A new strategy for enhancing imputation quality of rare variants from next-generation sequencing data via combining SNP and exome chip data

Background: Rare variants have gathered increasing attention as a possible alternative source of missing heritability. Since next generation sequencing technology is not yet cost-effective for large-scale genomic studies, a widely used alternative approach is imputation. However, the imputation approach may be limited by the low accuracy of the imputed rare variants. To improve imputation accuracy of rare variants, various approaches have been suggested, including increasing the sample size of the reference panel, using sequencing data from study-specific samples (i.e., specific populations), and using local reference panels by genotyping or sequencing a subset of study samples. While these approaches mainly utilize reference panels, imputation accuracy of rare variants can also be increased by using exome chips containing rare variants. The exome chip contains 250 K rare variants selected from the discovered variants of about 12,000 sequenced samples. If exome chip data are available for previously genotyped samples, the combined approach using a genotype panel of merged data, including exome chips and SNP chips, should increase the imputation accuracy of rare variants. Results: In this study, we describe a combined imputation which uses both exome chip and SNP chip data simultaneously as a genotype panel. The effectiveness and performance of the combined approach was demonstrated using a reference panel of 848 samples constructed using exome sequencing data from the T2D-GENES consortium and 5,349 sample genotype panels consisting of an exome chip and SNP chip. As a result, the combined approach increased imputation quality up to 11 %, and genomic coverage for rare variants up to 117.7 % (MAF < 1 %), compared to imputation using the SNP chip alone. Also, we investigated the systematic effect of reference panels on imputation quality using five reference panels and three genotype panels. The best performing approach was the combination of the study specific reference panel and the genotype panel of combined data. Conclusions: Our study demonstrates that combined datasets, including SNP chips and exome chips, enhances both the imputation quality and genomic coverage of rare variants

Search for supersymmetry in events with large missing transverse momentum, jets, and at least one tau lepton in 20 fb−1 of √s=8 TeV proton-proton collision data with the ATLAS detector

A search for supersymmetry (SUSY) in events with large missing transverse momentum, jets, at least one hadronically decaying tau lepton and zero or one additional light leptons (electron/muon), has been performed using 20.3fb−1 of proton-proton collision data at √s= 8 TeV recorded with the ATLAS detector at the Large Hadron Collider. No excess above the Standard Model background expectation is observed in the various signal regions and 95% confidence level upper limits on the visible cross section for new phenomena are set. The results of the analysis are interpreted in several SUSY scenarios, significantly extending previous limits obtained in the same final states. In the framework of minimal gauge-mediated SUSY breaking models, values of the SUSY breaking scale Λ below 63 TeV are excluded, independently of tan β. Exclusion limits are also derived for an mSUGRA/CMSSM model, in both the R-parity-conserving and R-parity-violating case. A further interpretation is presented in a framework of natural gauge mediation, in which the gluino is assumed to be the only light coloured sparticle and gluino masses below 1090 GeV are excluded

What Will Come from the Supreme Court’s Stay of EPA’s Clean Power Plan?

