Identification of genes for childhood heritable diseases.

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Identification of Genes for Childhood Heritable Diseases Kym M. Boycott, David A. Dyment, Sarah L. Sawyer, Megan R. Vanstone, and Chandree L. Beaulieu Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, K1H 8L1 Canada; email: [email protected], [email protected], [email protected], [email protected], [email protected],

Annu. Rev. Med. 2014. 65:19–31 The Annual Review of Medicine is online at med.annualreviews.org This article’s doi: 10.1146/annurev-med-101712-122108 c 2014 by Annual Reviews. Copyright All rights reserved

Keywords next-generation sequencing, rare childhood genetic diseases, gene discovery, mutation

Abstract Genes causing rare heritable childhood diseases are being discovered at an accelerating pace driven by the decreasing cost and increasing accessibility of next-generation DNA sequencing combined with the maturation of strategies for successful gene identification. The findings are shedding light on the biological mechanisms of childhood disease and broadening the phenotypic spectrum of many clinical syndromes. Still, thousands of childhood disease genes remain to be identified, and given their increasing rarity, this will require large-scale collaboration that includes mechanisms for sharing phenotypic and genotypic data sets. Nonetheless, genomic technologies are poised for widespread translation to clinical practice for the benefit of children and families living with these rare diseases.

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INTRODUCTION Clinical variability: differences in the clinical presentation of a given syndrome


Genetic heterogeneity: mutations in different genes can cause the same phenotypic presentation Next-generation sequencing (NGS): highly parallel DNA-sequencing technologies that produce many hundreds of thousands or millions of short reads (25-500 bp) for a low cost and in a short time Positional cloning: the identification of a disease gene based on its location in the genome, which has most often been established using linkage analysis

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Heritable diseases of childhood are rare conditions caused by highly penetrant mutation(s) in a single gene. These diseases are defined as rare because they each affect fewer than 1:2,000 individuals in Europe or fewer than 200,000 people in the United States. The Online Mendelian Inheritance in Man (OMIM) database (1) estimates the number of rare genetic diseases to be ∼7,000. Approximately 75% of rare diseases affect children (2, 3). Thus, there are likely more than 5,000 pediatric rare diseases, and in aggregate, they affect millions of children worldwide. Unfortunately, many childhood genetic diseases can be chronically debilitating and life limiting. Although several body systems are usually affected in a given rare disease, the central nervous system is most often involved, with cognitive, behavioral, sensory, and motor symptomatology observed. Overall, 30% of infants with a genetic disease succumb in their first year (2, 3), and those who survive experience comparatively high morbidity and mortality over their lifetime (4, 5). Children with a rare disease have a disproportionate number of hospital admissions, and they have longer and more costly hospital stays than other patients (5). In some instances, if diagnosed early and managed optimally, the affected children can maintain a good quality of life; however, rare diseases, by their very nature, are difficult to diagnose. All too frequently, children with a rare genetic disease undergo a “diagnostic odyssey” comprising years of invasive investigations and visits to multiple specialists before reaching a diagnosis, if that outcome is achieved at all. Early in the disease course a child may not present with the recognizable diagnostic features of the disease, either because a particular clinical feature has not yet developed in a progressive disease or because the child has not yet developed to an age at which it would be obvious (e.g., intellectual disability). Clinical variability as well as genetic heterogeneity can also complicate a genetic diagnosis. A survey of eight rare diseases in 17 European countries showed that 25% of patients waited 5-30 years for the Boycott et al.

correct diagnosis, 40% had initially received an incorrect diagnosis, and the others remained undiagnosed (6, 7). Importantly, a genetic diagnosis can be realized only when the disease gene is known; failing this, the family becomes part of the large percentage of people who remain without answers. The molecular etiology of half of rare childhood genetic diseases is known (1), leaving many disease genes yet to be identified. The burgeoning number of new technologies, particularly next-generation sequencing (NGS) and associated computational sequence analyses, is resulting in the increasing identification of genes and thus of mechanisms and pathways that contribute to the development of rare genetic diseases in children. Here we discuss the current status of, and successful strategies for, NGS-based rare childhood disease gene discovery; highlight insights into clinical syndromes and biological mechanisms; and outline the international cooperation and coordination needed to elucidate the mechanism of the remaining several thousand genetic diseases of childhood. We conclude by discussing the impact of NGS-based technology on the clinical care of children with rare heritable diseases.

