Base Genética Da DI

ME64CH31-Shaffer ARI 12 December 2012 21:54

Genetic Basis of IntellectualDisabilityJay W. Ellison, Jill A. Rosenfeld, and Lisa G. ShafferSignature Genomic Laboratories, PerkinElmer, Inc., Spokane, Washington 99207;email: [email protected], [email protected], [email protected]

Annu. Rev. Med. 2013. 64:44150

First published online as a Review in Advance onSeptember 27, 2012

The Annual Review of Medicine is online atmed.annualreviews.org

This articles doi:10.1146/annurev-med-042711-140053

Copyright c 2013 by Annual Reviews.All rights reserved

Keywords

microarray analysis, chromosome disorder, next-generationsequencing, neurodevelopmental phenotypes

Abstract

In the past decade, we have witnessed a ood of reports about muta-tions that cause or contribute to intellectual disability (ID). This rapidprogress has been driven in large part by the implementation of chro-mosomal microarray analysis and next-generation sequencing meth-ods. The ndings have revealed extensive genetic heterogeneity for ID,as well as examples of a common genetic etiology for ID and otherneurobehavioral/psychiatric phenotypes. Clinical diagnostic applica-tion of these new ndings is already well under way, despite incom-plete understanding of non-Mendelian transmission patterns that aresometimes observed.

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INTRODUCTION

Intellectual disability (ID) is the current termfor what was formerly called mental retarda-tion. The designation mental retardation stillfrequently appears in print, but there is inter-national consensus on the use of intellectualdisability, although it, too, may be replaced inthe future (1). The World Health Organiza-tion currently denes ID as . . .a signicantlyreduced ability to understand new or complexinformation and to learn and apply new skills(impaired intelligence). This results in a re-duced ability to cope independently (impairedsocial functioning), and begins before adult-hood, with a lasting effect on development (2).Another denition, provided by the AmericanAssociation of Intellectual and DevelopmentalDisability, is a disability characterized bysignicant limitations both in intellectual func-tioning and in adaptive behavior, which coversmany everyday social and practical skills. Thisdisability originates before the age of 18 (3). Acommonly used cutoff for a limitation in intel-lectual functioning is an intelligence quotient(IQ) below 70. ID is estimated to affect 1%3%of the population in Western societies (4),and the monetary burden is high: the Centersfor Disease Control and Prevention estimatedthat the cost to care for those born in the year2000 with ID will total $51.2 billion over theirlifetimes (5).

ID can be caused by environmental insultssuch as infection, trauma, and teratogens,but a sizable proportion is caused by geneticabnormalities. Still, 60% of cases of IDdo not have a known etiology (6). Rapidprogression of new technologies, such aswhole-genome sequencing, promises to in-crease understanding of the etiology of IDby identifying genes and mechanisms thatcontribute to its development. In this review,we address the following: (a) known geneticcauses of ID, including classes of mutations andtheir relative frequencies when determined;(b) the divergent neurodevelopmental pheno-types associated with mutations in some genes;and (c) the inheritance patterns observed for the

susceptibility to ID, including highly penetrantMendelian patterns, oligo/polygenic modesof transmission, and sporadic cases due to denovo mutations. We do not attempt to provideexhaustive lists but instead focus on recent andcurrent trends in research into genetic aspectsof ID.

VISIBLE AND SUBMICROSCOPICCHROMOSOMAL CAUSES

Approximately 15% of ID is attributable tocytogenetically visible abnormalities, with atleast two-thirds of these cases accounted forby trisomy 21 (46). Other microscopicallyvisible causative alterations include deletions,translocations (usually unbalanced), and super-numerary marker chromosomes. Traditionalchromosome analysis is limited to the iden-tication of abnormalities of 510 millionbase pairs (Mb) or larger. Smaller genomicalterations require molecular methods, such asgenomic microarrays, for their detection.

