954involving a sample of over a million children.(c)A unique event which by its very nature can never be replicated,such as the outcome of a particular historical event;for example,whether a particular president will survive an impeachment trial.The conditions of this experiment cannot be duplicated. The frequentist concept of probability can be applied in cases(a)and(b)but not in the third situation.An alternative approach to probability which is applicable in all cases is the notion of probability as degree of belief;i.e.,of a state of mind (for a discussion of this approach,see Robert(1994)). The inference methods based on these two interpreta-tions of the meaning of probability are called fre-quentist and Bayesian,respectively.Although frequentist probability is considered ob-jective,it has the following subjective feature.Its impact on a particular person will differ from one person to another.One patient facing a surgical procedure with a1percent mortality rate will consider this a dire prospect and emphasize the possibility of a fatal outcome.Another will shrug it offas so rare as not to be worth worrying about.There exists a class of situations in which both approaches will lead to the same probability assess-ment.Suppose there is complete symmetry between the various outcomes;for example,in random sam-pling which is performed so that the drawing favors no sample over another.Then we expect the frequencies of the various outcomes to be roughly the same and will also,in our beliefs,assign the same probability to each of them.Let us now turn to a second criticism of frequentist probability.This concerns the difficulty of specifying what is meant by a repetition in thefirst sentence of this section.Consider once more the surgical pro-cedure with1percent fatalities.Thisfigure may represent the experience of thousands of cases,with the operation performed by different surgeons in different hospitals and—of course—on different pat-ients.The rate of fatalities may vary from one hospital or surgeon to another and may,in particular,vary drastically with the condition,for example,the age and general health,of the patient.Suppose a young woman requires this operation although her general health is very good.The fre-quency of a fatal outcome with patients sharing these characteristics may be much lower,and the1percent figure in that sense would be quite misleading for her. And yet she might be considered to have been obtained under‘roughly the same conditions,’namely to be drawn at random from the total population of persons5797Frequentist Interpretation of Probabilityrequiring this surgery.To obtain the most useful figures one should identify the most important vari-ables,classify the cases accordingly(for example, young,middle-aged,old;male,female;etc.)and then provide the frequency for each class.They will,of course,be meaningful only for the classes which contain a reasonable number of cases.1.A Terminology NoteA source of much confusion in the discussion of probability is the fact that‘probability’is used both as a mathematical term,i.e.,as a concept in the math-ematical model and also in everyday language when talking about real events.When reading about prob-ability,it is important to be aware of these two meanings and to keep them distinct.See also:Frequentist Inference;Probability:Formal; Probability:Interpretations;Statistical Methods, History of:Post-1900;Statistical Methods,History of: Pre-1900BibliographyBarnett V1982Comparati e Statistical Inference,2nd edn. Wiley,New YorkDe Moivre A17331738,1756.In:Doctrine of Chance,Millar, London,Reprinted by Chelsea Publishers,New York(1967), pp.235–43(1738),243–54(1754)1878–1912Kolmogorov A1933Grundbegriffe der Wahrscheinlichkeits-rechnung.Ergebnisse der Mathematik,Vol.2.Springer,Berlin Kolmogorov A1968Logical basis for information theory and probability theory.IEEE Transactions on Information Theory 14:662–4Laplace P S Oe res comple tes de Laplace.Gauthier-Villars, ParisMartin-Lo f P1966The definition of random sequences.In-formation and Control9:602–19Robert C P1994The Bayesian Choice.Springer,New York SolomonoffR J1964The formal theory of inductive inference. Information and Control7:224–54Venn J1866The Logic of Change.Reprinted by Chelsea Publishers,New York,(1967)von Mises R1957Probability,Statistics and Truth.Macmillan, New YorkP.J.Bickel and E.L.Lehmann Freud,Sigmund(1856–1939)1.Family Background and Early LifeSigmund Freud,neuroscientist turned founder of psychoanalysis,was born on May6,1856,in Freiberg, Moravia,now part of the Czech Republic.His father,Jakob(1815–96),a wool merchant,came from Galicia, and married Amalie(1835–1930,nee Nathansohn),20 years younger,when he was40.Jakob had two sons by a previous marriage,Emanuel and Philipp.Jakob was warm and affectionate,with a strong sense of humor, and Freud evidently admired and respected him. Amalie was a lively and attractive woman who was proud of Sigmund,herfirst-born.The family multiplied quickly:five daughters and two more sons were born within10years.Thefirst of these,Julius,died when8months old and Sigmund was aged19months.Both parents were Jews,with no religious affiliations,though a devout Catholic Nanny took Sigmund to Church.She left when he was two and a half.A nephew,John,a year older than Freud was very close to him:the two fought and played together.That childhood ambivalence,Freud reflected years later,must have had a profound effect on his character and on his ability to defend himself(Freud 1900).Financially,times were hard.In1859the family moved to Leipzig,and in the following year to Vienna. Freud missed the beauty of the countryside round Freiberg.Although the children were well looked after,poverty was not assuaged by rapid family growth.By1875family fortunes improved:Amelie’s family were helping,making possible a move to a larger house.Freud had a room of his own that served as a study.Freud’s memories of his childhood as revealed in his writings are without early detail,but one unforgettable recollection was of urinating in his parents’bedroom while they were present.Reprimanding him,his father said bluntly:‘The boy will come to nothing!’Freud’s wounded ambitions were reflected recurrently in dreams in which he listed his achievements as if to say:‘You see!I have come to something!’(Freud1900;see also Shengold1993).cation and Early InterestsFreud’s schooling began with his mother,until his father took over before sending him to a private school.Freud learned rapidly,and was reading Shakespeare(whom he loved all his life)from the age of eight years.When nine years of age,he won a place at the Sperl Gymnasium,where he was a distinguished pupil,passing out,at17,with the distinction‘summa cum laude.’He became an accomplished linguist,with afirm foundation in Latin and Greek,a sound knowledge of Hebrew,fluency in English and French, and good Italian.He corresponded with an adolescent friend in Spanish.He became one of the greatest stylists in the German language(Kaufmann1980).He studied at every opportunity.He loved the Arts,but took an early dislike to music,which he never felt able to appreciate.He was fond of walking,swimming,and skating.He liked travel,and made hisfirst visit to England at the age of19.5798Frequentist Interpretation of ProbabilityCopyright#2001Elsevier Science Ltd.All rights reserved.International Encyclopedia of the Social&Behavioral Sciences ISBN:0-08-043076-7。
变时滞随机Lotka-Volterra_生物模型的渐近性质
第 42 卷第 3 期2023年 5 月Vol.42 No.3May 2023中南民族大学学报(自然科学版)Journal of South-Central Minzu University(Natural Science Edition)变时滞随机Lotka-Volterra生物模型的渐近性质胡军浩,王朝航*(中南民族大学数学与统计学学院,武汉430074)摘要研究了变时滞随机Lotka-Volterra (LV)生物模型,其中变时滞函数是不可微的,放宽了现有文献变时滞是可微且导数小于1的假设. 使用Ito公式和线性矩阵不等式(LMI)研究了这类生物模型全局正解的存在性和唯一性,并进一步给出了其正解渐近有界、时间均值意义下矩有界和多项式增长的充分条件. 最后给出实例验证了结论的有效性.关键词随机生物模型;Lotka-Volterra生物模型;不可微时滞函数;LMI不等式;渐近有界性中图分类号O241.8 文献标志码 A 文章编号1672-4321(2023)03-0402-06doi:10.20056/ki.ZNMDZK.20230316Asymptotic properties of the stochastic Lotka-Volterra system withvariable time delayHU Junhao,WANG Zhaohang*(College of Mathematics and Statistics, South-Central Minzu University, Wuhan 430074, China)Abstract This paper is concerned with stochastic Lotka-Volterra (LV) system with variable time delay. Comparing with most existing papers,the time delay functions in the LV system are no longer required to be differentiable,their derivatives are less than 1 is not to be mentioned. The existence and uniqueness of the global positive solutions of this system are investigated by using Ito formula and linear matrix inequality (LMI). Further,sufficient conditions are also obtained for the asymptotic boundedness,time average moment boundedness and the polynomial pathwise growth of the positive solution. Finally, an example is given to illustrate the effectiveness of the results.Keywords stochastic biological model; Lotka-Volterra system; non-differentiable time delay function; LMI inequality;asymptotic boundedness1 模型介绍本文考虑如下形式的变时滞随机Lotka-Volterra 系统:d x(t)=diag(x(t)){[a+Ax(t)+By(t)]d t+[b+Dx(t)+Ey(t)]dω(t)},(1)其中x(t),y(t)=x(t-δ(t))∈R n分别表示种群和变时滞种群,δ(t)表示变时滞函数.diag(x)= diag(x1,⋯,x n)表示n×n阶对角矩阵. a,b∈R n,矩阵A=[a ij],B=[b ij],D=[d ij],E=[e ij]∈R n×n. 