Skip to main content
Premium Trial:

Request an Annual Quote

MSU Researcher Claims New TOF-MS Method Offers Significant Mass Accuracy and Sensitivity Gains


A Montana State University researcher has developed a technique for time-of-flight mass spectroscopy that he claims can provide a substantial improvement in mass accuracy and an up to 10-fold increase in sensitivity.

The technique, which is described in a paper to be published in an upcoming issue of Rapid Communications in Mass Spectrometry, uses physical signal modulation to improve the performance of TOF mass spec instruments without requiring any hardware changes.

The basic idea behind the technique is to shift the arrival time of the target ions over multiple MS scans so as to increase the number of data points collected for each peak, Brian Bothner, assistant professor of chemistry and biochemistry at Montana State University and the developer of the method, told ProteoMonitor. Increasing the number of data points defining each peak allows for more accurate centroiding and thus better mass accuracy, as well as a reduction in noise that results in an increase in sensitivity.

"Everybody keeps trying to get faster and faster digitizers, so you can increase the number of data points you're collecting, which is important because that defines your peak shape," Bothner said. "If you have a lot of data points, then you can centroid very accurately."

"The problem is, particularly when you're in low m/z, you actually have very few data points — sometimes as few as four — defining your peak. So what we came up with was a way to collect more data points by physically or temporally shifting the arrival time of the ions," he said.

To achieve this shift in ion arrival times, Bothner's lab changed its machines' reflector voltages, writing a software script that cycles through a number of different voltages. They developed another software package to then take the data generated by these multiple shifts and compose from it a single peak.

"We know how much we shifted [the ions], so then we can put them back in a single peak, and then you get essentially a peak with 20 datapoints instead of what we had before with only four points defining the peak," he said. "And because you have this very nice peak now, you can centroid it much more accurately. So you get a substantial increase in mass accuracy using the same instrument."

Bothner noted that the researchers expected the increase in mass accuracy. They didn't anticipate, however, the gains in sensitivity that it provided, he said. These gains come from the fact that, while the ions' signals are being modulated, the instrument noise remains unmodulated.

"[The noise] is fixed, so by moving your signal around, you can actually detect signals that are below the signal-to-noise threshold," he said, estimating that the technique provides roughly a "10-fold increase in sensitivity. Normally, a peak of signal-to-noise of 10-to-1 would be a very acceptable peak. We can generate peaks with that sort of acceptable noise after processing our data from things that are essentially at a signal-to-noise of one before we start."

Bothner and Jonathan Hilmer — a graduate student in Bothner's lab who also worked on developing the method — initially presented these findings at the American Society of Mass Spectrometry's annual meeting this May, where, he said, they drew interest from a number of mass spec vendors.

Although he is not currently in talks with any vendors about commercializing the method, he has a provisional patent on it and is considering pursuing a full patent. The technique was developed using Bruker TOF machines, Bothner said, but should be applicable to other vendors' instruments, as well. And while in his work he used adjustments to reflector voltage to achieve the required ion shifts, this isn't the only option, he noted.

"There are other parameters you could use to affect the same change," he said. "You could change your pulse voltage, for example. We just chose the reflector because it was easy to play with. It's something you routinely have to adjust when you're tuning your instrument, so on any instrument it's on your standard tune parameter."

The ion-shifting capability is something Bothner said he believes mass spec vendors could integrate into their future TOF instruments fairly easily.

"If you knew you wanted to do this, particularly when you were making your firmware for the instrument, then it would be pretty straightforward for [instrument vendors] to do," he said. "The product would most likely be completely invisible to the user. It could just be an added function – you click on a tab that says 'high resolution' and then the instrument just starts doing this."

John Fjeldsted, LC/MS general manager at Agilent, suggested that his company is, in fact, already applying insights similar to Bothner's in its TOF machines.

"[Bothner] is investigating important aspects of mass accuracy in time-of-flight instrumentation — the ability to accurately capture ion arrival times, increase sampling density, and achieve accurate centroiding," he told ProteoMonitor. "It's interesting to note that these same concepts are actively applied in Agilent's time-of-flight instrumentation with similar improvement."

Because the technique requires multiple scans to generate the additional data points, it is good for relatively simple samples, but not ideal for more complex ones, Bothner said.

"The tradeoff is that it slows down your data collection, so it wouldn't be good, for example, for situations where you're analyzing a very complex sample — say a set of metabolites — and your peak widths may be just a couple of seconds wide," he said. "It's for less complex samples where what you're really interested in is improving your mass accuracy and sensitivity."

The Scan

Genetic Risk Factors for Hypertension Can Help Identify Those at Risk for Cardiovascular Disease

Genetically predicted high blood pressure risk is also associated with increased cardiovascular disease risk, a new JAMA Cardiology study says.

Circulating Tumor DNA Linked to Post-Treatment Relapse in Breast Cancer

Post-treatment detection of circulating tumor DNA may identify breast cancer patients who are more likely to relapse, a new JCO Precision Oncology study finds.

Genetics Influence Level of Depression Tied to Trauma Exposure, Study Finds

Researchers examine the interplay of trauma, genetics, and major depressive disorder in JAMA Psychiatry.

UCLA Team Reports Cost-Effective Liquid Biopsy Approach for Cancer Detection

The researchers report in Nature Communications that their liquid biopsy approach has high specificity in detecting all- and early-stage cancers.