The use of microarrays has led to theidentication of numerous pathogenic gainsand losses of chromosomal segments that pre-viously escaped detection by light microscopy.A number of recent reviews document thegrowing number of copy number alterationsassociated with ID, often leading to thedesignation of new clinical syndromes (710).Current estimates are that approximately 15%20% of cases of ID are due to submicroscopiccopy number variants (CNVs) (7, 1113).In a number of instances, the gene or genesresponsible for the developmental abnormalityhave been identied through their locationin the critical regions of pathogenic CNVs(1419). Identication of these genes has insome cases led to the detection of mutations inaffected individuals who do not have the CNV,thus adding to the list of single-gene causesof ID.

The additional yield of diagnoses providedby microarray analysis over that of karyotypeis illustrated by the case of an unbalancedtranslocation involving chromosomes 1 and 14

442 Ellison Rosenfeld Shaffer

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14p11.214p12 14q12 14q21.3 14q23.1 14q24.3 14q31.3 14q32.225.00 Mb 50.00 Mb 75.00 Mb

Chromosome 14

Material from 14q32 on derivative chromosome 1

1p31.1 1q12 1q4150.00 Mb 100.00 Mb 150.00 Mb 200.00 Mb

Chromosome 1

1q43

Figure 1Microarray and idiogram characterization of an unbalanced 1;14 translocation. In a two-month-old female referred for developmentaldelay and seizure disorder, oligonucleotide-based array comparative genomic hybridization (aCGH) showed a 4.4-Mb terminaldeletion of the short arm of chromosome 1 (blue highlighted region on aCGH results) and a 3.5-Mb terminal duplication of the long armof chromosome 14 ( pink highlighted region on aCGH results). Fluoresence in situ hybridization (FISH; not shown) conrmed this to bean unbalanced translocation. The idiograms represent the chromosome complement of the proband, with a derivative chromosome 1showing the deletion of 1p36 and presence of material from 14q32, a normal chromosome 1, and two normal chromosomes 14.Monosomy 1p36 is the most common subtelomeric deletion syndrome in our population and is characterized by intellectual disability,usually severe, and typical dysmorphic facial features in all affected individuals, with additional congenital anomalies and seizures in amajority. Because this child also has extra material from the long arm of chromosome 14, it is likely that she also manifests additionalclinical features not found in monosomy 1p36 syndrome.

(Figure 1). The imbalance reected a replace-ment of a segment in 1p by a similarly sizedsegment derived from 14q. Such a change isbelow the limit of resolution of karyotype,but was clearly evident following microarrayanalysis, as shown in the gure.

SINGLE-GENE CAUSES

One of the best-known single genes causingID is FMR1, in which mutations lead tofragile X syndrome (2022). It was the rstof many X-linked ID genes to be identied,and it remains the most common single-gene

www.annualreviews.org Genetic Basis of Intellectual Disability 443

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etiology of ID, with an estimated incidence of1 in 5,000 males (thus accounting for 0.5%of cases of ID) (23). Another notable X-linkedgene is MECP2, originally implicated in Rettsyndrome and since found to be causative forseveral ID phenotypes that affect both malesand females (24). Identication of a largenumber of X-linked ID genes was facilitatedby the characteristic inheritance pattern andthe availability of pedigrees for linkage analysis(25), as well as the collaborative efforts ofinternational consortia (26). More recently,the number of ID-associated X-linked geneshas further grown through the implementationof high-throughput sequencing technologies(27). As of this writing, the number of identiedX-linked genes leading to ID is >100 (28).