记f(x,y)=a+Ax+By,g(x,y)=b+Dx+Ey.过去几十年,Lotka-Volterra (LV)生物模型受到了越来越多学者的关注[1-2]. 生物模型经常受到噪音因素的影响,用随机微分方程(SDE)来描述这类生物模型更具现实意义. NIE和MEI[3]研究了白噪声与时滞对LV生物模型的影响,证明了白噪声和时滞完全抑制了LV生物模型种群的爆破. LI和MAO[4]进一步研究了非自治的LV生物模型在随机扰动下的持久性和非持久性. 文献[5-8]研究了常收稿日期2022-11-07 * 通信作者王朝航,研究方向:随机生物数学,E-mail:****************作者简介胡军浩(1974-),男,教授,博士,研究方向:随机系统理论及应用,E-mail:******************基金项目国家自然科学基金资助项目(61876192);中南民族大学研究生学术创新基金项目(3212023sycxjj003)第 3 期胡军浩,等:变时滞随机Lotka-Volterra生物模型的渐近性质时滞随机LV生物模型正解的存在唯一性及相关性质. HU等[9]研究了变时滞随机LV生物模型的动力学行为,其中变时滞函数导数小于1. 然而,变时滞也可能不可微[10-11],如分段时滞.本文在文献[10-11]此基础上,讨论不可微变时滞随机LV生物模型全局正解的存在性和唯一性及其他渐近性质.2 基本引理设A是一个向量或矩阵,用A T表示它的转置. 若x∈R n,则|x|表示Euclidean范数. 若A是矩阵,则|A|表示其迹范数,即|A|=trace(A T A). 若A是一个实值对称矩阵,用λmin(A)和λmax(A)分别表示其最小和最大的特征值,A≤0和A<0分别表示A半负定和负定. 设a,b是实数,则a∧b=min{a,b},a∨b=max{a,b},a+=a∨0. 令R n+={x∈R n:x i≥0, 1 ≤ i≤ n},Rˉn+= {x∈ R n:x i> 0, 1≤ i≤ n}.设(Ω,F,{F t}t≥0,P)是一个完备的概率空间,其σ代数流{F t}t≥0满足一般条件(即它是单调递增和右连续的,且F0包含所有空集). 对于h>0,用C([-h, 0];R n)表示从[-h,0]映射到R n的连续函数族,其范数为 φ=sup-h≤u≤0|φ(u)|.设ω(t)是定义在概率空间上的一维布朗运动.对任意给定的对称矩阵A∈R n×n,定义:λ+max(A)=sup x∈R n+,||x=1x T Ax,由定义可直接推出,对任意的x∈R n+,有:λ+max(A)≤0⇔x T Ax≤0,x T Ax≤λ+max(A)|x|2.对时滞函数δ(t)提出如下假设:(A1)时滞函数δ(t) :R+→[h1,h]是Borel可测函数且具有以下性质:hˉ:=lim supΔ→0(sup s≥-hμ()M s,ΔΔ)≤∞,其中,h1和h都是正的常数且h1<h,M s,Δ={t∈R+:t-δ(t)∈[s,s+Δ)},μ(⋅)表示R+上的勒贝格测度.下面两个引理起着关键作用.引理1[10-11]假设(A1)成立,设T>0且f:[-h,T-h1]→R+是一个连续函数,则:∫0T f()t-δ()t d t≤hˉ∫-h T-h1f()t d t.注:令f(t)≡1,∀t≥-h,可知hˉ≥1.引理2 (Schur补)[12]对于适当阶数的矩阵S,Q,R,其中Q=Q T,R=R T,以下条件相互等价:(1)éëêêùûúúQ SS T R<0,(2)R<0,Q-SR-1S T<0.3 主要结论定理1 假设(A1)成立,若存在正数γ,η和c1,⋯,cn使得:CˉA+A T Cˉ+4ηhˉI<0,(2)H=éëêêêêêêêêêêêêêêêùûúúúúúúúúúúúúúúúCˉA+A T Cˉ2CˉB A T0D T02B T Cˉ-ηI0B T0E TA0-6γI0000B0-6γI00D000-6Cˉ-100E000-6Cˉ-1≤0,(3)其中Cˉ=diag(c1,⋯,c n),I表示n阶单位矩阵. 则对任意给定的初值ξ∈C([-h,0];Rˉn+),方程(1)存在唯一的全局正解.证明方程(1)的系数局部Lipschitz连续,故对任意给定的初值ξ∈C([-h,0];Rˉn+),方程(1)在t∈[-h,σ∞]上存在唯一的最大的局部正解x(t),其中σ∞表示爆炸时间. 为了证明x(t)是全局的,只需证明σ∞=∞ a.s.设k0是一个充分大的正数满足:1k0<min-h≤t≤0|ξ(t)|≤max-h≤t≤0|ξ(t)|<k0.对每个满足k≥k0的整数k,定义停时:τk=inf{t∈[-h,σ∞):x i∉(1k,k)对某一i=1,⋯,n}.本文总约定inf∅=∞. 显然,当k→∞时,τk是递增的. 设τ∞=lim k→∞τk,则τ∞≤σ∞ a.s.如果τ∞=∞ a.s.,即可以推出σ∞=∞ a.s.且x(t)∈R n+ a.s.对t∈[- h,∞]恒成立. 这也等价于证明,对任意的t>0有P(τk≤t)→0,k→∞. 因此,定义一个C2函数U:R n+→R+:403第 42 卷中南民族大学学报(自然科学版)U (x )=∑i =1n c i (x i -log x i ),其中u (x )=x -log x ≥0对x >0恒成立,且u (0+)=u (∞)=∞. 由Ito公式可得:E U (x (t ∧τk))=U (ξ(0))+E ∫t ∧τk L U ()x ()s ,y ()s d s ,L U 定义为:L U (x ,y )=x T C ˉf (x ,y )-c T f (x ,y )+12||C ˉg (x ,y )||2,其中c =(c 1,⋯,c n )T. 注意到:12|||C ˉg (x ,y )|||2≤32(b T C ˉb +x T D T C ˉDx +y T E T C ˉEy ),(4)且:-c T f (x ,y )≤12γ|c |2+γ2|f (x ,y )|2≤12γ|c |2+3γ2(|a |2+x T A T Ax +y T B T By ).(5)由(4)式和(5)式可知:L U (x ,y )≤c 1+14z T H 1z +a T C ˉx +12x T C ˉAx +η|y |2,其中c 1=12γ|c |2+3γ2|a |2+32b T C ˉb ,z =(x ,y )T 且H 1=éëêêùûúúC ˉA +A T C ˉ+6γA T A +6D T C ˉD 2C ˉB 2B T C ˉ-ηI +6γB T B +6E T C ˉE =éëêêùûúúA T 0D T 00B T 0E T éëêêêêêùûúúúúú6γI6γI6Cˉ6CˉéëêêêêêêêùûúúúúúúúA00B D 00E +éëêêùûúúC ˉA +A T C ˉ2C ˉB 2B T C ˉ-ηI .由引理2可知,H 1≤0⇔H ≤0,故(3)式可得:z TH 1z ≤0,因此:L U (x ,y )≤c 1+a T Cˉx +12x T C ˉAx +η|y |2.(6)由引理1可知:η∫t ∧τk ||y ()s 2d s ≤h ˉη∫-ht ∧τk ||x ()s 2d s ≤hhˉη ξ2+hˉη∫t ∧τk ||x ()s 2d s ,(7)由(6)式和(7)式可得:E U (x (t ∧τk))=U (ξ(0))+E ∫t ∧τk éëêc 2+a T C ˉx (s )+ùûúú14x T(s )()CˉA +A T C ˉ+4ηh ˉI x (s )d s ,其中c 2=hhˉη ξ2+12γ|c |2+3γ2|a |2+32b T C ˉb . 令α=λ+max (C ˉA +A T C ˉ+4ηh ˉI ),由(2)式可知α<0,因此:E U ()x ()t ∧τk=U ()ξ()0+E ∫t ∧τk éëêc 2+a T C ˉx (s )+ùûúú14x T(s )()CˉA +A T C ˉ+4ηh ˉI x (s )d s ≤U ()ξ()0+E éëêêùûúú∫t ∧τkc 2+a T C ˉx (s )+14α||x (s )2d s ≤U ()ξ()0+c 3t ,其中c 3是一个正常数. 由τk 的定义可知,x i (τk )=k 或1k对某个i =1,⋯,n 成立,因此:P ()τk ≤t éëêêùûúúu ()1k ∧u ()k ≤P ()τk ≤t U ()x ()t ∧τk ≤E U ()x ()t ∧τk≤U ()ξ()0+c 3t ,令k →∞可得:lim k →∞P (τk ≤t )=0.证毕.定理2 假设定理1的条件成立,x (t )是方程(1)具有初值ξ∈C ([-h ,0];R ˉn +)的正解,则x (t )有如下性质:lim sup t →∞E |x (t)|≤∞,lim sup t →∞1t ∫0tE ||x ()t 2≤∞.证明 定义一个C 2函数V :R n +→R +:V (x )=∑i =1n c i x i ,由Ito 公式可得:e εt E V (x (t))=V (ξ(0))+E ∫0t e εs []L V ()x ()s ,y ()s +εV ()x ()s d s ,其中ε是一个充分小的正数使得:C ˉA +A T C ˉ+4ηh ˉe εh I <0,L V 定义为:L V (x ,y )=x T C ˉf (x ,y )≤14z T H 2z +a T Cˉx +12x T C ˉAx +η|y |2,(8)其中:404第 3 期胡军浩,等:变时滞随机Lotka -Volterra 生物模型的渐近性质H 2=éëêêùûúúC ˉA +A T C ˉ2C ˉB 2B T C ˉ-ηI ,由H ≤0可以推出H 2≤0,因此:L V (x ,y )+εV (x )≤+a T Cˉx +12x T C ˉAx +η|y |2+εc T x ,(9)由引理1可知:η∫0te εs||y ()s 2d s ≤ηe εh∫0te ε()s -δ()s||x ()s -δ()s 2d s ≤hh ˉηe εhξ2+h ˉηe εh∫0te εs||x ()s 2d s ,(10)由(9)式和(10)式可知:e εt E V ()x ()t ≤V ()ξ()0+hhˉηe εhξ2+E∫0te εs éëêê()a T C ˉ+εc T x ()s +14x T ()s (C ˉA +A T C ˉ+])4hˉηe εh I x ()s d s ≤V ()ξ()0+hh ˉηe εh ξ2+c 4∫t e εs d s ,其中c 4是一个正常数. 立得:lim sup t →∞E |x (t)|≤∞,又由Ito 公式可得:E V (x (t))=V (ξ(0))+E ∫0t L V ()x ()s ,y ()s d s ,由(7)式和(8)式可得:E V (x (t))+ε1E ∫0t|x (s )|2d s ≤V (ξ(0))+hhˉη ξ2+E éëêa TC ˉx ()s +ùûúú14x T()s ()CˉA +A T C ˉ+4()h ˉη+ε1I x ()s d s ≤V (ξ(0))+hhˉη ξ2+c 5t ,其中c 5是一个正常数,ε1是一个充分小的正数使得:CˉA +A T C ˉ+4(h ˉη+ε1)I <0,因此:lim supt →∞1t ∫t E ||x ()t2≤∞.证毕.定理3 假设定理1的条件成立. 若存在非负常数q 和r 使得以下条件成立:H 3=éëêêêêêùûúúúúúCˉA +A T C ˉC ˉB c 0B T C ˉ00c c T001r0c T 1r 2q r 2≤0,(11)q >rhˉ,(12)则方程(1)具有初值ξ∈C ([-h ,0];Rˉn +)的正解x (t )有如下性质:lim supt →∞log ||x ()tlog t≤1 a.s.证明 定义一个C 2函数V :R n+→R +:W (x )=log (c T x ),由Ito公式可得:e ε2t W (x (t))=W (ξ(0))+M (t )+∫0t e ε2s[]L W ()x ()s ,y ()s +ε2V ()x ()s d s =W (ξ(0))+M (t )+e ε2séëêêJ ()s -12||Z ()s 2+ùûúε2W ()x ()s d s ,其中:0<ε2<1h log(q rhˉ),Z =x T C ˉg c T x ,J =x T Cˉf c T x ,M (t )=∫0t e ε2sZ ()s d ω(s ),对任意给定的θ>1和k ∈N ,由指数鞅不等式可知:P ìíîsup 0≤t ≤k +1éëêêM (t )-12e ε2(k +1)∫0te 2ε2s |Z (s )|2d s ùûúú≥e ε2(k +1)log k θüýþ ≤1kθ ,级数∑k =1∞1kθ≤∞,由Borel -Cantelli 引理,对几乎所有ω∈Ω,当k 充分大且k ≤t ≤k +1时有:M (t )≤12e ε2(k +1)∫0te 2ε2s |Z (s )|2d s +e ε2(k +1)log k θ≤12∫0t e ε2s|Z (s )|2d s +θe ε2e ε2t log t ,因此:e ε2t W (x (t))≤W (ξ(0))+θe ε2eε2tlog t +∫0te ε2s[]J ()s +ε2W ()x ()s d s ,(13)由引理2和(11)式可知:H 4=éëêêùûúúC ˉA +A T C ˉ+2qM C ˉB -rM B T Cˉ-rM 0≤0,其中M =cc T , 因此对任意给定的x ,y ∈R n+有:0≥(x T ,y T )H 4()xy=x T (CˉA +A T C ˉ+2qM )x +2x T (C ˉB -rM )y =2x T(CˉAx +C ˉBy )+2q (c Tx )2-2r (c Tx )(c Ty ) ,405第 42 卷中南民族大学学报(自然科学版)即:x T (CˉAx +C ˉBy )≤r (c T x )(c T y )-q (c T x )2,因此:J =x T Cˉ()a +Ax +By c T x≤max i {a i }+rc T y -qc T x ,(14)由(13)式和(14)式可知:e ε2t W (x (t))≤W (ξ(0))+θe ε2e ε2tlog t +∫0t e ε2s[]J +ε2W ()x ()s d s ≤W (ξ(0))+θe ε2e ε2tlog t +e ε2s[max i{}a i+]rc Ty ()s -qc Tx ()s +ε2log ()c Tx d s ,由引理1可知:r∫t e ε2s c Ty (s )d s ≤reε2h∫t e ε2()s -δ()s c T x (s -δ(s))d s ≤rhhˉe ε2h |c | ξ+rh ˉe ε2h ∫0t eε2s c Tx (s )d s ,因此:e ε2tW (x (t))≤W (ξ(0))+θeε2e ε2tlog t +rhh ˉe ε2h |c | ξ+∫0te ε2s[max {aˉi}+(rhˉe ε2h -q )c Tx (s )+ε2log (c Tx )]d s ≤θe ε2e ε2tlog t +c 6(1+e ε2t) ,其中c 6是一个正的常数. 令θ→1,ε2→0,则:lim supt →∞log ||x ()t log t≤1 a.s.证毕.4 实例考虑文献[13]中的二维Lotka -volterra 系统:d x 1(t )x 1(t )=[]-8x 1(t )+x 2(t )-y 1(t )+y 2(t )d t +[]λx1(t )+λx 2(t )+μy 1(t )-μy 2(t )d ω(t ),d x 2(t )x 2(t )=[]x 1(t )-7x 2(t )+y 1(t )-y 2(t )d t +[]λx2(t )-μy 2(t )d ω(t ),其中λ和μ是非负常数,且:δ(t )=[()0.1+0.1()t -2k I [)2k ,2k +1()t +]()0.2-0.1()t -2k -1I [)2k +1,2()k +1()t ,显然,δ(t )满足假设(A1),此时,h 1=0.1,h =0.2,hˉ≈1.1. 令:A =éëêêùûúú-811-7,B =éëêùûú-111-1,D =λéëêùûú1101,E =μéëêùûú1-10-1,令c =(1 , 1)T,γ=130,计算得:A +A T +4ηh ˉI =éëêêùûúú-16+4.4η22-14+4.4η,H 1=éëêêêêêêêùûúúúúúúú-3+6λ2-1+6λ2-22-1+6λ2-4+12λ22-2-22-η+25+6μ2-25-6μ22-2-25-6μ2-η+25+12μ2,H 4=éëêêêêêêêêùûúúúúúúúú2q -162q +2-1-r 1-r 2q +22q -141-r -1-r -1-r 1-r 001-r-1-r0.应用定理1和定理2可得:A +A T +4ηh ˉI <0⇔ìíî-16+4.4η<019.36η2-132η+220>0,即η<又对任意给定的z ∈R 4+,有:z T H 1z =()-3+6λ2z 21+2()-1+6λ2z 1z 2-4z 1z 3+4z 1z 4+()-4+12λ2z22+4z 2z 3-4z 2z 4+()-η+25+6μ2z 23+2()-25-6μ2z 3z 4+()-η+25+12μ2z 24≤()-3+6λ2z 21+()-1+6λ2+()z 21+z 22+2()z 21+z 24+()-4+12λ2z 22+2()z 22+z 23+()-η+25+6μ2z 23+()-η+25+12μ2z 24=[]-1+6λ2+()-1+6λ2+z 21+[]-2+12λ2+()-1+6λ2+z 22+()-η+25+6μ2z 23+()-η+25+12μ2z 24 ,显然,当0≤μ≤η≥125,0≤λ≤时, z T H 1z ≤0,因此H ≤0.即定理1和定理2成立的条件为:406第 3 期胡军浩,等:变时滞随机Lotka -Volterra 生物模型的渐近性质ìíîïïïïïïïï0≤μ≤0≤λ≤125≤η<应用定理3,对任意给定的z ∈R 4+,有:z T H 4z =()2q -16z 21+2()2q +2z 1z 2-2()1+r z 1z 3+2()1-r z 1z 4+()2q -14z22+2()1-r z 2z3-2()1+r z 2z 4≤()2q -16z 21+()2q +2()z 21+z 22+()2q -14z 22+()1-r +()z 21+z 24+()1-r +()z 22+z 23=[]4q -14+()1-r +z 21+[]4q -12+()1-r +z 22+()1-r +()z 23+z 24.显然,当r ≥1,q ≤3时H 4≤0,故H 3≤0. 又由(12)式有q >1.1r ,即定理3成立的条件为:r ≥1,1.1r <q ≤3.注:当δ(t )退化为一个常数,即δ(t )=τ(τ>0), hˉ=1~定理3成立的条件为0≤λ≤0≤μ<r ≥1,r <q ≤3. 此时,文献[9]中的定理7也成立.参 考 文 献[1] WANG Z , BAYLISS A , VOLPERT V. Asymptoticanalysis of the bistable Lotka -Volterra competition -diffusionsystem [J ]. Appl Math Comput , 2022, 432: 127371.