GENE DISCOVERY: THEN AND NOW Prior to NGS, rare disease genes were typically identified by using positional information to decrease the number of candidate genes followed by PCR-based Sanger sequence analyses. Although family-based positional cloning has been relatively efficient for large families, increasingly researchers are studying smaller families (or an individual family) with critical gene-containing region(s) that are too large to be effectively analyzed by traditional approaches. In addition, multigenerational families with many affected individuals are predisposed to ascertainment bias for those diseases associated with lesser mortality and morbidity, which is a scenario not often observed when the condition presents shortly after birth. As well, de novo germline mutations (in the absence of


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a chromosome rearrangement to identify the candidate region) cannot be identified using positional cloning techniques. Thus, many rare genetic diseases affecting children are refractory to traditional gene-discovery approaches. The advent of NGS has overcome these obstacles, changing the landscape of rare genetic disease research such that causative genes are being discovered at an impressive rate (Figure 1). Whole-genome sequencing (WGS) and whole-exome sequencing (WES) are powerful, unbiased NGS-based approaches for detecting genetic variation within an individual and provide an unprecedented degree of sequence depth and genome coverage (Figure 2). In WES, the ∼1% of the protein-coding portion of the genome (the exome) is enriched by one of several capture approaches (reviewed in 9), whereas in WGS, no capture-based enrichment occurs prior to sequencing. The initial proof of concept of the utility of WES in childhood disease gene discovery came with the identification of genes for three previously intractable diseases: autosomal dominant Freeman-Sheldon syndrome (MIM 193700) (10), recessive Miller syndrome (MIM 263570) (11), and dominant Schinzel-Giedion syndrome (MIM 269150) (12). Early successes for WGS in childhood disease included Miller syndrome (13) and metachondromatosis (MIM 156250) (14). However, given the greater complexity and cost of WGS analysis, as well as the fact that most rare disease mutations are within the exome, WES is currently the more popular platform for the discovery of rare childhood disease genes (Figure 1). To date, based on our review of the literature, we estimate that 234 novel rare disease genes have been discovered using either WES (228 genes) or WGS (6 genes), with 87 discoveries reported in the past six months alone (Figure 1).

STRATEGIES FOR GENE DISCOVERY The genes that cause rare childhood diseases may be altered by any of several mechanisms, but in this review we focus on inherited and

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Figure 1 Number of novel genes discovered by whole-exome sequencing (WES) or whole-genome sequencing (WGS). This graph represents the results of PubMed searches on “exome sequencing” and “whole genome sequencing,” sorted by date of publication and filtered for only single-gene diseases (references to complex diseases and cancer were excluded). Results were sorted to identify those that reported novel gene discovery, and duplicates were removed. The number of novel disease genes identified using WES is significantly greater than that by WGS. Adapted from Reference 8.

de novo mutations in single genes. The recurrence of a rare disease in a single family or a high degree of parental consanguinity suggests an inherited mutation, whereas a well-defined phenotype that is always reported as an isolated occurrence suggests the disease is secondary to de novo mutations. The mode of inheritance, likelihood of a de novo mutation, and availability of patient material (e.g., from one or several families) influences the design and analytical approach utilized, and three robust strategies have emerged on the basis of these various contingencies (Figure 3).

