Alan E. Guttmacher

Finding the missing heritability of complex diseases

Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, ‘missing’ heritability can be explained. Here we examine potential sources of missing heritability and propose research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.

A vision for the future of genomics research

A blueprint for the genomic era.

Replicating genotype-phenotype associations.

What constitutes replication of a genotype–phenotype association, and how best can it be achieved?

New models of collaboration in genome-wide association studies: the Genetic Association Information Network.

The Genetic Association Information Network (GAIN) is a public-private partnership established to investigate the genetic basis of common diseases through a series of collaborative genome-wide association studies. GAIN has used new approaches for project selection, data deposition and distribution, collaborative analysis, publication and protection from premature intellectual property claims. These demonstrate a new commitment to shared scientific knowledge that should facilitate rapid advances in understanding the genetics of complex diseases.

Personalized genomic information: preparing for the future of genetic medicine

The falling cost of sequencing means that we are rapidly approaching an era in which access to personalized genomic information is likely to be widespread. Here, four experts with different insights into the field of genomic medicine answer questions about the prospects for using this type of information. Their responses highlight the diverse range of issues that must be addressed — ranging from scientific to ethical and logistical — to ensure that the potential benefits of personal genomic information outweigh the costs to both individuals and societies.

Genetic Testing and Psychology: New Roles, New Responsibilities.

Advances in genetics and genetic testing promise to catalyze a fundamental change in the practice of medicine. Psychologists have much to offer as psychotherapists, researchers, educators, and policymakers to a society heavily influenced by the genetic revolution. To make the most of new opportunities available to mental health professionals in genetics, psychologists must know basic genetic principles and learn what is new about 21st-century genetics. The core competencies for all health professionals developed by the National Coalition for Health Professional Education in Genetics are related in this article to the significant roles psychologists can play in helping individuals with genetic concerns to cope with vulnerability, optimize family interaction, and improve health behaviors.

We Don't Know What We Don't Study: The Case for Research on Medication Effects in Pregnancy

This Commentary addresses issues related to exposures to teratogens and makes the case for increased research into the safety of medication usage during pregnancy for mothers and fetuses. Not only are medications commonly used during pregnancy, but evidence points to an increasing prevalence and number of drug exposures experienced by the embryo or fetus, particularly during the critical first trimester of pregnancy. Although the first trimester represents a particularly vulnerable period of organogenesis, exposures during other gestational time periods may also be associated with deleterious outcomes. In addition to the changing (and in many cases unknown) risks to a developing fetus, other challenges to studying medication exposures and their effects during pregnancy include the dramatic changes in physiology that occur in pregnant women and the ethical dilemmas posed by including this vulnerable population in randomized controlled trials of safety and efficacy. However, without adequate knowledge of the pharmacokinetics, pharmacodynamics, efficacy, and safety of medication use in pregnancy, women may be under‐dosed to minimize exposure or not treated at all, resulting in inadequate treatment and potential harm to the mother and her baby. The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) is undertaking studies on medications and teratogenic exposures during pregnancy, including alcohol, maternal diabetes, oral hypoglycemic agents, and antiviral medications, through several of its research networks. Although this is a start, there is a critical need for further research on medications used during pregnancy, especially their effects on both the mother and her developing child. Published 2011 Wiley‐Liss, Inc.

A solution pathway for preterm birth: accelerating a priority research agenda

Open access under CC BY-NC-ND license. Correspondence to: Eve M Lackritz. Members of the Preterm Birth Research Priority Setting Group are: Shams El Arifeen, José M Belizán, Zulfiqar Bhutta, Wally Carlo, A J Challis, Jennifer F Culhane, Carolyn D Deal, Michal A Elovitz, Charles J Homer, Christopher P Howson, Joy E Lawn, James A Litch, Yvonne T Maddox, Carole R Mendelson, Sam Mesiano, David A Relman, Roberto Romero, Yoel Sadovsky, Susan B Shurin, Hyagriv N Simhan, Peter Waiswa, Peter Winch, and Paul H Wise. The views expressed in this Comment are the responsibility of the authors and do not necessarily represent the views of their institutions or organisations. We declare that we have no conflicts of interest. Funding and leadership for the preterm birth research meetings were provided by the Bill & Melinda Gates Foundation, GAPPS, March of Dimes, and NICHD. HHS Public Access Author manuscript Lancet Glob Health. Author manuscript; available in PMC 2017 September 07.