[2] WANG H , PAN C , OU C. Propagation dynamics offorced pulsating waves of a time periodic Lotka -Volterra competition system in a shifting habitat [J ]. J Differ Equ , 2022, 340: 359-385.[3] NIE L , MEI D. Noise and time delay : Suppressed populationexplosion of the mutualism system [J ]. Europhysics Letters , 2007, 79(2): 20005.[4] LI X , MAO X. Population dynamical behavior of non -autonomous Lotka -Volterra competitive system withrandom perturbation [J ]. Discrete Contin Dyn Syst , 2009, 24(2): 523.[5] BAHAR A , MAO X. Stochastic delay populationdynamics [J ]. Int J Pure Appl Math , 2004,11: 377-400.[6] MAO X , YUAN C , ZOU J. Stochastic differential delayequations of population dynamics [J ] J Math Anal Appl , 2005, 304(1): 296-320.[7] BAHAR A , MAO X. Stochastic delay Lotka -Volterramodel [J ]. J Math Anal Appl , 2004, 292(2): 364-380.[8] MAO X , MARION G , RENSHAW E. EnvironmentalBrownian noise suppresses explosions in population dynamics [J ]. Stoch Proc Appl , 2002, 97(1): 95-110.[9] HU Y , WU F , HUANG C. Some new results on theLotka -Volterra system with variable delay [J ]. Abstr Appl Anal , 2014,2014: 537674.[10] DONG H , MAO X. Advances in stabilization of highlynonlinear hybrid delay systems [J ] Automatica , 2022, 136: 110086.[11] HU J , MAO W , MAO X. Advances in nonlinear hybridstochastic differential delay equations : existence , boundedness and stability [J ]. Automatica , 2023, 147: 110682.[12] MAO X , YUAN C. Stochastic differential equations withMarkovian switching [M ]. London : Imperial College Press , 2006.(责编 曹东,校对 姚春娜)407。
数理统计mle的英语解释
数理统计mle的英语解释Maximum Likelihood Estimation (MLE) is a fundamental statistical method used for estimating the parameters of a statistical model. It is based on the principle of findingthe parameter values that maximize the likelihood function, which is the probability of observing the given sample data under the model.In the context of MLE, the likelihood function is defined as the joint probability of the observed data given the parameters of the model. The goal is to find the set of parameter values that make the observed data most probable. This is achieved by taking the derivative of the likelihood function with respect to the parameters, setting these derivatives equal to zero, and solving for the parameters.The process of MLE involves the following steps:1. Specify the Model: Choose a statistical model that is appropriate for the data. This could be a normal distribution, a binomial distribution, or any other probabilitydistribution that fits the nature of the data.2. Formulate the Likelihood Function: Write down the likelihood function based on the chosen model. This istypically the product of the probability density functions (for continuous data) or probability mass functions (for discrete data) of the individual observations.3. Differentiate the Likelihood Function: Calculate the first derivative of the likelihood function with respect to each parameter of the model.4. Set Derivatives to Zero: Set each derivative equal to zero to find the critical points. These points are potential candidates for the maximum likelihood estimates.5. Solve for the Parameters: Solve the set of equations obtained from the previous step to find the parameter values that maximize the likelihood function.6. Verify the Maximum: Ensure that the critical points found are indeed maxima, not minima or saddle points, by checking the second derivative or using other methods.MLE has several desirable properties, such as consistency and asymptotic efficiency, which make it a popular choice in statistical inference. However, it is important to note that MLE is based on certain assumptions about the data and the model, and these assumptions should be checked before applying MLE to ensure the validity of the results.。
Understanding the properties of microemulsions
Understanding the properties ofmicroemulsionsMicroemulsions are a type of dispersion system consisting of two immiscible liquids, usually oil and water, stabilized by an emulsifying agent or surfactant. These systems have unique properties that make them useful in a wide range of applications, including pharmaceuticals, cosmetics, and industrial processes.One of the most notable properties of microemulsions is their transparency and stability. Unlike traditional emulsions, which can separate into phases over time, microemulsions remain stable for extended periods of time, making them useful for products where stability is critical.Another property of microemulsions is their ability to solubilize both hydrophobic and hydrophilic compounds. This makes them useful for delivering drugs and other active compounds to their intended targets. For example, microemulsions can be used to deliver topical medications or to create self-emulsifying drug delivery systems for oral administration.Microemulsions also have the ability to reduce interfacial tension between the two immiscible liquids. This makes them useful in industrial processes where emulsification is necessary, such as in the production of food or cosmetics.The droplet size of microemulsions is another important factor in their properties. The small droplet size, typically in the range of 10-100 nanometers, gives microemulsions a large interfacial area, which enhances their solubilizing and emulsifying abilities.The composition of the microemulsion can also play a role in its properties. For example, the type of oil used can affect the size and stability of the droplets. The concentration and type of surfactant used can also affect the properties of the microemulsion.Understanding the properties of microemulsions is important in developing new applications for these systems. Researchers continue to study the properties of microemulsions and develop new formulations for specific applications.In conclusion, microemulsions are a unique type of dispersion system with properties that make them useful in a wide range of applications. Their transparency, stability, solubilizing abilities, and ability to reduce interfacial tension make them valuable in pharmaceuticals, cosmetics, and industrial processes. By understanding the properties of microemulsions, researchers can continue to develop new and innovative applications for these systems.。
On-line learning through simple perceptron with a margin
On-Line Learning with a margin
Abstract We analyze a learning method that uses a margin κ a la Gardner for simple perceptron learning. This method corresponds to the perceptron learning when κ = 0, and to the Hebbian learning when κ → ∞. Nevertheless, we found that the generalization ability of the method was superior to that of the perceptron and the Hebbian methods at an early stage of learning. We analyzed the asymptotic property of the learning curve of this method through computer simulation and found that it was the same as for perceptron learning. We also investigated an adaptive margin control method.
1
Keyword
On-line learning, Margin, Simple perceptron, Generalization ability, Perceptron learning
On-Line Learning with a margin
2
Symbols x: N : B: J: v: ul u: sgn(·) Θ(·) κ: R: l: ǫg : ϕ: A input Dimension of a input Teacher’s weight vector Student’s weight vector Teacher’s total input Student’s total input Normalized student’s total input Sign function Threshold function Margin Overlap between teacher and student weight vectors Student’s weight vector length Generalization error Argument of teacher and student weight vectors
Maximum Likelihood Estimation
The Linear (Normal) Model
Definition of the likelihood function - joint density of the observed data, written as a function of the parameters we wish to estimate.
the MLE.
Efficiency (we have not developed the tools to prove this.) The Cramer-Rao lower bound for efficient estimation (an asymptotic version of Gauss-Markov).
The oft cited disadvantage of their mediocre small sample properties is probably overstated in view of the usual paucity of viable alternatives.
Setting up the MLE
g = [log-L/ , log-L/2]’
= log-L/ = i [(1/2)xi(yi - xi) ] log-L/2 = i [-1/(22) + (yi - xi)2/(24)]
For the linear regression model, the first derivative vector of log-L is
What they mean
Moment conditions and convergence. We need to obtain expectations of derivatives.
Discovery of modulators of HIV-1 infection from the human peptidome