The United States Supreme Court did something extraordinary this month: it halted the implementation of an administrative regulation before the circuit court of appeals could decide whether the regulation is valid. There is no known precedent for this action. And yet, it is unclear what significance the stay, as it is called, will have. The stay concerns the U.S. Environmental Protection Agency’s (EPA) Clean Power Plan, which the agency issued under the Clean Air Act. This Plan is an important part of the United States’ efforts to meet its December pledge made in Paris to lower greenhouse gas emissions by 26 to 28% from 2005 levels by 2025. The Plan seeks to reduce greenhouse gas emissions from American electricity generators, which account for about one-third of the U.S.’s greenhouse gas emissions, by requiring States and electricity generating plants to speed the replacement of greenhouse gas-intensive coal by natural gas, and eventually by clean renewable fuels such as wind or solar. The Plan has been challenged before the Court of Appeals for the District of Columbia Circuit by 150 different parties, but even with an expedited schedule ordered by the court, it will be months before briefs are filed and oral argument heard. The Circuit Court itself had declined to stay the rule while the case is going on. Thus, the Supreme Court’s decision to intervene at this stage is remarkable. Yet the stay may have little significance. Originally, the stay was thought to presage an invalidation of the Plan by the Court. The death of Justice Antonin Scalia just three days after issuance of the stay means that those voting for it no longer hold the majority on the Court. Rather, the key may well be the identity of Justice Scalia’s replacement. It was not clear even before Justice Scalia’s death that the stay reflected a view on the merits. The five Justices who voted to grant the stay are the same justices who voted for the Court’s decision last spring in Michigan v. EPA, holding that the EPA had violated the Clean Air Act in promulgating a regulation to reduce emissions of mercury and other hazardous air pollutants from electricity generators. That decision had little impact because the rule had not been stayed pending review, and so, before the Court decided the case, the vast majority of plants had already complied with the rule. Possibly the Court wants to prevent a repetition. But the Plan lacks the same potential for making the Court’s eventual decision moot. The final deadline for compliance is not until 2032. All that would have happened for the next year or two — the likely period before the Supreme Court can decide the case if it chooses to do so — is that the States would develop plans to implement the Plan. Even this is not clear, because the EPA has said that it will be generous in giving states two additional years before submitting their plans to EPA. So it is unclear whether the Court was seeking to preserve the status quo pending judicial review. The stay’s significance is also doubtful because it does not have that much practical importance. The stay does not prevent states from developing strategies to carry out the Plan, and at the least, the eighteen states that have intervened in court to support the Plan can be expected to do so. The stay does allow opposing states – twenty-seven have joined the suits against the Plan – to halt their efforts, but the deadline for submitting plans is, as detailed above, hardly immediate and so a delay in plan development pending judicial review will probably not have much effect. Moreover, the Court, like King Canute, cannot stop the tide. In the short-term, federal tax incentives will do more than the Plan to increase the use of renewable energy. And, even without the Plan, drastic changes in electricity generation are coming. The EPA thinks that the Plan does nothing more than accelerate a trend from coal toward natural gas and renewables that is happening anyway, primarily for economic reasons. Already, utilities are building new natural gas-fired turbines rather than keeping coal-burning generators in existence, and utilities and others are investing in renewables, which are rapidly growing as sources of electricity. Perhaps even without the Plan, the shift to cleaner fuels will happen sooner rather than later. The stay does, however, illustrate how controversial the rule is. Issues of statutory interpretation alone raise concerns about whether the Plan is valid. The EPA promulgated the Clean Power Plan under section 111(d) of the Clean Air Act. Traditionally, this section can take effect when EPA sets a “new source performance standard” (NSPS) — a limit on emissions from new and modified sources — for a category of industrial plant, e.g. cement makers. Under its traditional wording, section 111(d) applies to pollutants that are regulated by a category’s NSPS if those pollutants are not regulated under either of the Act’s major programs: the national ambient air quality standards and the hazardous air pollution program. Section 111(d) sets up a program for regulating existing sources in the NSPS category these otherwise non-regulated pollutants. For instance, consider paper mills, which emit large quantities of total reduced sulfur. This pollutant smells like rotten eggs and it is regulated by the NSPS for such mills. But total reduced sulfur does not amount to a significant nationwide problem, and