Until next-generation sequencing methodscame into use a few years ago, only a handful ofautosomal genes were known to be associatedwith ID. That number is changing so rapidlythat this review will likely be outdated by thetime it reaches print. Multiple strategies havebeen employed to identify the culpable genes.Besides the characterization of genes in CNVs(see, e.g., 1517), an approach that uses next-generation sequencing methods has provensuccessful in identifying pathogenic genes andstrong candidates. This approach is illustratedby the report of Vissers et al., who performedexome sequencing for ten individuals withmoderate to severe ID and a negative familyhistory of the phenotype (29). The hypothesiswas that at least some of the patients wereaffected because of de novo mutations, whichwere sought through the sequencing of affectedpatients and their parents (trio analysis). Inaddition to one maternally inherited mutationin a known X-linked ID gene, they found ninede novo mutations, two of which involvedgenes known to cause ID (oneX-linked and oneautosomal dominant). Of the remaining sevengenes, four have functions suggestive of roles inneurodevelopment. This suggestive evidenceincluded interactions of the encoded proteinswith known neurodevelopmental genes (twocases) and a mouse knockout model that hasneural tube defects (one case); the fourth gene

has a putative role in granule cell developmentin the central nervous system. Two reportsof mutations in one of these four candidates(DYNC1H1) have subsequently been foundin additional individuals with ID (30, 31). Asimilar approach was taken by Need et al.,who performed exome sequencing for twelvetrios, eight of which involved developmentaldelay/ID in the proband. They reported likelycausal variants in ve of these eight cases; fourof the alterations were de novo, and in the fthcase, biallelic inherited mutations were found(32). These studies indicate that the approachof trio sequence analysis in cases of ID withouta family history is sure to reveal additionalgenes with causal roles in ID.

A strategy for identifying autosomal reces-sive single-gene causes of ID uses autozygositymapping in consanguineous families with mul-tiple affected offspring. In these studies, linkageanalysis was carried out to identify candidategenomic intervals, and sequence analysis wasthen performed, either on candidate genes bytraditional sequencing methods or by usingexome capture techniques coupled with next-generation sequence analysis (33, 34). In thelargest such report, involving 136 families (34),homozygous mutations were found in 23 genesknown to be associated with ID and/or otherneurologic disorders. In addition, mutationswere observed in 50 novel genes (two of thegenes had different mutations in two familieseach). Validation of the causative role of thesegenes awaits conrmatory studies in othercohorts, and for the time being they should beformally considered as candidates for playingroles in intellectual development. Still, anumber of these genes are quite attractive can-didates, based on their brain-specic functionsand/or interactions with known ID-causativegenes.

In this review, we do not attempt to catalogevery report of single-gene mutations leadingto ID but rather focus on current trends in genediscovery strategies. It is too early to tell whatproportion of ID is attributable to mutations insingle genes because many of the examples rep-resent extremely rare disorders, and verication


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in additional cases is needed. One current es-timate for the total number of single genescontributing to ID is >450 (A. Schenck, per-sonal communication); in time, the total couldwell reach the thousands. In the coming fewyears, as widespread sequencing studies attemptto validate the many identied candidates andgive incidence numbers for known culprits, theextent of the locus heterogeneity of Mendelianand X-linked forms of ID, and their aggre-gate contribution to the phenotype, will beapparent.

FUNCTIONS OF GENESASSOCIATED WITHINTELLECTUAL DISABILITY

As the number of genes associated with IDhas grown, many authors have searched fortrends regarding the functions of the pro-teins encoded by these genes. One biologicfunction that is often mentioned is that ofsynapse formation and transmission (29,3538). It is clear, however, that diversecellular functions are affected by mutations ingenes linked to ID. These functions includetranscriptional and translational control,protein modication, chromatin remodel-ing, differentiation of neural and supportingcells of the nervous system, and centrosomefunction (29, 34, 3840).

There is a growing list of exampleswhere knowledge of the function of provencausative ID genes can help assess the potentialpathogenicity of newly identied candidates.This analysis typically uses two related pieces ofknowledge: specic physiologic pathways andinteracting protein partners. If the protein en-coded by a newly implicated candidate gene isknown to interact with the protein produced byan acknowledged pathogenic ID gene, the can-didate becomesmore attractive as a contributorto the phenotype. The likelihood of causativeinvolvement is also increased if the candidategene operates in a pathway that contains one ormore bona de pathogenic genes. Examples ofthis type of inferential evidence are reviewed byKaufman et al. (41).