Strategy 1: Multiple Unrelated Patients with the Same Disease The central tenet of this strategy is that unrelated patients with the same disease have www.annualreviews.org • Genes for Childhood Heritable Diseases

De novo mutation: a new mutation that was not inherited from either parent

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3.38 Mb 2,435,718K 2,435,937K 2,436,156K 2,436,375K 2,436,594K 2,436,813K 2,437,032K 2,437,251K 2,437,470K 2,437,689K 2,437,908K 2,438,127K 2,438,346K 2,438,565K 2,438,784K

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Figure 2 Schematic representation of next-generation sequencing results. Zooming in on a 3-Mb region of chromosome 18p provides a glimpse of a next-generation sequencing coverage profile from a patient with a rare disease (using NextGENeTM software v2.10 from SoftGenetics) . Further magnification of a 32-bp stretch within the coverage profile from the region demonstrates the alignment of multiple sequence reads from the patient to a reference genome. A 3-bp heterozygous insertion that is not found in the reference genome is highlighted in blue. Abbreviations: bp, base pair; Mb, megabase.

mutations in the same gene (Figure 3a). Most often these cases are sporadic/isolated occurrences in a family, and therefore the rare disease in these children may be either secondary to an ultrarare recessive disease or a de novo

dominant mutation. This strategy has the added value of validation of a novel gene as definitively disease-causing incorporated into the study design because multiple independent mutations in the same gene will ultimately be identified. As

−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−→ Figure 3 Strategies for gene discovery. (a) Strategy 1 is based on the assumption that because all patients have the same disease, they will all harbor alterations in the same gene. Multiple unrelated affected individuals are sequenced as singletons or trios (affected child with unaffected parents) with the same disease to identify the gene that contains mutations in all affected individuals. (b) Strategy 2 is used for autosomal dominant (AD) families with multiple affected individuals (usually >5) or consanguineous families with at least one affected individual. Linkage or haplotype analysis is performed to exclude large areas of the genome from further study and thus refine the region harboring the disease-causing mutation to a more manageable size. (c) Strategy 3 is used to identify autosomal recessive compound heterozygous mutations in the disease gene by sequencing affected siblings. One parent is often also sequenced to rapidly establish the phase of identified variants (i.e., in cis or in trans). 22

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described below, two approaches can be utilized within this strategy to discover disease genes.


Analysis of multiple unrelated patients or families. This approach can be used to identify a gene with any mode of inheritance, including diseases secondary to a de novo dominant mutation. An example of the analysis of multiple isolated patients by WES for a dominant disorder is illustrated by the recent discovery of the gene for mandibulofacial dysostosis with microcephaly (MFDM; MIM 610536). Originally described in 2006 (15), MFDM is a rare syndrome characterized by craniofacial malformations, microcephaly, developmental delay, a recognizable dysmorphic appearance, and variable features such as choanal atresia, sensorineural hearing loss, and cleft palate. Recurrence or transmission of MFDM has never been reported, suggesting either an ultrarare recessive condition or a dominant disorder secondary to de novo mutations. WES of four unrelated MFDM patients was conducted and the data assessed for rare (allele frequency of 30 participating global funding organizations (http://www.irdirc.org; accessed September 2013) and their aligned research projects; a main objective is to provide diagnostic tools for all rare genetic diseases by the year 2020. This will require sophisticated tools to share and integrate phenotypic and genetic data sets, and we envision that within the near future one will be able to contribute such data to a much larger data set in an effort to find a clinical and genetic match and rapidly move gene discovery forward.


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CLINICAL IMPACT FOR CHILDREN A genetic diagnosis in a child with a rare disease is simultaneously the end of the diagnostic odyssey and the first step toward informed management—and, in some cases, a definitive treatment. As we come to understand the breadth of the phenotypes caused by rare mutations as well as the genes and common pathways involved, genetic diagnoses for children with 28