The human genome contains only about 21,000 distinct protein-coding genes1, which is substantially fewer than originally expected. However, owing to alternative splicing mechanisms and many post-translational modifications, these ~21,000 genes are estimated to produce more than one million different proteins2. Although the proteome (that is, the whole set of proteins that are expressed in a specified cell, tissue or organism) is highly complex, it is outnum-bered by the many smaller peptides that are generated from full-length proteins by pro-teolytic cleavage. The largest fraction of the peptidome (that is, all of the peptides that are present in a specific cell, tissue, organ-ism or system) comprises peptide fragments that are generated by the proteolysis of larger precursor molecules. Only a small fraction of the peptidome has been functionally char-acterized, owing to its enormous complexity and the lack of broadly applicable methods that enable its unbiased analysis.For many years, the peptidome was commonly regarded as ‘biological trash’. However, it has recently been recognized that the expression and activities of the more than 500 human proteases that generate these peptides are altered under pathologi-cal conditions3. Furthermore, accumulat-ing evidence suggests that some cleavage products of larger precursor proteins exert specific and sometimes highly unexpectedactivities against human pathogens4–14. Thus,the human peptidome is a rich source ofdisease-specific biomarkers. It has long beenknown that humans and other mammalianspecies have evolved various antimicrobialpeptides as a first line of defence againstviruses, bacteria and fungi15–18. Although therole of some antimicrobial peptides, such asdefensins and cathelicidins, in innate immu-nity, immune modulation and inflamma-tion is well-established15–18, it seems highlylikely that many important peptidic immunemodulators and effectors in the human bodyremain to be identified.Thousands of antimicrobial peptideshave been isolated from various natu-ral sources (for example, bacteria, fungi,plants and animals). Furthermore, severalinhibitors of bacterial infections have beenisolated from human immune cells (forexample, α-defensins)19, skin (for exam-ple, β-defensins)20, saliva (for example,histatins)21, nasal secretions (for exam p le,lysozyme)22, seminal plasma (for example,cathelicidins)23,24 and sweat (for exam p le,dermicidin)25. The various types of anti-microbial peptides15–25 and their possibleclinical applications26–31 have been the topicsof several recent reviews. In this Innovationarticle, we discuss the discovery of novelantimicrobial peptides by the systematicscreening of highly complex peptide librariesthat are derived from human bodily fluidsor tissues. In particular, we focus on theisolation of endogenous agents that affectHIV-1 infection by unexpected mechanismsand that may have implications beyondHIV/AID S. Furthermore, we present theadvantages and disadvantages of this strategy.Finally, we discuss how endogenous peptidesthat have been isolated from the human pep-tidome can be optimized for therapeutic orbasic research applications, and we highlightfuture directions and challenges.Human-derived peptide librariesPeptide libraries that have been generatedfrom human bodily fluids or tissues, suchas blood or lymphoid tissues, contain essen-tially all peptides and small proteins of therespective source in their final processedand physiologically relevant forms32–34. Thus,they are an excellent source for the identifi-cation of as-yet-unknown bioactive peptides.Bioactive peptides from human sources.Most clinically approved drugs are smallmolecules, and most of these compoundshave a molecular weight of much less than1 kDa. Such a small size is one of the require-ments for uptake through the gastrointesti-nal tract and thus oral application. By con-trast, large protein drugs, such as antibodies,have molecular weights of up to 150 kDaand need to be administered parenterally.The size of peptides, which are usually upto 50 amino acids in length, is betweenthese two drug classes, although there isno strict demarcation28–31. Antimicrobialmolecules are found in all three size classes,including small molecules such as penicil-lin (which is 0.334 kDa), the glycopeptidevancomycin (which is 1.449 kDa) and largerabies-specific immunoglobulins (which areabout 150–170 kDa)28. Other examples ofclinically approved antimicrobial peptidesare the antibiotics polymyxin B and poly-myxin E (also known as colistin) and theantiviral agent interferon-α. Owing to theincreasing resistance of microorganisms toconventional antibiotics, there is currently agrowing interest in the development of anti-microbial peptides for clinical applications,and several candidates are in clinical trials orI N N OVAT I O NDiscovery of modulators of HIV‑1infection from the human peptidomeJan Münch, Ludger Ständker, Wolf-Georg Forssmann and Frank KirchhoffAbstract | Almost all human proteins are subject to proteolytic degradation, whichproduces a broad range of peptides that have highly specific and sometimesunexpected functions. Peptide libraries that have been generated from human bodilyfluids or tissues are a rich but mostly unexplored source of bioactive compounds thatcould be used to develop antimicrobial and immunomodulatory therapeutic agents.In this Innovation article, we describe the discovery, optimization and application ofendogenous bioactive peptides from human-derived peptide libraries, with aparticular focus on the isolation of endogenous inhibitors and promoters of HIV-1infection.PERSPECTIVES NATURE REVIEWS |MICROBIOLOGY ADVANCE ONLINE PUBLICATION |1 Nature Reviews Microbiology| AOP, published online 11 August 2014; doi:10.1038/nrmicro3312antibacterial and antiviral peptides that have responses than small-molecule or protein drugs, particularly if they are derived from a human source16. However, the isolation of individual bioactive peptides from highly complex human bodily fluids or tissues is a challenging task.Generating peptide libraries from human haemofiltrate.Human tissues and bodily fluids are usually only available in very lim-ited quantities, and standardized methods to purify bioactive agents from the large number of highly diverse peptides and proteins that are contained in these tissues and fluids are mostly unavailable. Large quantities of starting materials are advanta-geous from a technical and experimental standpoint. One abundant source of human peptides is haemo f iltrate, which is a waste product of dialysis that contains essentially all blood components that have a molecu-lar weight of less than 20–30 kDa (BOX 1) and is available from patients with chronic renal failure at quantities of thousands of litres. A combination of ultrafiltration, fol-lowed by cation-exchange separation and reverse-phase chromatography, enables the standardized separation and concentration of all of the peptides and small proteins that are present in haemofiltrate into about 300–500 fractions32,33(BOX 1). The analysis of these fractions does not require the high-throughput methodologies and facilities that are required for the testing of other libraries, which often comprise hundreds of thou-sands of compounds. For example, specific assays that test the inhibition of a particular pathogen, the modulation of specific cel-lular functions or the induction of selected immune factors can be used to identify and purify the most active agents that are present in these fractions. Such peptide libraries are a useful source for the discovery of novel bioactive agents, as they represent the enor-mous structural and functional diversity of the human peptidome and the peptides are present in their final processed, and thus bioactive, forms32–35. Notably, haemofiltrate contains not only endocrine peptides but also peptides that function in a paracrine or autocrine manner, as a small fraction of these peptides are released into the extracel-lular space and are found in the blood34,35. Thus, haemofiltrate-derived peptide librar-ies contain essentially the entire circulating blood peptidome in a lyophilized, bioactive and highly concentrated form. However, in addition to peptides that naturally exist in the human body, these libraries may also contain proteolytic cleavage products that specifically arise and accumulate during the collection or storage of body fluids orP E R S P E C T I V E S2 | ADVANCE ONLINE PUBLICATION /reviews/microtissues. Nonetheless, these peptide libraries are an excellent source for the identification of endogenous bioactive peptides.Alternative human rge quantities of starting material are advantageous but not always obligatory for the identification of novel endogenous bioactive peptides. In fact, many peptides or proteins only become active and exert their respective functions in specific compartments or at sites of infec-tion and/or inflammation; for example, saliva, genital fluid, milk and sweat contain particularly large numbers of antimicrobial peptides16. To isolate agents that are not cir-culating in the bloodstream, it is important to generate peptide libraries from sources other than haemofiltrate, and in principle, they can be produced from any tissue or bodily fluid. Using ultrafiltration and cation exchange followed by reverse-phase chroma-tography, peptide libraries have been gener-ated from human plasma, milk, placenta, sweat, seminal plasma and saliva (J.M., L.S., W.