COMMON ETIOLOGYOF INTELLECTUALDISABILITY AND OTHERNEURODEVELOPMENTALPHENOTYPES

There is great phenotypic variability in indi-viduals with ID, not only in IQ levels but alsowith respect to other neurologic and neurobe-havioral manifestations. For example, a signif-icant fraction of individuals with ID have beenshown to meet diagnostic criteria for autism;in the most recent study, this proportion was28% (42). Conversely, an even higher fractionof individuals with autism have been shown tohave ID (43).This co-occurrence of clinical fea-tures is reected in the ndings of individualgenes or CNVs that can cause one or the otherphenotype (or both) in different individuals(44).

As the use of genomic microarray analysisfor the evaluation of individuals with psychi-atric diseases grows, it has become clear thatsome of the same CNVs that lead to ID insome patients are associated with psychiatricdisorders such as schizophrenia in others (45,reviewed in 46). The variable phenotypes ex-hibited by individuals with alterations in knownID-causing genes extend to other neurodevel-opmental disorders, including bipolar disorder,attention decithyperactivity disorder, andepilepsy. The involved genes are too numerousto list here, but examples can be found in severalrecent reviews and reports (36, 41, 44, 4749).The basis for this type of variable expressivityis not known, but possible explanations includemodifying alleles in the individuals geneticbackground, somatic mutations and/or epi-genetic events, environmental exposures, andstochastic processes. The latter are likely tobe especially important during development ofthe nervous system, as discussed by Mitchell(50). Further research involving the relevantpathways and players, in addition to continuedgenotypephenotype analysis, promises toenhance our understanding of the pathophys-iology of neurocognitive and neuropsychiatricdisorders.


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INHERITANCE OF GENETICSUSCEPTIBILITY

One of the earliest comprehensive genetic anal-yses of ID was conducted by Lionel Penrose,who published his work in the 1938monographA Clinical and Genetic Study of 1280 Casesof Mental Defect (51). His study included notonly clinical evaluation of individuals with vary-ing degrees of ID but also detailed examinationand evaluation of immediate and extendedfamily members. He was aware of well-knownMendelian disorders such as phenylketonuria,TaySachs disease, and tuberous sclerosis,but a key contribution came from his analysisof familial clustering of cases without knowncauses. Two major ndings were that therisk of mental defect to family members ofa proband was signicant and that this riskdecreased greatly with decreasing relatedness.He also observed that the risk to family mem-bers was greater for more mildly affected cases.He acknowledged the possible explanations ofde novo mutations, multifactorial inheritance,and incomplete penetrance to account for thenon-Mendelian segregation of the phenotypein many families. These same themes are stillpertinent today, as we discuss in the followingparagraphs.

A seeming paradox is the relatively highprevalence of ID given the reproductivedisadvantage of affected individuals. A partialexplanation could be that an appreciablefraction of cases have an autosomal recessiveetiology, so that pathogenic alleles maintaintheir signicant frequency in unaffected car-riers. There are not reliable estimates on whatproportion of ID such cases represent, in partbecause inWestern societies (wheremost of theresearch has been done), family size is limitedand singleton cases appear to be sporadic. Therecent identication of candidate genes for re-cessive ID, and imminent testing of these genesin large populations, should help determinetheir aggregate contribution to the mutationalspectrum of ID cases. Another explanationfor the observed frequency of ID is that manycases may be due to de novo mutationseither

CNVs or point mutations in single genes.The high yield of presumed pathogenic denovo mutations in the small studies of Visserset al. (29) and Need et al. (32) suggests thata signicant fraction of sporadic cases will beaccounted for by de novo mutations (5254).