Promoting Education, Mentorship, and Support for Pediatric Research

Pediatricians play a key role in advancing child health research to best attain and improve the physical, mental, and social health and well-being of all infants, children, adolescents, and young adults. Child health presents unique issues that require investigators who specialize in pediatric research. In addition, the scope of the pediatric research enterprise is transdisciplinary and includes the full spectrum of basic science, translational, community-based, health services, and child health policy research. Although most pediatricians do not directly engage in research, knowledge of research methodologies and approaches promotes critical evaluation of scientific literature, the practice of evidence-based medicine, and advocacy for evidence-based child health policy. This statement includes specific recommendations to promote further research education and support at all levels of pediatric training, from premedical to continuing medical education, as well as recommendations to increase support and mentorship for research activities. Pediatric research is crucial to the American Academy of Pediatrics’ goal of improving the health of all children. The American Academy of Pediatrics continues to promote and encourage efforts to facilitate the creation of new knowledge and ways to reduce barriers experienced by trainees, practitioners, and academic faculty pursuing research.

Ending Preventable Child Death in a Generation

DURING THE PAST 20 YEARS, THERE HAS BEEN A SUBstantial decline in mortality among children younger than 5 years from 12.0 million deaths in 1990 to 7.6 million in 2010. In these decades alone, global health and development efforts have saved the lives of more than 50 million children, half of them by preventing deaths due to pneumonia, diarrhea, and measles. This improvement in child survival was catalyzed in part by setting aspirational global targets such as the Millennium Development Goals (MDGs). As 2015 approaches, and with it a final assessment of progress toward MDG 4 on reducing child mortality, it is appropriate to consider a post-2015 vision for child health. A new common vision for a global commitment to end all preventable child deaths is needed. Such a vision will not be compelling unless it can be tied to concrete and measurable benchmarks at the global and country levels that are both ambitious and plausible. In this Viewpoint, a new benchmark is detailed: that all countries achieve a national under-5 mortality rate (U5MR) of no more than 20 deaths per 1000 live births by 2035 and that the global average U5MR should decline to 15 deaths per 1000 in 2035. Of 195 countries, 98 already have U5MRs of 20 per 1000 or fewer; 43 countries would be expected to reach this goal by 2035 at current annual rates of reduction (ARRs), and 54 countries would have to accelerate progress above the 2000-2010 ARRs. The proposed U5MR benchmark of 20 deaths per 1000 live births is supported by modeling analyses by UNICEF as well as similar exercises at Johns Hopkins Bloomberg School of Public Health and the Institute for Health Metrics and Evaluation at the University of Washington. The consensus of a consultation at the National Institutes of Health’s Fogarty International Center in May 2012 was that this benchmark, while ambitious, could be achieved for most countries. In addition, for countries in which the U5MR is already near or below 20 deaths per 1000, the focus could be on ensuring that all subpopulations (defined in local terms of geography, socioeconomic groups, or other equity measures) have a U5MR of fewer than 20 deaths per 1000. The global average of 15 deaths per 1000 in 2035 would be within the current range of U5MRs in industrialized countries of 3 deaths per 1000 to 18 deaths per 1000 (FIGURE). Achieving these benchmarks would require a global ARR in U5MR of 5.3% over the period 2010 to 2035, more than doubling the ARR of the last decade of 2.5%. Clearly, significant accelerations in progress will be required in many countries, including those that are among the largest contributors to global child deaths—India, Nigeria, Pakistan, the Democratic Republic of the Congo, and Ethiopia. For instance, India, which accounts for nearly a quarter of all child deaths, has had an ARR of 3.1% for the last decade. It would need to increase this ARR to 4.6% to reach the U5MR of 20 deaths per 1000 by 2035. Pneumonia, diarrhea, and malaria remain significant global causes of death, but recent progress against these diseases means an increasing proportion of under-5 deaths are due to neonatal conditions (40% of the total currently), including preterm birth complications, intrapartum complications, and severe neonatal infections. Preventing these deaths will require different interventions such as safe deliveries, chlorhexidine cord care, or antibiotics for treatment of sepsis, meningitis, and pneumonia. The Lives Saved Tool estimates the improvements in mortality rates that can be achieved in 2035 by scaling up current interventions to provide full and equitable coverage. Such modeling provides insights into the individual value of each intervention, but preliminary results indicate that a major effort will be required on many fronts— from malaria control in endemic areas to the prevention of neonatal deaths in all settings. Success in bending the curve of child mortality is predicated on renewed commitment and political will as well as continued innovation in health technology and implementation science to scale solutions in a sustainable manner, including harnessing the power of such modern tools as mobile phones. Continued gains in reducing poverty, improving education for girls, and strengthening health systems and family planning would also help improve child survival. Ending preventable child deaths will not be due only to tradi-