so EPA probably could not set a national ambient air quality standard for it. Nor is the pollutant so harmful that it would justify being regulated as a carcinogen under the hazardous air pollutant program. Thus, section 111(d) covers emissions of this pollutant from existing paper mills. Under section 111(d), each state is required to submit a plan to regulate existing sources within the NSPS category that emit pollutants like total reduced sulfur. Section 111(d) says that a state is allowed to take into account, among other factors, the remaining useful life of the source, and so a state need not adopt for existing plants the same standard that applies to new plants. The EPA produces guidelines to help the states, and must either approve or disapprove each state’s plan. Arguably, section 111(d) is merely an interstitial provision to cover a gap that would otherwise exist for pollutants that are deleterious, but not important enough to otherwise regulate under the Act. Indeed, section 111(d) has been little-used. Moreover, section 111(d) seems to give the primary role to the States in deciding what each existing source in the NSPS category must do. The Clean Power Plan, however, attempts to use section 111(d) to establish a substantial new program with EPA setting targets for the States to reach. On its face, section 111(d) would seem to cover greenhouse gases. There are neither ambient air quality standards for or standards under the hazardous air pollutant program for these pollutants. And the EPA has recently set an NSPS for emissions of greenhouse gases from new and modified fossil-fuel fired electricity generators, thus seemingly setting the stage for regulation of greenhouse gas emissions from existing generators under 111(d). But the EPA’s program is far from interstitial. Rather, it requires each state to formulate complex plans under which the generation mix in the state will include less use of coal, and more use of natural gas, with an eventual prominent role for renewable sources. This would be a profound transformation of an important sector of the economy. The Supreme Court, in opinions by the late Justice Antonin Scalia, has used the principle of “no elephants in mouseholes” – for this reason, the Court has refused to find that EPA can fully regulate greenhouse emissions from all major new and modified stationary sources. The Court has said that an existing regulatory provision should not be interpreted to allow an agency to create a broad new program. Clearly this principle – if the Court is still willing to follow it now that Justice Scalia is deceased — threatens an effort as novel and comprehensive as the Clean Power Plan. Congressional action in 1990 makes the use of section 111(d) even more controversial. In that year, Congress, as part of lengthy amendments to the Act, adopted two apparently conflicting amendments to section 111(d). One provision, originating in the Senate, made a minor conforming change that continued section 111(d)’s traditional coverage of pollutants regulated neither by ambient air quality or hazardous air pollutant standards. But a provision originating in the House appears to take a different approach. On its face, it prohibits the use of section 111(d) to regulate any source category that is also regulated under the hazardous air pollutant program. Because the EPA has set hazardous air pollutant standards for electricity generators, the House provision would apparently forbid EPA from using section 111(d) to regulate generators. The EPA asserts that the two amendments are actually not in conflict. The agency points out that following the literal language of the House’s provision would create a gap in regulation for harmful pollutants that are not appropriate for regulation under the national ambient air quality standards or hazardous air pollutant program, but come from sources being regulated for a hazardous air pollutant. Seeing no evidence that Congress intended such a gap — indeed, Congress was silent on what either amendment meant – the EPA concludes that the House amendment, like the Senate amendment, merely continues the traditional approach. But the EPA’s position arguably is not easy to reconcile with the rather straightforward language of the House amendment. Moreover, it is at least plausible that Congress did intend to create a gap. The hazardous air pollutant program was extensively tightened in 1990, and Congress may have thought that a source category should not be subject both to that program and section 111(d). Indeed, this would parallel what happened with regulation of emissions of hazardous air pollutants from electricity generators. Congress specifically said in 1990, in section 112(n) of the Act, that utility emissions of hazardous air pollutants like mercury could be regulated only after a special finding by the EPA that regulation would be appropriate and necessary. Here, too, Congress was concerned about an industry that was going to be controlled sharply under newly-established parts of the Act. The EPA and its allies say they have strong arguments in favor of the Plan on these and other points (e.g., on whether a plant can be required to take steps “outside the fenceline” to reduce its emissions). All that can be stated for sure is that the Plan’s validity is being sharply challenged. But it is far from clear that the Court’s stay will have a substantial effect