The vast majority of recent studies thatidentify causative or candidate genes for IDhave involved cases of moderate to severe ID,and the study protocols are typically designedto ascertain highly penetrant pathogenic alleles.Still unaccounted for are the majority of casesof mild to moderate ID, the category for whichfamilial clustering is most often observed.It is generally assumed that intelligence is acontinuous trait (like height or blood pressure),and that mild ID represents the lower end ofthe IQ spectrum. Such continuous traits, aswell as other common conditions such as heartdisease and diabetes, are most often thoughtto be multifactorial/polygenic in nature, withmultiple alleles each producing a small effect.Multifactorial/polygenic models can explainnon-Mendelian segregation patterns and re-duced penetrance, phenomena that are evidentin family studies of idiopathic ID and that areoften observed for cases of ID associated withCNVs. But multifactorial models of commondisorders have been questioned recently, asgenome-wide association studies have revealedonly a small fraction of the observed heritabilityfor such conditions (reviewed in 55).

Although traditional multifactorial modelsmay not be able to explain the non-Mendelianfamilial transmission of many cases of ID, thereis recent evidence that a related concept likelyoperates in at least some instances. Girirajanet al. (56) showed that expressivity and pen-etrance of a neurodevelopmental phenotypeassociated with a 16p12.1 microdeletion werestrongly affected by the presence of additionallarge CNVs. They used the term two-hit to ex-plain the effect of the co-occurring CNVs, butoligogenic or polygenic would also be ap-propriate descriptors. In another recent report,Schaaf et al. used the term oligogenic het-erozygosity to describe their ndings in whichprobands with autism were much more likely


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than controls to carry multiple heterozygousvariants in autism susceptibility genes (57).

The above two examples illustrate that thedichotomy between single-gene and polygenicetiologies is often arbitrary and in fact isprobably inappropriate (58), and it is beliedby the well-recognized concept of modiergenes. Modifying alleles by denition affectthe expressivity and penetrance of single-genedisorders, and their presence could thus explainthe non-Mendelian transmission patterns oftenobserved for ID, even if de novo alterationsand recessive mutations turn out to be involvedin the majority of cases. In fact, for the latterexamples, there are scant data on the pene-trance of the phenotype other than for CNVs,although one report (34) mentions 12 variantsthat did not cosegregate with ID. It is worthpointing out that the current approach ofsearching for de novo mutations (trio analysis)seems tomake itmore difcult to identify allelesthat are associated with dominant inheritanceand incomplete penetrance. This is becauseif a nonmanifesting parent carries a reduced-penetrance allele that leads to the phenotypein the offspring, that variant will likely beremoved by the ltering process of the analysis.

Before sequence analysis is implemented ona large scale in a clinical diagnostic setting, a key

issue needs to be considered: the penetrance as-sociated with mutations in individual genes. Ahigh penetrance value lends condence to theconclusion that a mutation is contributing tothe phenotype of a given affected individual,and for asymptomatic individuals and prenatalcases, penetrance is a measure of the predictivevalue of the test. Figures for penetrance repre-sent averages for large numbers of carriers, butfor a given patient the value is inuenced bythe particular set of modifying alleles present.Therefore, to derive the maximum diagnosticand predictive utility from clinical sequencingtests, it seems important to identify thesemodi-fying alleles.The pool of candidates formodify-ing genes is huge: it includes hundreds of knowncausative or candidate genes that have recentlybeen identied, in addition to the genes en-coding their interacting protein partners andother proteins in implicated physiologic path-ways. Identication of modifying alleles shouldbe achievable through large-scale sequencingstudies of patients, family members, and unre-lated controls, especially if detailed phenotypicanalysis of controls and relatives of affected in-dividuals is performed. It seems reasonable toenvision that in a few years we will be able topaint amuch clearer picture of the genetic etiol-ogy of ID for families with affected individuals.

SUMMARY POINTS

1. There is tremendous genetic heterogeneity for ID,with hundreds of genes already knownto contribute to the phenotype.

2. Technological advances such as genomic microarray analysis and next-generation se-quencing have contributed to the recent rapid progress in gene identication.

3. Genes associated with intellectual disability are also involved in the pathogenesis of otherneurobehavioral/neuropsychiatric phenotypes.

4. Despite recent progress in gene discovery, the fraction of cases of ID that is explainableis still small.

FUTURE ISSUES

1. Large studies in patient cohorts and controls are needed to validate candidate genes andestimate the penetrance levels for mutations in individual genes.


