A Turning Point for Genetic Testing:
The FDA plans to overhaul its regulation of the increasingly common diagnostic tests.:
In a prelude to overhauling its regulatory oversight of genetic diagnostic testing, the U.S. Food and Drug Administration will convene a public meeting next week to gather input from test makers and others.
The event reflects a turning point in genetic testing, a cornerstone of personalized medicine. Once mainly the domain of rare diseases, scientists have discovered a growing number of genetic variations linked to both the risk of more common disease and patients' response to drugs. The number of genetic diagnostic tests has expanded rapidly, and tests have become increasingly complex, making it more challenging to interpret and act on the results.
"We don't think physicians are going to be able to interpret the results; they are relying on the labs that make them," says Alberto Gutierrez, director of the Office of In Vitro Diagnostic Device Evaluation and Safety at the FDA. "So we think a third party should assess these devices."
The early generation of genetic tests was relatively simple, testing for a single cancer-linked gene, for example. The possible treatment decisions or other responses were well-defined. But in the last few years, these tests have incorporated more genes and tackled more complex and common diseases. "The scope of these tests and how they can be used is growing rapidly," says Alexis Borisy, chief executive officer of Foundation Medicine, a startup based in Cambridge, MA, that is developing genetic tests to predict the most effective drugs for cancer patients. More than 2,000 genetic tests are now available through clinical laboratories.
However, tests developed and performed in a single laboratory today face little federal regulation other than that they be performed in a certified laboratory. (Some states, such as New York and California, have stricter laws, such as requiring that a physician order clinical tests.) For these "laboratory developed" tests, physicians collect a sample from patients and then send them to a specific lab. So-called test kits, which are sold to hospitals and other labs so that they can perform the tests themselves, are subject more extensive regulation.
The FDA has made several moves toward more extensive regulation in recent years, but the regulatory issue came to a head in May when Pathway Genomics announced plans to sell its genetic tests in drugstores. Those plans were halted when the agency sent Pathway and other genetics testing companies a letter questioning whether the tests could be sold without the agency's approval. A month later, the agency issued a statement describing its intent to rethink its approach to all laboratory-developed tests.
"These tests, which are becoming more complex and high risk, are playing an increasingly important role in clinical decision-making. As a result, LDTs [laboratory developed tests] that have not been properly validated put patients at risk, such as for missed diagnosis, wrong diagnosis, and failure to receive appropriate treatment," the agency explained in the statement. Because of the lack of existing regulation, little data exists on error rates or misinterpretation of the tests.
"The primary concern was once just analytic validity; does it accurately measure what it says it does?" says Daniel Vorhaus, an attorney at Robinson, Bradshaw & Hinson, in Charlotte, NC, and editor of the firm's Genomics and Life Sciences blog. "That's still very important, but now there are other issues as well. How are people using the information? Is the interpretation of information accurate? What do I do with the information?" For example, if a test predicts that someone is at greater risk for diabetes, a physician could suggest diet and exercise or a more aggressive approach involving drugs.
The agency says it plans to take a risk-based approach, meaning that tests linked to major medical decisions will be more tightly regulated than those that might predict a minor increase in risk for disease.
Jul 13, 2010
Tiny Springs Could Reduce Microchip Waste
Tiny Springs Could Reduce Microchip Waste:
Using springs and glue instead of solder to make electronic connections between computer chips could end one of the electronics industry's most wasteful habits, say researchers at the Palo Alto Research Center and Oracle.
Spring board: Metal springs turn the connection of computer chips to circuit boards into a reversible process, making it possible to replace a broken chip without throwing out the whole board.
Credit: PARC
"The whole industry is based on nonreworkable technology like solder or tape," explains Eugene Chow, of PARC. "If one chip in a module of several doesn't work after you've soldered them down, you have to throw out the whole thing."
Chow and colleagues are fine-tuning an alternative approach. They pattern a surface with microscale springs that compress slightly under a chip's weight, and these form a lasting, secure electronic connection when the two surfaces are glued together. "You can turn it on, and if it works great, do a final bond with adhesive," says Chow. "If it doesn't work, you can just take off the die that failed and replace it."
For now, the collaborators are developing their springy approach for the high-performance processors used in supercomputers or high-end servers. These chips are combined in closely packed groups known as multichip modules. Such modules need the processors to be packed closely together in order to speed the transfer of signals between them.
"I think it's just a matter of course that this approach will get to the lower-end applications, too, though," says Chow. "Eventually this could be in a high-end cell phone--everyone wants to get more chips into everything, and this can help, because the pitch [the horizontal distance between connections] can be so small." The team has shown that their springs can be made as close together as six microns, compared to the tens of microns necessary with solder connections.
The springs are flat metallic strips that curve up from a substrate that a chip is fixed to. "Fundamentally it's the simplest spring you can imagine," says Chow. The spring-building process starts with the addition of a thin titanium layer to the substrate. On top of this, the spring material is deposited in such a way that builds strain into the top layer. Photolithography is used to carve out the outlines of the many springs before the titanium is etched away from underneath.
"The tension makes the springs simply pop up," says Chow. "It's an elegant way of making a three-dimensional structure." The finished spring is coated with a layer of gold for added strength and a better electronic connection. The manufacturers must design the layout of the springs so that they match up to the contacts on the chips. Small sapphire balls or other peg-like structures on the surface of the substrate fit into notches in the chip to ensure the two are positioned correctly.