The Need to Protect Health from Fine Particles

This December, the Obama Administration will again have to decide how much air quality is needed to protect public health and welfare. Last year, the administration, after a prolonged internal battle, decided not to tighten the air quality standards for ozone because achieving the standards would be too costly. Now the administration will have to decide whether and how much to tighten the air quality standards for fine particles—those capable of penetrating into the deep lung. Fine particles are, the Environmental Protection Agency (EPA) says, a threat to public health. The most important effect is premature mortality, particularly in the very old. Premature deaths number in perhaps the tens of thousands annually, often in the form of cardiovascular mortality. Other effects include increases in hospital and emergency room visits, and the development of chronic obstructive pulmonary disease. Those of low socio-economic status seem particularly at risk. And, so far as we know, there is no safe level of fine particles. The Clean Air Act requires EPA to establish ambient air quality standards – limits on the permissible concentration of a pollutant in the air – for such pollutants. EPA first set ambient air quality standards for fine particles in 1997. The long-term annual standard—the key to reducing exposures—was set at 15 micrograms per cubic meter of air. After a prolonged judicial fight, these standards were upheld by the courts. In 2006, EPA decided not to tighten the 15 microgram standard despite the recommendation of the agency’s science advisors that it do so. The agency’s standard was remanded by the D.C. Circuit for failure to provide an adequate explanation–e.g. why the agency would not use studies of short-term effects to help set a standard for long-term effects, and vice versa. The court allowed the standard, though, to remain in place. EPA has been ordered to complete its current review promptly, and has just issued proposed standards. The agency asked that it be given until August, 2013, to issue a final rulemaking; instead, the court set this December as the deadline. As a result, the fine particle standards will be the midnight rulemaking par excellence. The agency deserves sympathy, even though its review was delayed—the staff that works on such standards has been steadily developing other air quality standards for the past six years. The time for action is so short that it will strain the agency’s scarce resources. Moreover, the task of standard-setting is quite difficult. It is hard to decide precisely the particle level that results in measurable premature deaths. So EPA must make a policy choice about how to deal with the uncertainties and gaps in what we know—that is, how protective should we be in the face of our ignorance. Some commentators have suggested that Congress or EPA should set principles to follow in setting the standards. But while principles would help cabin EPA’s judgment, it seems unlikely that one could ever devise a principle for deciding, for instance, how much uncertainty is too much to justify regulation, or how to appraise a scientific study. Cost-benefit, advocated by some as a possible principle, contains many uncertainties. In general, any principles are bound to be so vague as to be of limited use. This situation is hardly unique to environmental law. Doctors learn criteria to use in diagnosing and treating disease. Yet curing a patient cannot be reduced to rules, because it requires judgment. The same is as true in protecting public health. Indeed, the Clean Air Act recognizes this relationship when it says that standards to protect public health have to be requisite “in the judgment of the Administrator.” Yet to say something is a matter of judgment does not immunize EPA. Administrative law sensibly mandates that an agency explain its judgment in a non-arbitrary matter. Being laypeople, we cannot expect to know as much as the expert, but we at least are entitled to an explanation we can understand—just as one would expect a doctor to explain in lay terms why one must undergo an uncomfortable medical test. Unfortunately, EPA does not well explain its proposed decision to set the health-based standard in the 12-13 microgram range. EPA staff urged that the standard be set in the 11-12 range. Even the top of this level would be below the annual average at which health effects have been shown. A standard of 11 would afford a greater margin between the standard and the studies finding health effects. The staff added that considering a standard as high as 13 would be “reasonable” if the agency chose to discount on technical grounds the prime long-term study showing effects at lower levels than that. On the other hand, the staff conceded, there were still reliable studies showing effects below that level. Then, too, the staff said that there were uncertainties about effects occurring at the lower levels. Thus, the staff suggested that policymakers should consider the 11-13 range, and the agency’s science advisors concurred. EPA opted for the high end. The agency acknowledges in the proposal that four studies show effects down to below 12 micrograms. But it picks 12 to 13 on the grounds that this range places the most emphasis on the most robust studies—without explaining why it decided that the studies showing lower effects are not robust enough. It also suggests that the 12-13 range offers an adequate margin of safety to account for our ignorance, as required by the Clean Air Act, but does not explain why or how. Some in Washington believe that consideration of cost, although barred by the statute, influenced the decision, just as with the Obama Administration’s decision last year not to tighten the ozone standard. One account is that EPA decided that a standard of 11 would cause more unemployment than politically possible, and so the agency picked the high end of the plausible range. It would not be surprising if this happened. As Senator Edmund Muskie, father of the Clean Air Act, remarked over thirty years ago, the failure to find safe levels means that the Administrator must make a pragmatic judgment about where to set the standard. Costs inevitably play a role; yet, benefits should play a role as well, and a standard of 11 would actually result in the greatest net benefits. The bar against considering cost is in part a way of telling the Administrator not to put much emphasis on cost. It also means that the Administrator, in setting a standard, must speak the language of public health. Here the agency has so far failed to do so. This is undesirable because the proposed standard will attract a firestorm of criticism. Industry representatives are already arguing that the health effects do not arise from fine particles as a class, but rather are due to specific chemicals in the mass; taking that stance would exempt many sources needing to comply. Some in Congress are questioning, as with other EPA rules, the impact of the rules on a weak economy. And the standard will, of course, affect protection of public health. It is important for EPA to get the standard right and to articulate its rationales clearly