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2. The same large studies should help answer questions about major genes and modiersi.e., the monogenic versus polygenic nature of genetic etiologies of ID.

3. Animal models should be useful to help elucidate the pathophysiology of ID and otherassociated phenotypes.

DISCLOSURE STATEMENT

The authors are employees of Signature Genomic Laboratories, PerkinElmer, Inc.

ACKNOWLEDGMENTS

The authors thank A. Michelle Caldwell, BS (Signature Genomic Laboratories), for preparationand editing of the manuscript.

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ME64-frontmatter ARI 18 December 2012 10:19

Annual Review ofMedicine

Volume 64, 2013Contents

Abiraterone and Novel Antiandrogens: Overcoming CastrationResistance in Prostate CancerR. Ferraldeschi, C. Pezaro, V. Karavasilis, and J. de Bono 1

Antibody-Drug Conjugates in Cancer TherapyEric L. Sievers and Peter D. Senter 15

Circulating Tumor Cells: From Bench to BedsideMarija Balic, Anthony Williams, Henry Lin, Ram Datar, and Richard J. Cote 31

Cytokines, Obesity, and Cancer: New Insights on Mechanisms LinkingObesity to Cancer Risk and ProgressionCandace A. Gilbert and Joyce M. Slingerland 45

Glioblastoma: Molecular Analysis and Clinical ImplicationsJason T. Huse, Eric Holland, and Lisa M. DeAngelis 59

Harnessing the Power of the Immune System to Target CancerGregory Lizee, Willem W. Overwijk, Laszlo Radvanyi, Jianjun Gao,

Padmanee Sharma, and Patrick Hwu 71

Human Papillomavirus Vaccines Six Years After ApprovalAlan R. Shaw 91

Reduced-Intensity Hematopoietic Stem Cell Transplants forMalignancies: Harnessing the Graft-Versus-Tumor EffectSaar Gill and David L. Porter 101

The Need for Lymph Node Dissection in NonmetastaticBreast CancerCatherine Pesce and Monica Morrow 119

The Role of Anti-Inammatory Drugs in Colorectal CancerDingzhi Wang and Raymond N. DuBois 131

The Human Microbiome: From Symbiosis to PathogenesisEmiley A. Eloe-Fadrosh and David A. Rasko 145

The Rotavirus Saga RevisitedAlan R. Shaw 165

v

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Staphylococcal Infections: Mechanisms of Biolm Maturation andDetachment as Critical Determinants of PathogenicityMichael Otto 175

Toward a Universal Inuenza Virus Vaccine: Prospects and ChallengesNatalie Pica and Peter Palese 189

Host Genetics of HIV Acquisition and Viral ControlPatrick R. Shea, Kevin V. Shianna, Mary Carrington,

and David B. Goldstein 203

Systemic and Topical Drugs for the Prevention of HIV Infection:Antiretroviral Pre-exposure ProphylaxisJared Baeten and Connie Celum 219

Hyperaldosteronism as a Common Cause of Resistant HypertensionDavid A. Calhoun 233

Mechanisms of Premature Atherosclerosis in RheumatoidArthritis and LupusJ. Michelle Kahlenberg and Mariana J. Kaplan 249

Molecular Mechanisms in Progressive Idiopathic Pulmonary FibrosisMark P. Steele and David A. Schwartz 265

Reprogrammed Cells for Disease Modeling and Regenerative MedicineAnne B.C. Cherry and George Q. Daley 277

Application of Metabolomics to Diagnosis of Insulin ResistanceMichael V. Milburn and Kay A. Lawton 291

Defective Complement Inhibitory Function Predisposesto Renal DiseaseAnuja Java, John Atkinson, and Jane Salmon 307

New Therapies for GoutDaria B. Crittenden and Michael H. Pillinger 325

Pathogenesis of Immunoglobulin A Nephropathy: Recent Insightfrom Genetic StudiesKrzysztof Kiryluk, Jan Novak, and Ali G. Gharavi 339

