U.S. Air Force officials are narrowing their focus on new combinations of factors as they explore oxygen deprivation issues that have claimed the life of one F-22 Raptor pilot and have plagued the fleet for more than a year.

The officials remain frustrated, however, that a “smoking gun” for the cause of pilot hypoxia is still elusive despite an extraordinary effort by the service to enlist help from scientists, doctors and fighter experts.

The F-22 is the Air Force’s premier, twin-engine, stealthy fighter, and it costs more than $200 million per copy to produce by Lockheed Martin, including the cost of research and development. It entered service in 2005, and the final F-22 is being turned over to the Air Force on May 2.

The hypoxia situation came to light after a November 2010 crash that claimed the life of a pilot; an investigation team found the pilot to have been at fault for the incident and his family is suing the aircraft’s manufacturers.

The fleet was grounded for a total of four months last year as officials scrambled to understand the cause of the crash; flights resumed in September. Since then, Air Combat Command officials say there have been 11 “flying physiological unknowns,” or hypoxic events. Though these have not resulted in a crash, the unknown nature of the incidents has the service rattled. “There is no startling similarity [in the incidents] other than . . . hypoxic-like indications,” says Gen. Mike Hostage, ACC commander.

The F-22’s capabilities demand punishing performance from pilots. It is the only fighter capable of sustained supercruise at Mach 1.5 without using military power—or afterburner—and can operate for long periods at 60,000 ft. Pilots are also exposed to extreme forces owing to the aircraft’s ability to quickly accelerate, decelerate and execute intense maneuvers using thrust-vectored propulsion.

Service officials temporarily limited the altitude of the aircraft, but eventually lifted all restrictions. Officials once focused on whether a toxin was being introduced into the oxygen supply for the pilot—which is powered by a Honeywell onboard oxygen-generating system. However, Maj. Gen. Charles Lyon, ACC’s director of operations, says that investigations using filters introduced into the pilot’s oxygen system have not turned up any conclusive evidence. After analyzing hundreds of these filters used in flight and comparing them with filters not used for flight, Lyon said that those not used in flight often showed higher rates of toxins. “This informed our thinking and research,” he says. Although the toxin theory has not been completely discounted, it is not a central focus for now.

Initially, the study focused on the aircraft, Lyon told reporters April 30 during a press conference here. Now, however, the team is looking into the physiological support equipment used by pilots and exploring whether there are commonalities in the flight profiles—various altitudes, maneuvers, etc.—that could be common to the incidents. The majority of the incidents have occurred at the end of a flight, Lyon says, prompting officials to wonder if there is a cumulative effect of some factors on the pilots.

One potential link among the incidents is not the standard physiological support gear—a G-suit, helmet and vest (carrying emergency items in the event of a crash).

The majority of incidents have happened with F-22s at Langley or Joint Base Elmendorf-Richardson, Alaska. In addition to the standard physiological support gear of a G-suit, helmet and vest, the Alaska pilots also must wear cold-weather gear, while the Langley pilots must wear an anti-exposure suit when the Atlantic’s temperature dips lower than 55F. “That is what got me to thinking,” Lyon tells Aviation Week. In some cases, if the “fit is off by what would seem to be an insufficient amount,” it could impact the physiological support for the pilot. “It could be things such as the gear we are wearing and how it is assembled,” he says.

Lyon says the Air Force has teamed with experts supporting astronauts at NASA and divers in the Navy to study the extremes that humans can withstand in the hopes of finding clues.

Air Force officials are so sure about the toxin-related cause are sure enough of clearing the toxin cause that they are taking the filters off of the aircraft that were used to monitor the air, a decision made last week. However, they are researching whether better filters can be used to possibly uncover other types of elements in the cockpit air.

Additionally, pilots are wearing pulse oximeters to monitor their oxygen saturation levels during flight (the data are downloaded after landing and not dispatched in real time). Any time a pilot’s oxygen saturation drops below 85%, he is required to immediately return to base to allow officials to gather data.

Lyon acknowledges that this is having an affect on the amount of training hours that pilots can achieve. The service has conducted roughly 12,000 sorties since the Raptor returned to flight in September, totaling about 15,000 hr. of flight.

Hostage acknowledges that the incidents have some pilots leery about flying the warded some pilots off of flying the Raptor and opting not to, though he says these incidents are the exception. He notes that any guidance, such as returning to base with a low oxygen saturation level, can be waived in the event of an operational requirement for F-22 use.

Hostage is being trained to fly the F-22 soon; he says he is committed to taking the same risk in flying the F-22 as the young pilots now operating the Raptor.

Meanwhile, the Air Force acknowledged first to Aviation Week last week that F-22s have been deployed to Southwest Asia. The aircraft are operating out of Al Dhafra Air Base in the United Arab Emirates.

“The whole point is everybody pays attention” when F-22s are deployed to a particular region, Hostage says. “Our friends are very reassured by its presence.”

The F-22s are thought to be providing a presence to counter Iran’s ambitions to destabilize the Middle East and build long-range ballistic missiles and nuclear weapons.