Will the Trump Administration Drastically Deregulate Environmental Protection?

What regulatory shifts in environmental law can we expect from the Trump Administration? Answer: It’s hard to know. Everyone knows that the signs to date point toward deregulation. The head of the Trump Administration’s transition team for the U.S. Environmental Protection Agency (EPA), Myron Ebell of the Competitive Enterprise Institute, proposed cutting the agency’s staff by two-thirds—that is, down to EPA’s staffing levels during the Nixon years, when the agency’s responsibilities were far less than they are now. Ebell, at least, only had a place in government during the transition. Far more important is newly confirmed EPA Administrator Scott Pruitt, whose chief environmental activity as Oklahoma Attorney General was suing EPA to set aside new rules as overregulation. For instance, Pruitt and others challenged EPA’s Clean Power Plan—a rule aimed at reducing greenhouse gas emissions from electricity generating units —as well as its Mercury and Air Toxic Standards, which seek to limit mercury emissions and other toxic pollution from these same units. There are also rumors that Pruitt will initiate major staff shakeups and that soon-to-be-issued executive orders will call for weakening environmental requirements. Reinforcing this trend towards deregulation is Congress’s consideration of legislation that would make it more difficult for agencies to regulate. And perhaps most significant is President Trump’s executive order aimed at curbing regulation by focusing on cutting regulatory costs. Although the details of this executive order are far from clear, it apparently instructs agencies to repeal two existing rules for every new rule that they promulgate, and to ensure that the repealed rules are equivalent in cost to the costs imposed by a new rule. Of course, the order will discourage agencies from issuing new rules—even if the new rules have, as is the case with many of EPA’s regulations, monetized benefits far outweighing their costs. Under this executive order, EPA effectively will only be able to make rules required by statute. The consequence may be a retreat from many of the initiatives of the Obama Administration. For example, the Clean Power Plan may be repealed, or at the least, it will not be administered aggressively. EPA’s “Waters of the United States” rule—designed to clarify which waters are subject to federal regulation under the Clean Water Act—is similarly in trouble. But we must remember 1981, when the Reagan Administration came into power. Its choice for EPA administrator was Anne Gorsuch, who had little experience in environmental matters. Lobbyists seeking deregulation initially had much influence on the agency. During her short-lived tenure, a draft emerged of proposed amendments that would have eviscerated the Clean Air Act, much to the horror of environmental groups. Gorsuch also repeatedly weakened EPA’s enforcement office. Gorsuch warred with the agency’s career staff: a number of high-level executives were transferred—and some lost their jobs altogether—as punishment for not being sufficiently compliant with the Administration’s priorities. Capitol Hill looked unpromising, too, during the Reagan years. Then-Representative John Dingell (D-Mich.)—a firm environmentalist, but also someone who was concerned with the interests of auto companies, which employed many of the constituents in his Detroit congressional district—joined with industry and Republicans to put together a package of weakening amendments to the Clean Air Act, including a rollback of auto-emission standards l. And a so-called regulatory reform bill, designed to hamstring agencies from protecting public health and the environment, seemed in 1982 to have a considerable chance for some time of being enacted.. What was the outcome of these deregulatory efforts? For one, Gorsuch’s attempt to reduce the agency’s regulation of lead, a neurotoxin, ultimately led to a considerable tightening of the rules. Gorsuch herself was forced to resign in early 1983 because of a scandal concerning the agency’s Superfund program. In order to restore agency morale and credibility, the Reagan Administration felt obliged to name as the agency’s administrator the moderate William Ruckelshaus, who, years earlier under the Nixon Administration, had served as EPA’s first-ever administrator. The Clean Air Act amendments desired by Representative Dingell and his Republican allies never got out of committee; instead, they were defeated by grassroots lobbying and through aggressive opposition by such legislators as