Podocyte Biology and Pathogenesis of Kidney DiseaseJochen Reiser and Sanja Sever 357

Toward the Treatment and Prevention of Alzheimers Disease:Rational Strategies and Recent ProgressSam Gandy and Steven T. DeKosky 367

Psychiatrys Integration with Medicine: The Role of DSM-5David J. Kupfer, Emily A. Kuhl, Lawson Wulsin 385

vi Contents

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Update on Typical and Atypical Antipsychotic DrugsHerbert Y. Meltzer 393

Ataluren as an Agent for Therapeutic Nonsense SuppressionStuart W. Peltz, Manal Morsy, Ellen M. Welch, and Allan Jacobson 407

Treating the Developing Brain: Implications from Human Imagingand Mouse GeneticsB.J. Casey, Siobhan S. Pattwell, Charles E. Glatt, and Francis S. Lee 427

Genetic Basis of Intellectual DisabilityJay W. Ellison, Jill A. Rosenfeld, and Lisa G. Shaffer 441

Sickle Cell Disease, Vasculopathy, and TherapeuticsAdetola A. Kassim and Michael R. DeBaun 451

Duty-Hour Limits and Patient Care and Resident Outcomes: CanHigh-Quality Studies Offer Insight into Complex Relationships?Ingrid Philibert, Thomas Nasca, Timothy Brigham, and Jane Shapiro 467

Quality Measurement in HealthcareEliot J. Lazar, Peter Fleischut, and Brian K. Regan 485

Indexes

Cumulative Index of Contributing Authors, Volumes 6064 497

Article Titles, Volumes 6064 501

Errata

An online log of corrections to Annual Review of Medicine articles may be found athttp://med.annualreviews.org/errata.shtml

Contents vii

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AnnuAl Reviewsits about time. Your time. its time well spent.

AnnuAl Reviews | Connect with Our expertsTel: 800.523.8635 (us/can) | Tel: 650.493.4400 | Fax: 650.424.0910 | Email: [email protected]

New From Annual Reviews:Annual Review of Statistics and Its ApplicationVolume 1 Online January 2014 http://statistics.annualreviews.org

Editor: Stephen E. Fienberg, Carnegie Mellon UniversityAssociate Editors: Nancy Reid, University of Toronto

Stephen M. Stigler, University of ChicagoThe Annual Review of Statistics and Its Application aims to inform statisticians and quantitative methodologists, as well as all scientists and users of statistics about major methodological advances and the computational tools that allow for their implementation. It will include developments in the field of statistics, including theoretical statistical underpinnings of new methodology, as well as developments in specific application domains such as biostatistics and bioinformatics, economics, machine learning, psychology, sociology, and aspects of the physical sciences.

Complimentary online access to the first volume will be available until January 2015.

table of contents:What Is Statistics? Stephen E. FienbergA Systematic Statistical Approach to Evaluating Evidence

from Observational Studies, David Madigan, Paul E. Stang, Jesse A. Berlin, Martijn Schuemie, J. Marc Overhage, Marc A. Suchard, Bill Dumouchel, Abraham G. Hartzema, Patrick B. Ryan

The Role of Statistics in the Discovery of a Higgs Boson, David A. van Dyk

Brain Imaging Analysis, F. DuBois BowmanStatistics and Climate, Peter GuttorpClimate Simulators and Climate Projections,

Jonathan Rougier, Michael GoldsteinProbabilistic Forecasting, Tilmann Gneiting,

Matthias KatzfussBayesian Computational Tools, Christian P. RobertBayesian Computation Via Markov Chain Monte Carlo,

Radu V. Craiu, Jeffrey S. Rosenthal

Build, Compute, Critique, Repeat: Data Analysis with Latent Variable Models, David M. Blei

Structured Regularizers for High-Dimensional Problems: Statistical and Computational Issues, Martin J. Wainwright

High-Dimensional Statistics with a View Toward Applications in Biology, Peter Bhlmann, Markus Kalisch, Lukas Meier