-G.F. and F.K., unpublished observations), and some antimicrobial peptides that have been isolated from these libraries are listed in TABLE 1.Human peptides that affect HIV-1 infection Most clinically used antiretroviral drugs are small molecules that have been selected to specifically target and inhibit viral proteins that are essential for HIV-1 replication.Enfuvirtide (also known as T-20; Trimeris)is the only currently licensed peptidicantiretroviral drug36. Enfuvirtide is derivedfrom an α-helical region in the viral trans-membrane glycoprotein known as heptadrepeat 2 (HR2). By mimicking HR2 andcompetitively binding to another α-helicalregion of gp41, known as HR1, enfuvirtideprevents the interaction between HR1 andHR2 and thus prevents the conformationalchange that is required for virion fusionwith the host cell37. Although this proteinis not from a human source, enfuvirtideprovides an example of the feasibility ofdeveloping peptide antiretroviral agents.In addition, chemokines, such as CXC-chemokine ligand 12 (CXCL12; also knownas SDF-1) and CC-chemokine ligand 3(CCL3; also known as MIP-1α), CCL4 (alsoknown as MIP-1β) or CCL5 (also known asRANTES), bind to the G protein-coupledreceptors (GPCRs) CXC-chemokine recep-tor 4 (CXCR4) and CC-chemokine recep-tor 5 (CCR5), respectively, and they preventinfection by HIV-1 strains that use the samereceptors for viral entry. In fact, these inhibi-tory activities were crucial for the discoveryof CCR5 as the main co-receptor for HIV-1entry38,39. Modified derivatives of CCL5 areextremely potent inhibitors of R5-tropicHIV-1 strains in vitro40, but they have a lowefficiency in vivo. Several intracellular hostproteins that inhibit HIV-1 replication at dif-ferent steps of the viral life cycle41 — whichare known as restriction factors — have morerecently been discovered, and it seems highlylikely that additional antiretro v iral peptidesand/or proteins remain to be discovered.Identification of novel endogenous HIV‑1inhibitors.An initial screen of a haemo-filtrate-derived peptide library for CCR5ligands identified a naturally occurringtruncated form of the abundant humanchemokine CCL14 as a potent agonist ofthe receptor, which inhibits infection byR5-tropic HIV-1 strains6,42. Notably, otherchemokines, such as CXCL4 and specificfragments of CXCL4, also inhibit HIV-1(REF. 43)and other important pathogens,such as Plasmodium falciparum44. Screen-ing of further haemofiltrate-derived peptidefractions identified another HIV-1 inhibitor:a 20-residue C-proximal subfragment of theserine protease α1-antitrypsin, which hasbeen designated virus-inhibitory peptide(VIRIP). This peptide was purified by mul-tiple rounds of peptide separation and anti-viral screening8(FIG. 1). VIRIP specificallyinteracts with the viral fusion peptide thatis located at the amino terminus of the gp41transmembrane domain, which is a regionthat is distinct from the HR1 region that istargeted by enfuvirtide. VIRIP blocks anentry step before membrane fusion — thatTable 1 |Modulators of microbial infections identified from human peptide libraries*peptide 2; E.coli, Escherichiacoli; hBD1, human β-defensin 1; hBNP, human brain-type natriuretic peptide; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; HCMV, human cytomegalovirus; hHEMβ , human β-chain of haemoglobin; LEAP1, liver-expressed antimicrobial peptide 1; S.carnosus, Staphylococcuscarnosus; PAP, prostatic acid phosphatase; VIRIP, virus-inhibitory peptide. *This table only lists peptides that have been identified by the systematic screening of human peptide libraries, which is outlined in FIG. 1. Many other important antimicrobial peptides have been discovered by different approaches and are described in recent reviews15–18. Peptides that are in clinical development or have recently been approved by the FDA are described in REFS 28–31,91.P E R S P E C T I V E S NATURE REVIEWS |MICROBIOLOGY ADVANCE ONLINE PUBLICATION |3is, penetration and insertion of the viral fusion peptide into the host cell membrane (FIG. 2). This is a novel and unexpected mech-anism, as the fusion peptide only becomes accessible during the viral entry process after conformational changes of gp41 (REF. 45). Thus, it was assumed that this anchoring step cannot be inhibited45. The finding that viral fusion peptides can be targeted by an antiviral agent may offer perspectives beyond HIV/AIDS, as many enveloped viruses, such as influenza virus, hepatitis C virus, filovirus, coronaviru s, arenavirus and hepadnaviruses use fusion peptides to infect their target cells46–50. Owing to this distinct inhibitory mechanism, VIRIP is active against HIV-1 strains that are resistant to other antiretro-viral drugs, including other entry inhibitors8.A proteomics approach identified VIRIP in plasma from patients with acute HIV-1 infec-tion, which suggests that it may contribute to the earliest systemic antiviral responsein HIV-1 infection51. Thus, screening ofh a emofiltrate-derive d peptide libraries enabled the isolation of two novel HIV-1 inhibitors: a CCR5 agonist and a peptide that targets the HIV-1 gp41 fusion peptide (FIG. 2). It is remarkable that this approach did not identify the well-known CCR5 ligand CCL5 but instead identified a novel agonist, and this suggests that other relevant peptide ligands of GPCRs that are targets of many modern drugs remain to be discovered. Endogenous peptides that promote HIV‑1infection.The success of screening haemo-filtrate-derived peptide libraries encouragedthe screening of smaller-scale libraries fromother sources for novel antiviral agents. Theefficiency of virus transmission by sexualcontact is surprisingly low, which suggeststhat inhibitors of HIV-1 infection are presentin semen. Furthermore, it has been reportedthat semen contains various antimicrobialagents23,24,52–55 and cationic peptides thathave anti-HIV-1 activity56. However, unex-pectedly, screening of a semen-derivedpeptide library only identified fractions thatpromoted HIV-1 infection57, which mightreflect the specific adaptation of the virus forefficient transmission in this environment.Further analyses showed that C-proximalfragments of prostatic acidic phosphatase(PAP), which is an abundant enzyme insemen, self-assemble into cationic amyloidfibrils57. These fibrils, which are known assemen-derived enhancers of virus infection(SEVIs), increase the infectious virus titre incell culture by several orders of magnitude57and can facilitate virus infection in non-human primate models after exposure tolow viral doses that approximate the in vivosituation58. Virus attachment is usually inef-fective as the densities of the viral envelopeglycoproteins on the virion and the CD4receptor on the target cell are low and thesurfaces of viral and cellular membranesare negatively charged and usually repeleach other. Both SEVI fibril formation andits positive surface charge are crucial forincreased HIV-1 infection59, which suggeststhat SEVI promotes the attachment of thevirus to target cells by neutralizing the repul-sion between negatively charged viral andcellular membranes (FIG. 2). Interestingly, fol-low-up studies showed that an N-proximalfragment of PAP, as well as peptides that arederived from semenogelin 1 and semeno-gelin 2, which are the most abundant pro-teins in semen, also form amyloid fibrils thatincrease HIV-1 infection60,61. Endogenousamyloid fibrils have recently been detectedand structurally characterized in freshnon-modified ejaculates62. Notably, theirlevels correlate with the efficiency of semen-mediated promotion of HIV-1 infectionin vitro61,63. Thus, semen, which is the mainvector for HIV-1 transmission, containsamyloid fibrils that boost viral infectivityand are therefore novel targets to reduce therisk of sexual transmission. In fact, severalagents that block the formation or infection-promoting activity of semen-derived fibrilshave been reported64–68. Such amyloids mayalso be exploited by other pathogens, asrecent data show that semen amyloids alsoincrease cytomegalovirus (CMV) infec-tion69. Semen is the first bodily fluid that hasbeen identified to naturally contain amyloidfibrils in a non-diseased state62. The physi-ological role of seminal amyloids in healthyindividuals remains to be defined; however,it is tempting to speculate that they mightbe involved in both innate immunity70 andfertility.Optimization and development.VIRIPand CCL14(9–74) are both active againstHIV-1 in the lower micromolar range. Thisconcentration may well be physiologicallyrelevant, as it can readily be achieved byproteolytic cleavage of