then-Representative Henry Waxman (D-Calif.). And the deregulatory legislation collapsed in the Senate. Notably, however, by the end of the Reagan Administration, some pieces of environmental legislation had been strengthened. For instance, President Reagan signed the Hazardous and Solid Waste Amendments of 1984, which considerably escalated the controls on the disposal of hazardous wastes. In 1986, the President also signed the Superfund Amendments and Reauthorization Act, which put more teeth into the Superfund program. This is not to say, of course, that all was ideal for environmental protection during the Reagan Administration. The Administration, for example, fought against proposed regulation of acid rain almost to the end. Still, the results of the Reagan Administration’s efforts turned out to be much less antiregulatory than anyone could have predicted when President Reagan took the oath of office. There were several constraints on the Reagan Administration, many of which still exist. One limiting factor was the grassroots activity of environmental groups, as with the groups’ successful defeat of efforts to alter the Clean Air Act. Such activity is on full display today: the advent of the Trump Administration has brought about a remarkable growth in fundraising by environmental groups, just as was true in the Reagan years. Another constraint was litigation brought by these groups. The courts did at times defer to the Reagan EPA’s deregulatory actions (the decision in the famous Chevron case being a prime example). But in the 1970s, the courts had made it clear that agency actions would be carefully examined to determine if they were the product of reasoned decision-making , and the courts established procedural requirements (such as disclosing relevant data and responding to material comments) to help judges make that examination. The Supreme Court made it clear in the State Farm case early in the Reagan Administration that these requirements apply to deregulation as well as regulation. These judicial mandates still exist today; if anything, they may become more limiting now that Chevron deference is being challenged by conservative judges. Thus the courts will remain an obstacle to deregulation. Congress can be another bulwark. True, unlike in the Reagan Administration, the party that currently controls the White House also controls both houses of Congress. Thus there is no immediate chance that there will be the kind of aggressive congressional oversight of EPA that marked the Reagan years. But the existence of the filibuster means that the Trump Administration will need the votes of at least eight Democratic senators to pass most significant legislation. Although 10 Democratic senators are up for reelection in states that President Trump carried, his popularity will be crucial in determining whether these senators think that they must approve his policies. He may find that a significant number of his supporters fear that their health and welfare would be endangered by pro-industry environmental policies. The business community will also provide an important check. Already, executives of major corporations are urging President Trump not to retreat from the Paris accords that the Obama Administration signed. These executives recognize that environmental protection is good for business, in that it leads to the development of innovative technology that can be marketed overseas. Finally, we should not forget about the states. In general, states in the United States have the power to regulate environmental pollution more strictly than does the federal government. States are, of course, under pressure not to regulate stringently for fear of losing industry to other states, and states also tend systemically to under regulate pollution that has significant effects on other states. Still, stricter state regulation can and does happen. The greenhouse gas issue is the leading example. States in the Northeast have collaborated on the Regional Greenhouse Gas Initiative, which requires that electricity generators pay for emitting greenhouse gases. California has launched an ambitious cap-and-trade system that gives industry clear economic incentives to reduce those same emissions. It seems unlikely that Congress can restrict these state authorities—at least not without establishing an emissions control program of its own. Thus, although initial signs suggest that drastic environmental deregulation looms, there may well be much less than the Trump Administration currently envisions

When Must EPA Set Ambient Air Quality Standards - Looking Back at NRDC v. Train

[No abstract