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rare diseases will become progressively easier. In addition, a diagnosis represents a significant step forward for families in several ways: it facilitates more effective advocacy for school- and community-based resources to help the child as well as access to natural history information to enable planning for the future. A genetic diagnosis also provides accurate recurrence risk counseling for the family and identification of others who may be at risk of the disease or carriers of the mutation (38). The beneficial results of clinical WES guiding medical management decisions are exemplified by the care of a child with intractable gastrointestinal abscesses and a diagnosis of Crohn’s disease. The child underwent significant investigations and multiple surgeries (including a total abdominal colectomy and end ileostomy) over a span of several years. WES identified mutations in the XIAP gene (Xlinked inhibitor of apoptosis), and the child’s diagnosis was corrected to X-linked lymphoproliferative syndrome (MIM 300635). As a result, the child underwent an allogenic hematopoietic progenitor stem cell transplant, which led to complete resolution of his symptoms at the time of reporting (39). Occasionally a genetic diagnosis will present an obvious therapeutic approach based on new insight into the mechanism of the disease. For example, WES of twins afflicted with a debilitating movement disorder identified mutations in the SPR gene, which encodes sepiapterin reductase (SPR) (40). Disruption of SPR causes a decrease in tetrahydrobiopterin, a cofactor required for the synthesis of the neurotransmitters dopamine and serotonin (MIM 612716). Treatment with 5-hydroxytryptophan, a serotonin precursor, in addition to L-dopa therapy, resulted in significant clinical improvement for both twins. A second example of immediate therapeutic insight comes with the recent WES-based identification of VMAT2 as causative for an infantile-onset movement disorder characterized by severe parkinsonism, nonambulation, mood disturbance, autonomic instability, and developmental delay (41). VMAT2 encodes vesicular monoamine

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transporter 2, a translocator of dopamine and serotonin into synaptic vesicles, and subsequent use of dopamine agonists resulted in marked clinical improvement. To have a beneficial impact on patient care, NGS and its analyses need to be available to the clinic in a timely manner (42). In a recent study examining clinical translation of WGS to the bedside in the neonatal intensive care unit, the time from blood sample collection to preliminary reporting was two days (43), a remarkable

achievement considering it has not been many years since clinical geneticists waited at least two days for an urgent karyotype to guide the management of a critically ill baby. Although clinical exomes are emerging as a testing option at a few centers, they are currently available only to a fraction of patients with rare diseases; clearly a significant amount of clinical translation remains to bring the benefits of a genetic diagnosis to all children with heritable diseases.


SUMMARY POINTS 1. Although childhood heritable diseases are individually rare, they are collectively common, representing a significant and unmet medical need. 2. For the estimated >5,000 rare childhood genetic diseases, the causative genes are known for only half. 3. Next-generation sequencing is contributing to the recent rapid progress in gene identification. 4. Our understanding of these diseases is expanding as we gain insight into the mild and severe ends of the phenotypic spectrum and the underlying biological mechanism(s).

FUTURE ISSUES 1. Maintaining the pace of gene discovery for the increasingly rare diseases that remain will require large-scale collaboration. 2. Advances in care for children with rare heritable diseases will require translation of genomic technologies to the clinic. 3. Although the majority of heritable childhood diseases still have no definitive treatment, advances in our understanding of the mechanisms for many diseases will provide therapeutic opportunities.

DISCLOSURE STATEMENT The authors are not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this review.

ACKNOWLEDGMENTS We thank the FORGE Canada Consortium and each participating child and his/her family for providing the opportunity to explore best practices around rare disease gene discovery. Funding for FORGE was provided by the Government of Canada through Genome Canada, the Canadian Institutes of Health Research (CIHR), and the Ontario Genomics Institute (OGI-049) and by www.annualreviews.org • Genes for Childhood Heritable Diseases

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Genome Québec, Genome British Columbia, and the McLaughlin Center (Toronto). The authors would like to thank Dr. Alex MacKenzie for critical reading of the manuscript.

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RELATED RESOURCES EURORDIS: http://www.eurordis.org/ FORGE Canada Consortium: http://www.care4rare.ca International Rare Disease Research Consortium: http://www.irdirc.org/ OMIM: http://www.ncbi.nlm.nih.gov/sites/entrez?db=omim Orphanet: http://www.orpha.net/consor/cgi-bin/index.php www.annualreviews.org • Genes for Childhood Heritable Diseases