their highly abun-dant α1-antitrypsin and CCL14 precursors.However, this concentration is suboptimalfor therapeutic applications, which usuallyrequire activities in the nanomolar range71.Specific modifications of these naturalHIV-1 inhibitors increased their antiviralactivity by about two orders of magnitude.Chemical modifications of the N termi-nus of CCL14(9–74) rendered the peptideresistant to degradation and thereby stronglyincreased its antiretroviral potency72. In thecase of VIRIP, the introduction of aminoacid alterations that stabilize the active con-formation of the peptide and increase itshydrophobic interactions with the HIV-1fusion peptide greatly increased its antiviralgraphy. Each cycle of separation and screening reduces the complexity of the peptide samples untilthe purified bioactive agent can be identified by mass spectrometry analysis and peptide sequencing.VIRIP was shown to be a 20-residue (LEAIPMSIPPEVKFNKPFVF) fragment of the serine proteaseα1-antitrypsin8. The identified peptides can be functionally characterized and optimized for clinicaldevelopment.P E R S P E C T I V E S4 | ADVANCE ONLINE PUBLICATION /reviews/micropotency 8. Notably, short-term monotherapy with one of these optimized derivatives (known as VIR-576) was well tolerated and reduced plasma viral loads in treatment-naive patients with HIV-1 (REF . 73). This provides proof-of-concept that naturally occurring antiviral peptides can be opti-mized for therapeutic applications. Owing to their mode of application (that is, injection) and the high costs that are involved in pep-tide synthesis, VIRIP derivatives are not yet competitive with the many highly effec-tive and orally available small-molecule drugs that are available for the treatment of HIV/AIDS. Several strategies are underway to further increase the efficacy and applica-tion of VIRIP derivatives, including packag-ing them into nanoparticles to improve their delivery and stability, as well as structure-based optimization.Semen-derived amyloid fibrils have also been developed for further applications; as they boost HIV-1 infection, they could be used to improve retroviral gene delivery. Indeed, SEVI increases the efficiency of retroviral gene transfer, although only with moderate and variable efficiency 74. On the basis of these findings, broader screens were carried out for amyloidogenic peptides that function as promoters of retroviral transduc-tion. These studies led to the development of a synthetic 12-residue peptide known as EF-C (Protransduzin; Pharis Biotec GmbH)that instantaneously self-assembles into nanofibrils and promotes retroviral gene transfer more efficiently than semen-derived fibrils 75. Furthermore, EF-C captures virions and thus enables retroviral particles to be concentrated by conventional low-speed centrifugation instead of the more labori-ous ultracentrifugation, which has so far been used for virus concentration. These developments pave the way for a new class of promoters of retroviral gene transfer in basic research and clinical applications.Proteolytic cleavage as a common defence mechanism? It is remarkable that a single assay system (that is, the inhibition of HIV-1 infection) led to the discovery of three novel endogenous agents that affect HIV-1 entry by distinct mechanisms (FIG. 2). As discussed above, these peptides are structurally and functionally distinct from other positively charged amphipathic antimicrobial peptides and might have implications in addition to HIV/AIDS in innate and adaptive immunity as well as in sperm function and fertility. It is also striking that these newly identified modulators of HIV-1 infection are generated from highly abundant precursor proteins: α1-antitrypsin, PAP and semenogelins. The proteases that generate the bioactive pep-tides remain to be fully defined. However, at least in some cases, these proteases are released from immune cells and are inducedor activated by inflammation; for example, VIRIP is generated by matrix metallopro-teinase 9 (MMP9)8 and CCL14(9–74) is generated by serine proteases 6. Furthermore, these endogenous peptides interact with their respective targets in a highly specific manner, and subtle structural changes at the N terminus (for example, removing or add-ing single amino acid residues) disrupt their functional activities 6,8. Thus, it is tempting to speculate that the cleavage of abundant precursors may be a more common, fast and effective means to generate immunomodula-tors and antimicrobial peptides at the loca-tions and times that they are actually needed, and it is likely that such peptides have roles in various biological processes. Moreover, the rapid generation of specific effectors by the proteolysis of abundant precursor proteins instead of de novo protein synthe-sis may be particularly advantageous for innate defence mechanisms against invading pathogens for which immediate responses are crucial for effective counteraction.Notably, the local extracellular acidification that activates various proteases is currently emerging as a key regulatory concept of innate immunity 76,77.Other antimicrobial peptides. The use of peptide libraries from human sources for the discovery of novel factors that modu-late HIV-1 infection is a prime example of| MicrobiologyEnhanced attachment:PAP fibrilsInsertion inhibitor: VIRIPFusion inhibitor:EnfuvirtideCo-receptor binding inhibitor: CCL14(9-74)Figure 2 | Endogenous peptides that affect HIV-1 infection. Overview of the HIV-1 entry steps that are targeted by peptides. Amyloidogenic peptides that are derived from human semen, such as fragments of pros-tatic acidic phosphatase (PAP), can self-assemble into amyloid fibrils that promote the attachment of the virus to target cells by neutralizing the repulsion between negatively charged viral and cellular membranes 8,61. Unlike these semen-derived enhancing agents, human peptides that are isolated from haemofiltrate have antiviral activity. The truncated form of the abundant human chemokine CC-chemokine ligand 14 (CCL14(9–74)) inhibits entry of R5-tropic HIV-1 strains by binding to the CC-chemokine receptor 5 (CCR5) co-receptor 6,42. Human-derived virus-inhibitory peptide (VIRIP; which is a subfragment of the serine protease inhibitor α1-antitrypsin) also targets the fusion peptide by specifically interacting with the amino terminus of its transmembrane domain to block penetra-tion and insertion of the viral fusion peptide 8. Enfuvirtide is a synthetic peptide that is derived from an α-helical region in the HIV-1 transmem-brane glycoprotein 36. This inhibitor binds to helical repeat region 1 (HR1) of gp41, which is a region that is distinct from the region that is targeted by VIRIP , and prevents the formation of a hairpin structure that is required for membrane fusion, thereby blocking HIV-1 infection. The target sites for VIRIP and enfuvirtide in gp41 are indicated. From Forssman, W.-G. et al . Short-term monotherapy in HIV-infected patients with a virus entry inhibitor against the gp41 fusion peptide. Sci.Transl.Med . 2, 63re3 (2010). Reprinted with permission from AAAS.NATURE REVIEWS | MICROBIOLOGYADVANCE ONLINE PUBLICATION | 5peptide drug discovery; however, in prin-ciple, such libraries can be used to identify endogenous peptides that have any activ-ity of interest. The main prerequisite is a robust bioassay that enables the reliable screening of several hundreds of peptide fractions. A list of antiviral and antibacterial peptides that have been identified by screen-ing human peptide libraries is provided in TABLE 1. These agents were isolated from var-ious sources, such as haemofiltrate, placental tissue, milk and semen, and target various bacterial and viral pathogens. This list also includes human β-defensin 1 (REF. 78) — the first member of the family of β-defensins to be discovered in humans — which medi-ates the resistance of epithelial surfaces to microbial colonization. Several agents that have been isolated from human-derived peptide libraries show the typical features of most antimicrobial peptides — that is, they are cationic and amphipathic, and destabilize the membranes of pathogens (TABLE 1). The microbicidal action of other endogenous peptides that were identified in this screen was less predictable; for example, a recently discovered derivative of the neutrophil-activating peptide 2 (known as CYVIP) inhibits human CMV (HCMV) infection by binding to heparan sulphate proteoglycans, which function as attachment receptors for CMV79. Moreover, an endogenous human glyceraldehyde 3-phosphate dehydrogenase (GAPDH) peptide has been isolated from human placental tissue. This fragment is internalized by Candida albicans and kills the pathogen by inducing rapid apoptotic death13. As these discoveries are