Last month, Chow and colleagues presented their work at the Electronics Components and Technology Conference in Las Vegas. They showed that their approach works on a test chip from Oracle that simulates the electrical and thermal behavior of a high-end processor. "It's a test vehicle to evaluate the finished module," Chow explains. The test chip has nearly 4,000 180-square-micron cells, each containing a thermometer, sensors to measure the power supplied to that part of the chip, and a heater so that the overall chip pumps out the same heat as a high-power processor working at full capacity.
Another reason to think beyond solder, says Chin Lee, a professor of electrical engineering and computer science at the University of California, Irvine, is the fact that it will soon limit the industry's ability to make ever-smaller devices. "Alternatives are needed, because solder is not going to continue to shrink," says Chin.
Manufacturers can position the electronic springs more accurately than solder, and this can boost performance, for example by letting them arrange the chips in more compact groups, says Chow. In the race to make faster chips, he says, chip makers can often overlook the ways that components are connected and packaged. "This isn't a glamorous field," says Chow. "Everyone focuses on transistors and components, but packaging is a real bottleneck for performance."
Bahgat Sammakia, director of the Small Scale Systems Integration and Packaging Center at Binghamton University, agrees. "You can have the best technology in the world, but without packaging, you won't get the best performance from them; it is what enables the creation of the finished systems we are aiming for."
Sammakia says that although research into novel approaches to packaging chips is valuable, ultimately the market must decide whether a particular solution will work. "You can always solve a problem, but not always in a way that is commercial."
Jennifer Ernst, PARC's director of business development, says the project is being directly shaped by what is possible at commercial scale. "Our first priority is to get this into manufacturing," she says. She notes that the springs are made simply, using just a few layers of metal and standard deposition and etching processes. "We are currently making these at our own fab, but expect the volume to be cost-competitive at commercial scale," she says.
Using springs and glue instead of solder to make electronic connections between computer chips could end one of the electronics industry's most wasteful habits, say researchers at the Palo Alto Research Center and Oracle.
Spring board: Metal springs turn the connection of computer chips to circuit boards into a reversible process, making it possible to replace a broken chip without throwing out the whole board.
Credit: PARC
"The whole industry is based on nonreworkable technology like solder or tape," explains Eugene Chow, of PARC. "If one chip in a module of several doesn't work after you've soldered them down, you have to throw out the whole thing."
Chow and colleagues are fine-tuning an alternative approach. They pattern a surface with microscale springs that compress slightly under a chip's weight, and these form a lasting, secure electronic connection when the two surfaces are glued together. "You can turn it on, and if it works great, do a final bond with adhesive," says Chow. "If it doesn't work, you can just take off the die that failed and replace it."
For now, the collaborators are developing their springy approach for the high-performance processors used in supercomputers or high-end servers. These chips are combined in closely packed groups known as multichip modules. Such modules need the processors to be packed closely together in order to speed the transfer of signals between them.
"I think it's just a matter of course that this approach will get to the lower-end applications, too, though," says Chow. "Eventually this could be in a high-end cell phone--everyone wants to get more chips into everything, and this can help, because the pitch [the horizontal distance between connections] can be so small." The team has shown that their springs can be made as close together as six microns, compared to the tens of microns necessary with solder connections.
The springs are flat metallic strips that curve up from a substrate that a chip is fixed to. "Fundamentally it's the simplest spring you can imagine," says Chow. The spring-building process starts with the addition of a thin titanium layer to the substrate. On top of this, the spring material is deposited in such a way that builds strain into the top layer. Photolithography is used to carve out the outlines of the many springs before the titanium is etched away from underneath.
"The tension makes the springs simply pop up," says Chow. "It's an elegant way of making a three-dimensional structure." The finished spring is coated with a layer of gold for added strength and a better electronic connection. The manufacturers must design the layout of the springs so that they match up to the contacts on the chips. Small sapphire balls or other peg-like structures on the surface of the substrate fit into notches in the chip to ensure the two are positioned correctly.
Last month, Chow and colleagues presented their work at the Electronics Components and Technology Conference in Las Vegas. They showed that their approach works on a test chip from Oracle that simulates the electrical and thermal behavior of a high-end processor. "It's a test vehicle to evaluate the finished module," Chow explains. The test chip has nearly 4,000 180-square-micron cells, each containing a thermometer, sensors to measure the power supplied to that part of the chip, and a heater so that the overall chip pumps out the same heat as a high-power processor working at full capacity.
Another reason to think beyond solder, says Chin Lee, a professor of electrical engineering and computer science at the University of California, Irvine, is the fact that it will soon limit the industry's ability to make ever-smaller devices. "Alternatives are needed, because solder is not going to continue to shrink," says Chin.
Manufacturers can position the electronic springs more accurately than solder, and this can boost performance, for example by letting them arrange the chips in more compact groups, says Chow. In the race to make faster chips, he says, chip makers can often overlook the ways that components are connected and packaged. "This isn't a glamorous field," says Chow. "Everyone focuses on transistors and components, but packaging is a real bottleneck for performance."
Bahgat Sammakia, director of the Small Scale Systems Integration and Packaging Center at Binghamton University, agrees. "You can have the best technology in the world, but without packaging, you won't get the best performance from them; it is what enables the creation of the finished systems we are aiming for."
Sammakia says that although research into novel approaches to packaging chips is valuable, ultimately the market must decide whether a particular solution will work. "You can always solve a problem, but not always in a way that is commercial."
Jennifer Ernst, PARC's director of business development, says the project is being directly shaped by what is possible at commercial scale. "Our first priority is to get this into manufacturing," she says. She notes that the springs are made simply, using just a few layers of metal and standard deposition and etching processes. "We are currently making these at our own fab, but expect the volume to be cost-competitive at commercial scale," she says.
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