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Contents

Annual Review of Medicine Volume 65, 2014


Adult Genetic Risk Screening C. Thomas Caskey, Manuel L. Gonzalez-Garay, Stacey Pereira, and Amy L. McGuire p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1 Identification of Genes for Childhood Heritable Diseases Kym M. Boycott, David A. Dyment, Sarah L. Sawyer, Megan R. Vanstone, and Chandree L. Beaulieu p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p19 Genomic Sequencing for Cancer Diagnosis and Therapy Linghua Wang and David A. Wheeler p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p33 Pathogenesis of Abdominal Aortic Aneurysms: MicroRNAs, Proteases, Genetic Associations Lars Maegdefessel, Ronald L. Dalman, and Philip S. Tsao p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p49 DNA Sequencing of Cancer: What Have We Learned? Juliann Chmielecki and Matthew Meyerson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p63 Applied Pharmacogenomics in Cardiovascular Medicine Peter Weeke and Dan M. Roden p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p81 Molecular Testing in Breast Cancer Costanza Paoletti and Daniel F. Hayes p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p95 Chemoprevention of Prostate Cancer Goutham Vemana, Robert J. Hamilton, Gerald L. Andriole, and Stephen J. Freedland p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 111 Thyroid Cancer Tobias Carling and Robert Udelsman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 125 Targeting Apoptosis Pathways for New Cancer Therapeutics Longchuan Bai and Shaomeng Wang p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 139 Targeting Metabolic Changes in Cancer: Novel Therapeutic Approaches Ekaterina Bobrovnikova-Marjon and Jonathan B. Hurov p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 157 Retinoblastoma: Saving Life with Vision David H. Abramson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 171 v

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Immune Modulation in Cancer with Antibodies David B. Page, Michael A. Postow, Margaret K. Callahan, James P. Allison, and Jedd D. Wolchok p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 185 Depression as a Risk Factor for Cancer: From Pathophysiological Advances to Treatment Implications M. Beatriz Currier and Charles B. Nemeroff p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 203 IL-1 Blockade in Autoinflammatory Syndromes Adriana A. Jesus and Raphaela Goldbach-Mansky p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 223 α7-Nicotinic Acetylcholine Receptor Agonists for Cognitive Enhancement in Schizophrenia Robert Freedman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 245 Annu. Rev. Med. 2014.65:19-31. Downloaded from www.annualreviews.org by University of Sydney on 01/31/14. For personal use only.

Anti–B Cell Antibody Therapies for Inflammatory Rheumatic Diseases Mikkel Faurschou and David R.W. Jayne p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 263 Nuclear Receptor Coactivators: Master Regulators of Human Health and Disease Subhamoy Dasgupta, David M. Lonard, and Bert W. O’Malley p p p p p p p p p p p p p p p p p p p p p p p 279 Male Circumcision: A Globally Relevant but Under-Utilized Method for the Prevention of HIV and Other Sexually Transmitted Infections Aaron A.R. Tobian, Seema Kacker, and Thomas C. Quinn p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 293 New Frontiers in Patient-Reported Outcomes: Adverse Event Reporting, Comparative Effectiveness, and Quality Assessment Ethan Basch p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 307 Evidence-Based Treatment of Post-Traumatic Stress Disorder JoAnn Difede, Megan Olden, and Judith Cukor p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 319 Chimeric Antigen Receptor Therapy for Cancer David M. Barrett, Nathan Singh, David L. Porter, Stephan A. Grupp, and Carl H. June p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 333 Renal Sympathetic Denervation for the Treatment of Refractory Hypertension Kui Toh Gerard Leong, Antony Walton, and Henry Krum p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 349 Transcatheter Aortic Valve Replacement: Game-Changing Innovation for Patients with Aortic Stenosis Kishore J. Harjai, Jean-Michel Paradis, and Susheel Kodali p p p p p p p p p p p p p p p p p p p p p p p p p p p p 367 Future of Cholesteryl Ester Transfer Protein Inhibitors Daniel J. Rader and Emil M. deGoma p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 385 Adaptive Clinical Trial Design Shein-Chung Chow p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 405

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Reduction of Low-Density Lipoprotein Cholesterol by Monoclonal Antibody Inhibition of PCSK9 Evan A. Stein and Frederick Raal p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 417 The Antithrombotic Effects of Statins A. Phillip Owens III and Nigel Mackman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 433 Delivering Value: Provider Efforts to Improve the Quality and Reduce the Cost of Health Care Jonathan E. Gordon, Joan M. Leiman, Emme Levin Deland, and Herbert Pardes p p p p 447