based on only a limited number of antimicrobial screens, this suggests that the human pepti-dome might yield more surprising findings.Obstacles to purifying bioactive peptides. Currently, a key challenge is the purification and identification of the active compounds from the complex peptide mixture in active fractions of the generated peptide libraries. However, rapid progress has been made in the development of improved methodolo-gies for peptide separation and analysis80; for example, state-of-the-art mass spectrometry methods enable the convenient deduction of peptide sequences from complex fragmenta-tion spectra. Furthermore, highly sensitive time-of-flight (TOF) mass spectrometers for matrix-assisted laser desorption–ionizatio n (MALDI) and electrospray ionization (ESI) already enable accurate mass determina-tion of peptides at femtomolar concen-trations. The combination of automated high-throughput sample handling, together with miniaturized liquid chromatographyapproaches and powerful mass spectrometrictechnologies, will greatly facilitate the iden-tification and characterization of bioactiveendogenous peptides in future studies.Endogenous peptides in the clinicThere are several disadvantages that limit theuse of peptides as therapeutic agents, includ-ing the fact they are usually not orally availa-ble and are often unstable. Nonetheless, theyare already used in the treatment of cancer,diabetes and cardiovascular diseases28,29.There is a growing interest in using peptidesin other therapeutic areas, particularly asantimicrobial agents, owing to the increas-ing number of multidrug-resistant bacteriaand viruses. Many antimicrobial peptides arebroadly active, as they often target conservedcomponents of bacterial membranes15–30.Furthermore, such peptides neutralize endo-toxins and it is difficult for most pathogensto develop resistance81; for example, HIV-1variants only showed reduced sensitivity toVIRIP after more than 1 year of cell culturepassage in the presence of the inhibitor82.Accumulating evidence also suggests thatantimicrobial peptides have immunomodu-latory and antineoplastic properties andthus offer prospects for the treatment ofinflammation and cancer83–85. Other poten-tial advantages of peptides are that they areusually easy to synthesize and can be readilymodified to optimize their activity, specific-ity and stability. Notably, the costs of peptidesyntheses are rapidly decreasing and noveldelivery methods may increase their efficacyand eventually even enable oral application.As a consequence, the number of peptidiccompounds that are entering clinical trialsis steadily increasing and many candidatesare in clinical and preclinical development29.Thus, although low stability under physi-ological conditions and lack of oral bioavail-ability are still important challenges26–31, thestrategy to optimize bioactive endogenouspeptides for clinical applications seems tobe highly promising. Alternatively, it maybe possible to induce or apply the proteasesthat generate the active peptides from theirabundant precursors to treat infectious orinflammatory diseases.Conclusions and perspectivesThe human peptidome probably containsmany unknown factors that may havekey roles in antimicrobial immunity andinflammatory processes. These bioactivepeptides cannot be identified by genomicsand transcriptomics approaches, as they donot detect post-translational modifications.Peptide libraries that are derived from bodilyfluids or tissues will facilitate the systematicand unbiased identification of these ‘hid-den treasures’. Some activities may certainlybe missed because they are relatively weakor because some antimicrobial agents maybe degraded or inactivated during sampleprocessing or storage. Nonetheless, thismethodology seems to be suitable to identifythe most potent and stable endogenous anti-microbial peptides. In the longer term, weenvision the highly reproducible generationof peptide libraries from multiple sources incombination with robust assays for the iden-tification of factors that affect key pathogensand biological activities. We also speculatethat novel powerful techniques for thepurification, optimization, production anddelivery of endogenous peptides will greatlyfacilitate their future clinical development.Jan Münch, Ludger Ständker, Wolf-Georg Forssmannand Frank Kirchhoff are at the Institute of MolecularVirology, Ulm University Medical Center,89081 Ulm, Germany.Jan Münch, Ludger Ständker and Frank Kirchhoffare also at Ulm Peptide Pharmaceuticals,Ulm University, 89081 Ulm, Germany.Wolf-Georg Forssmann is also at Pharis Biotec GmbH,30625 Hannover, Germany.Correspondence to F.K.e-mail: frank.kirchhoff@uni-ulm.dedoi:10.1038/nrmicro3312Published online 4 August 20141. Lander, E. S.et al. Initial sequencing and analysis ofthe human genome. Nature 409, 860–921 (2001).2.Jensen, O. N. Modification‑specific proteomics:characterization of post‑translational modifications bymass spectrometry. Curr. Opin. Chem. Biol. 8,33–41(2004).3.Petricoin, E. F., Belluco, C., Araujo, R. P. & Liotta, L. A.The blood peptidome: a higher dimension ofinformation content for cancer biomarker discovery.Nature Rev. Cancer 6, 961–967 (2006).4.Zucht, H. D., Raida, M., Adermann, K., Mägert, H. J. &Forssmann, W. G. Casocidin‑I: a casein‑αs2derivedpeptide exhibits antibacterial activity. FEBS Lett. 372,185–188 (1995).5. Mägert, H. J.et al. LEKTI, a novel 15‑domain type ofhuman serine proteinase inhibitor. J. Biol. Chem. 274,21499–21502 (1999).6. Detheux, M.et al. Natural proteolytic processing ofhemofiltrate CC chemokine 1 generates a potent CCchemokine receptor (CCR)1 and CCR5 agonist with anti‑HIV properties. J. Exp. Med. 192, 1501–1508 (2000).7. Liepke, C.et al. Human hemoglobin‑derived peptidesexhibit antimicrobial activity: a class of host defensepeptides. J. Chromatogr. B Analyt. T echnol. Biomed.Life Sci. 791, 345–356 (2003).8. Münch, J.et al. Discovery and optimization of anatural HIV‑1 entry inhibitor targeting the gp41 fusionpeptide. Cell 129, 263–275 (2007).9. Påhlman, L. I.et al. Antimicrobial activity of fibrinogenand fibrinogen‑derived peptides — a novel linkbetween coagulation and innate immunity. Thromb.Haemost. 109, 930–939 (2013).10.Papareddy, P., Mörgelin, M., Walse, B.,Schmidtchen, A. & Malmsten, M. Antimicrobial activityof peptides derived from human ß‑amyloid precursorprotein. J. Pept. Sci. 18, 183–191 (2012).11. Papareddy, P. et al. C‑terminal peptides of tissue factorpathway inhibitor are novel host defense molecules.J. Biol. Chem. 285, 28387–28398 (2010).12. Kalle, M. et al. Proteolytic activation transformsheparin cofactor II into a host defense molecule.J. Immunol. 190, 6303–6310 (2013).P E R S P E C T I V E S6 | ADVANCE ONLINE PUBLICATION /reviews/micro。
Fisher Kernel
Fisher KernelMartin Sewell2007Jaakkola and Haussler(1999a)introduced the Fisher kernel(named in hon-our of Sir Ronald Fisher),thus creating a generic mechanism for incorporat-ing generative probability models into discriminative classifiers such as SVMs. Jaakkola and Haussler(1999b)introduced a generic class of probabilistic re-gression models and a parameter estimation technique that can make use of arbitrary kernel functions.Jaakkola,Diekhans and Haussler(1999)applied the Fisher kernel method to detecting remote protein homologies which performed well in classifying protein domains by SCOP superfamily.Jaakkola,Diekhans and Haussler(2000)found that using the Fisher kernel significantly improved on previous methods for the classification of protein domains based on remote homologies.Moreno and Rifkin(2000)used the Fisher kernel method for large scale Web audio classification.Mika,Smola and Sch¨o lkopf(2001)presented a fast training algorithm for the kernel Fisher discriminant classifier.It improved upon the state of the art by more than an order of magnitude,thus rendering the kernel Fisher algorithm a viable option also for large datasets.Vinokourov and Girolami(2001)successfully employed the Fisher kernel for document classifi-cation.Saunders,Shawe-Taylor and Vinokourov(2003)showed how the string kernel can be thought of as a k-stage Markov process,and as a result interpreted as a Fisher kernel.Tsuda,et al.