Next-Generation Statistical Genetics: Modeling, Penalization, and Optimization in High-Dimensional Data, Kenneth Lange, Jeanette C. Papp, Janet S. Sinsheimer, Eric M. Sobel

Breaking Bad: Two Decades of Life-Course Data Analysis in Criminology, Developmental Psychology, and Beyond, Elena A. Erosheva, Ross L. Matsueda, Donatello Telesca

Event History Analysis, Niels KeidingStatisticalEvaluationofForensicDNAProfileEvidence,

Christopher D. Steele, David J. BaldingUsing League Table Rankings in Public Policy Formation:

Statistical Issues, Harvey GoldsteinStatistical Ecology, Ruth KingEstimating the Number of Species in Microbial Diversity

Studies, John Bunge, Amy Willis, Fiona WalshDynamic Treatment Regimes, Bibhas Chakraborty,

Susan A. MurphyStatistics and Related Topics in Single-Molecule Biophysics,

Hong Qian, S.C. KouStatistics and Quantitative Risk Management for Banking

and Insurance, Paul Embrechts, Marius Hofert

Access this and all other Annual Reviews journals via your institution at www.annualreviews.org.

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Annual Reviews OnlineSearch Annual ReviewsAnnual Review of MedicineOnlineMost Downloaded MedicineReviews Most Cited Medicine Reviews Annual Review of Medicine Errata View Current Editorial Committee

All Articles in the Annual Review of Medicine, Vol. 63Abiraterone and Novel Antiandrogens: Overcoming Castration Resistance in Prostate CancerAntibody-Drug Conjugates in Cancer TherapyCirculating Tumor Cells: From Bench to BedsideCytokines, Obesity, and Cancer: New Insights on Mechanisms LinkingObesity to Cancer Risk and ProgressionGlioblastoma: Molecular Analysis and Clinical ImplicationsHarnessing the Power of the Immune System to Target CancerHuman Papillomavirus Vaccines Six Years After ApprovalReduced-Intensity Hematopoietic Stem Cell Transplants for Malignancies: Harnessing the Graft-Versus-Tumor EffectThe Need for Lymph Node Dissection in Nonmetastatic Breast CancerThe Role of Anti-Inflammatory Drugs in Colorectal CancerThe Human Microbiome: From Symbiosis to PathogenesisThe Rotavirus Saga RevisitedStaphylococcal Infections: Mechanisms of Biofilm Maturation and Detachment as Critical Determinants of PathogenicityToward a Universal Influenza Virus Vaccine: Prospects and ChallengesHost Genetics of HIV Acquisition and Viral ControlSystemic and Topical Drugs for the Prevention of HIV Infection:Antiretroviral Pre-exposure ProphylaxisHyperaldosteronism as a Common Cause of Resistant HypertensionMechanisms of Premature Atherosclerosis in Rheumatoid Arthritis and LupusMolecular Mechanisms in Progressive Idiopathic Pulmonary FibrosisReprogrammed Cells for Disease Modeling and Regenerative MedicineApplication of Metabolomics to Diagnosis of Insulin ResistanceDefective Complement Inhibitory Function Predisposes to Renal DiseaseNew Therapies for GoutPathogenesis of Immunoglobulin A Nephropathy: Recent Insight from Genetic StudiesPodocyte Biology and Pathogenesis of Kidney DiseaseToward the Treatment and Prevention of Alzheimers Disease:Rational Strategies and Recent ProgressPsychiatrys Integration with Medicine: The Role of DSM-5Update on Typical and Atypical Antipsychotic DrugsAtaluren as an Agent for Therapeutic Nonsense SuppressionTreating the Developing Brain: Implications from Human Imaging and Mouse GeneticsGenetic Basis of Intellectual DisabilitySickle Cell Disease, Vasculopathy, and TherapeuticsDuty-Hour Limits and Patient Care and Resident Outcomes: Can High-Quality Studies Offer Insight into Complex Relationships?Quality Measurement in Healthcare

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