New Cost-Effective Treatment Strategies for Acute Emergency Situations Subani Chandra and David H. Chong p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 459 Reducing Hospital Readmission Rates: Current Strategies and Future Directions Sunil Kripalani, Cecelia N. Theobald, Beth Anctil, and Eduard E. Vasilevskis p p p p p p p p p 471 Indexes Cumulative Index of Contributing Authors, Volumes 61–65 p p p p p p p p p p p p p p p p p p p p p p p p p p p 487 Cumulative Index of Article Titles, Volumes 61–65 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 491 Errata An online log of corrections to Annual Review of Medicine articles may be found at http://www.annualreviews.org/errata/med

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ANNUAL REVIEWS It’s about time. Your time. It’s time well spent.

New From Annual Reviews:

Annual Review of Statistics and Its Application Volume 1 • Online January 2014 • http://statistics.annualreviews.org

Editor: Stephen E. Fienberg, Carnegie Mellon University


Associate Editors: Nancy Reid, University of Toronto Stephen M. Stigler, University of Chicago The 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. Fienberg • A 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

• High-Dimensional Statistics with a View Toward Applications in Biology, Peter Bühlmann, 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

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

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

• Brain Imaging Analysis, F. DuBois Bowman

• Event History Analysis, Niels Keiding

• Statistics and Climate, Peter Guttorp

• Statistical Evaluation of Forensic DNA Profile Evidence, Christopher D. Steele, David J. Balding

• Climate Simulators and Climate Projections, Jonathan Rougier, Michael Goldstein • Probabilistic Forecasting, Tilmann Gneiting, Matthias Katzfuss • Bayesian Computational Tools, Christian P. Robert • Bayesian 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

• Using League Table Rankings in Public Policy Formation: Statistical Issues, Harvey Goldstein • Statistical Ecology, Ruth King • Estimating the Number of Species in Microbial Diversity Studies, John Bunge, Amy Willis, Fiona Walsh • Dynamic Treatment Regimes, Bibhas Chakraborty, Susan A. Murphy • Statistics and Related Topics in Single-Molecule Biophysics, Hong Qian, S.C. Kou • Statistics 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.

ANNUAL REVIEWS | Connect With Our Experts Tel: 800.523.8635 (US/CAN) | Tel: 650.493.4400 | Fax: 650.424.0910 | Email: [email protected]

An estimate of the heritable fraction of childhood cancer.

Towards authentic transgenic mouse models of heritable PrP prion diseases.

Vaccination campaigns for common childhood diseases.

Use of oocytes from anonymous, matched, fertile donors for prevention of heritable genetic diseases.

Next-generation sequencing for mutation detection in heritable skin diseases: the paradigm of pseudoxanthoma elasticum.

[Myelodysplastic diseases in childhood].

DNA repair. Seven genes for three diseases.

[Salivary gland diseases in childhood].

Nontuberculous pulmonary cavitary diseases of childhood.

Identification of targets for rational pharmacological therapy in childhood craniopharyngioma.

Diseases of the middle ear in childhood.

Current management of selected childhood renal diseases.

[Diseases of the middle ear in childhood].

Neurologic manifestations of childhood rheumatic diseases.

Research into rare diseases of childhood.

Hypertension in acute neurological diseases of childhood.

Paralytic diseases of childhood in the tropics.

Phenolyzer: phenotype-based prioritization of candidate genes for human diseases.

On the definition and utilization of heritable variation among hosts in reproduction ratio R0 for infectious diseases.

Breast cancer risk after radiotherapy for heritable and non-heritable retinoblastoma: a US-UK study.

Nucleoporin genes in human diseases.

Heritable influences on behavioural problems from early childhood to mid-adolescence: evidence for genetic stability and innovation.

Gingival diseases in childhood - a review.

Recent advances in childhood diarrhoeal diseases.