(2004)analyzed the statistical properties of the Fisher kernel.Nicotra,Micheli and Starita(2004)extended the Fisher kernel to deal with tree structured data.Kersting and G¨a rtner(2004)extend the Fisher kernel to logical sequences(sequences over an alphabet of logical atoms).Their experiments showed a considerable improvement over results achieved without Fisher kernels for logical sequences.Holub,Welling and Perona(2005)suc-cessfully combined generative models with Fisher kernels to realize performance gains on standard object recognition data-sets.The log-likelihood of a data item x with respect to the model m(θ0)for a given setting of the parametersθ0is defined to belog Lθ0(x).Consider the vector gradient of the log-likelihoodg(θ,x)=∂log Lθ∂θiNi=1.1The Fisher score of a data item x with respect to the model m(θ0)for a given setting of the parametersθ0isg(θ0,x).The Fisher information matrix with respect to the model m(θ0)for a given setting of the parametersθ0is given byI M=E[g(θ0,x)g(θ0,x) ],where the expectation is over the generation of the data point x according to the data generating distribution.The Fisher score gives us an embedding into the feature space R N and hence immediately suggests a possible kernel.The matrix I M can be used to define a non-standard inner product in that feature space.The invariant Fisher kernel with respect to the model m(θ0)for a given setting of the parametersθ0is defined asg(θ0,z).κ(x,z)=g(θ0,x) I−1MThe practical Fisher kernel is defined asκ(x,z)=g(θ0) g(θ0,z).The Fisher kernel gives a“natural”similarity measure that takes into ac-count an underlying probability distribution.It seems natural to compare two data points through the directions in which they‘stretch’the parameters of the model,that is by viewing the score function at the two points as a function of the parameters and comparing the two gradients.If the gradient vectors are similar it means that the two data items would adapt the model in the same way,that is from the point of view of the given parametric model at the current parameter setting they are similar in the sense that they would require similar adaptations to the parameters.ReferencesHOLUB,Alex D.,Max WELLING,and Pietro PERONA,bining generative models andfisher kernels for object recognition.In:Proceedings of the Tenth IEEE International Conference on Computer Vision(ICCV’05), Volume1.Washington,DC,USA:IEEE,pp.136–143.JAAKKOLA,Tommi,Mark DIEKHANS,and David HAUSSLER,ing the Fisher kernel method to detect remote protein homologies.In:Thomas LENGAUER,et al.,eds.Proceedings of the Seventh International Conference on Intelligent Systems for Molecular Biology.Menlo Park,CA:AAAI Press, pp.149–158.JAAKKOLA,Tommi,Mark DIEKHANS,and David HAUSSLER,2000.A discriminative framework for detecting remote protein homologies.Journal of Computational Biology,7(1–2),95–114.2JAAKKOLA,Tommi S.,and David HAUSSLER,1999a.Exploiting genera-tive models in discriminative classifiers.In:Michael S.KEARNS,Sara A. SOLLA,and David A.COHN,eds.Advances in Neural Information Pro-cessing Systems11,Bradford Books.Cambridge,MA,USA:The MIT Press, pp.487–493.JAAKKOLA,Tommi S.,and David HAUSSLER,1999b.Probabilistic kernel regression models.In:David HECKERMAN and Joe WHITTAKER,eds. Proceedings of the1999Conference on AI and Statistics.San Mateo,CA: Morgan Kaufmann.KERSTING,Kristian,and Thomas G¨ARTNER,2004.Fisher kernels for logical sequences.In:Jean-Fran¸c ois BOULICAUT,et al.,eds.Machine Learning: ECML2004:15th European Conference on Machine Learning,Pisa,Italy, September2004,Proceedings.Berlin/Heidelberg:Springer,pp.205–216. MIKA,Sebastian,Alexander SMOLA,and Bernhard SCH¨OLKOPF,2001.An improved training algorithm for kernelfisher discriminants.In:Tommi JAAKKOLA and Thomas RICHARDSON,eds.Artificial Intelligence and Statistics2001:Proceedings of the Eighth International Workshop:January 4-7,2001Key West,Florida.San Francisco,CA:Morgan Kaufmann,pp.98–104.MORENO,Pedro J.,and Ryan RIFKIN,ing the Fisher kernel method for Web audio classification.In:2000IEEE International Conference on Acoustics,Speech,and Signal Processing:Proceedings,Volume IV.IEEE, pp.2417–2420.NICOTRA,Luca,Alessio MICHELI,and Antonina STARITA,2004.Fisher kernel for tree structured data.In:Proceedings:2004IEEE International Joint Conference on Neural Networks,Volume3.IEEE,pp.1917–1922. SAUNDERS,Craig,John SHAWE-TAYLOR,and Alexei VINOKOUROV, 2003.String kernels,fisher kernels andfinite state automata.In:Suzanna BECKER,Sebastian THRUN,and Klaus OBERMAYER,eds.Advances in Neural Information Processing Systems15,Bradford Books.Cambridge,MA: The MIT Press,pp.633–640.TSUDA,Koji,et al.,2004.Asymptotic properties of the Fisher kernel.Neural Computation,16(1),115–137.VINOKOUROV,Alexei,and Mark GIROLAMI,2001.Document classifica-tion employing the Fisher kernel derived from probabilistic hierarchic corpus representations.In:Proceedings of ECIR-01,23rd European Colloquium on Information Retrieval Research.British Computer Society Information Re-trieval Specialist Group.Berlin:Springer Verlag,pp.24–40.3。
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i;j q = P [Xn+1 = j j Xn = i] ; and initial probability distribution p0 = (pi0 ) independent of 2 , and possibly di erent of the true initial probability distribution p = (pi ) of X0 , i.e. for any i 2 S 4 pi = P [X0 = i] 6= P[X0 = i] = pi : 0
; F ; P), with values in the nite set S = f1; ; N g and Rd respectively. On the space (
; F ) we consider a family (P ; 2 ) of probability measures, with compact subset of Rp , such that under P : The unobserved state sequence fXn ; n 0g is a Markov chain with transition probability matrix i;j the primitive matrix Q = (q ), i.e. for any i; j 2
1 Introduction
In this paper, we consider the problem of identi cation of a partially observed nite{state Markov chain, based on observations in Rd. In a rst part, we investigate the consistency of the maximum likelihood estimator (MLE) as the number of observations increases to in nity. In the case of observations in a nite set, the problem has already been considered by Petrie [7], see also Le Gland and Mevel [3] for a study of the recursive MLE, and our contribution is to generalize his work to continuous observations, using results on the approximate prediction lter obtained in Le Gland and Mevel [4]. The consistency of the MLE has already been studied by Leroux [6] under stationarity of the Markov chain. In Rydn [9], this work has been e extended to Markov modulated Poisson process. In a second part, we are interested in conditions for the asymptotic normality of the MLE. The property has been obtained by Rydn [8] for the maximum split data e likelihood estimator (MSDLE) de ned therein.
Remark that all the tools used in this paper can be used to prove similar results about some others estimators. For example, we prove the consistency and the asymptotic normality of the conditionnal least squares estimator in LeGland and Mevel [5]. The statistical model is as follows. Let fXn ; n 0g and fYn ; n 0g be two sequences, de ned on the probability space (
This
The observations fYn ; n 0g are mutually independent given the sequence of states of the Markov chain, i.e.
P [Yn 2 dyn; ; Y0 2 dy0 j
j Xn = in ; ; X0 = i0 ] =
(y) =
Example 1.1 [Conditionally Gaussian observations] Assume that for any 2 , the observations are of
the form
Yn = h (Xn ) + Vn ; for all n 0, where, under P , fVn ; n 0g is a Gaus-
work was partially supported by the Commission of the European Communities, under the SCIENCE project System Identi cation, project number SC1*{CT92{0779, and under the HCM project Statistical Inference for Stochastic Processes, project number CHRX{CT92{0078, and by the Army Research Oce, under grant DAAH04{95{1{0164.
=
n Y k=0
P [Yk 2 dyk j Xk = ik ] :
For any n 0, and for any i 2 S , the conditional probability distribution of the observation Yn given that (Xn = i) is absolutely continuous with respect to a unique positive and { nite measure on Rd, i.e. for any i 2 S , with a {a.e. positive dn = i] = bi (y) (dy) ;
For any y 2 Rd, let b (y) = [ b1 (y); ; bN (y) ] ;
B (y) = diag[b1 (y); ; bN (y)] :
Assumption B' : For any y 2 Rd, the mapping ! b (y) is three{times di erentiable. For any y 2 Rd, and any 2 , de ne s max k ;;k =1;;p j@k0 ;;ks bi (y)j max i2S 0 s s
ASYMPTOTIC PROPERTIES OF THE MLE IN HIDDEN MARKOV MODELS
F. LeGland, L. Mevel IRISA / INRIA and IRMAR Campus de Beaulieu 35042 RENNES Cdex, France e fax : +33 2 99 84 71 71 | e-mail : flegland,lmevelg@irisa.fr Keywords : HMM, estimation, stochastic.
1 2 jy
hi j2
;
Assumption A : For the true value 2 , the tran-
ij sition probability matrix Q = (q ) is a positive matrix. This implies that Q is an irreducible and aperiodic matrix. Moreover, there exists some ", possibly i;j unknown, such that q ", for all i; j 2 S , and we de ne " = f 2 ; d(; @ ) "g : Remark 1.2 For the proof of the consistency, the assumption of positivity of the transition probability matrix Q can be relaxed to primitivity.
bi (y) = (2) d=2 exp
for any i 2 S . Finally, we add the following regularity assumptions about the transition probability matrix, and the observation densities :
sian white noise sequence, with identity covariance matrix. The mapping h from S to Rd is equivalently de ned as h = (hi ) where hi 2 Rd for all i 2 S . In this case, the mutual independence condition is satis ed, and