Pharmaceutical & medical


TOF MS that are related to signal digitization, including mass range, mass accuracy, mass resolution, repetition rate, and sensitivity. The mass range is the range of molecular weight of molecules in the sample and is related to several factors, including accelerating voltage, flight tube length, sampling rate, and repetition rate. The mass range requirement varies from application. For instance, the bacterial identification by MALDI TOF MS measures ribosomal markers in the mass ranges of 2,000 Da to 20,000 Da. Since mass is calculated from flight time, the mass accuracy of TOF MS is primarily determined by the accuracy of time measurement of the pulses. In practice, the arrival time of each pulse is calculated by fitting the pulse to a Gaussian function and finding the peak. The ADC sampling rate determines the number of samples for an individual pulse and is critical for fitting the pulse. The mass resolution is a measure of the closest distinguishable separation between two neighboring pulses in the spectrum. It is often defined as the ratio of the ion mass to the width of the corresponding mass pulse. A typical definition of the width of a pulse is the FWHM. The narrower the pulse is, the higher the mass resolution is, meaning a better differentiation between two ion packs with close molecular weights. While the mass resolution can be significantly improved by orthogonal acceleration and reflectron, the ADC sampling rate and noise performance also affect this key specification. In TOF MS, the mass spectrum is the summation of signals from many repeats rather than a single transient that includes only a single process of ionisation, acceleration and drifting, and ion detection and digitisation. More importantly, for test samples with multiple molecules of different molecular weights and concentrations, a single ionisation event may neither produce ions of all molecules of interest nor the ratios proportional to their concentration. Summation is an efficient and practical approach to reduce such sampling error and improve the signal-to-noise ratio (SNR). Hence, the repetition rate is an important and practical specification of TOF MS for SNR and throughput. The latest TOF MS can achieve 1 kHz or faster scan, meaning each transient takes one millisecond (ms) or less. Increasing the ADC sampling rate shortens the duration of each transient for a faster repletion rate. The sensitivity of TOF MS is the capability to detect the molecules with the lowest concentration in the samples. It is collectively determined by many factors such as the chemical background noise, the range of concentrations of all molecules of interest, the noise figure and dynamic range of the detector and the ADC, and the number of transients summed for the final mass spectrum. In practice, the system sensitivity can be optimised by identifying the bottleneck factor and/or balancing these factors.


DESIRED ADC SPECIFICATIONS FOR TOF MS Low noise, high speed ADC is critical to the system performance of TOF MS. As previously discussed, the accuracy of time measurement and the system noise level are two important specifications of TOF MS instrument. While there is a workaround for system noise level by summation of repetitive measurement, the accuracy of the time measurement is determined by the sampling rate and the aperture jitter of the high speed ADC. Considering the pulses can be as narrow as a few hundred ps in TOF MS instrument with orthogonal acceleration and reflectron, there are only a few samples for an individual pulse at a 5 GSPS sampling rate. Every sample is crucial to find the peak of the pulse when the samples are fitted to a Gaussian function. Hence, sampling rate and aperture jitter are desirable ADC specifications. The sensitivity is determined by the system noise level that can be improved by summation of repeated measurements. However, the number of repetitions limits the throughput of the instrument. The noise performance of ADC is important for achieving targeted sensitivity with fewer repetitions. There is often a misperception pertaining to the performance of ADC that its SNR is proportional to its bit resolution. ADCs with a sampling rate of 1 GSPS or above often use the pipelined architecture and have specifications including an effective number of bits (ENOB) and noise density/noise figure/SNR/etc. However, pipelined ADCs cannot achieve the bit resolution since they suffer several disadvantages contributing to the noise, including high gain and large bandwidth op amps required to reduce errors, capacitor


Figure 3. A block


diagram for high speed ADC test with the AD9082.


Instrumentation Monthly January 2024


Figure 4. Overlap of the 10 repeats demonstrated high reproducibility of the data acquisition.


mismatch, and the power dissipation of the front-end sample-and-hold (S/H) and op amps. The ENOB is input frequency and sampling rate dependent and calculated with signal-to-noise and distortion ratio (SNDR). For instance, the 12-bit AD9081 has an ENOB of 8 bits at 4 GSPS with an input frequency of 4,500 MHz. ENOB is not a good measure of the ADC noise performance. Noise density is a step closer to the practical noise level but bench test with Gaussian pulses holds the ground truth of the noise performance of ADC and therefore the sensitivity of TOF MS instrument.


BENCH TEST OF LOW NOISE, HIGH SPEED ADC The MxFE offers smart integration of RF ADCs, digital-to-analogue converters (DACs), on-chip digital signal processing, and clock/phase-locked loop (PLL) for multichip synchronisation. MxFE parts with high speed ADCs only are also available. For simplification, our bench test used the AD9082, which has both ADCs and DACs integrated, as shown in Figure 3. The integrated DAC was used to generate a narrow Gaussian pulse train with an FWHM of 0.5 ns and amplitude controlled by a combination of digital scaling and external attenuators. The Gaussian pulses are much closer to the signal in mass spectra than the typical single-tone signal for ADC characterisation. Two ADC channels are set up for digitising signal: CH1 for various amplitudes saturated or attenuated by varying the external attenuators and CH2 as reference for the signal strength above 90 per cent full-scale (FS) without saturation. The sampling rate was 6 GSPS in our test for sufficient samples for each pulse. Three types of tests were performed:


Attenuation and saturation tests: CH2 with fixed 7 dB attenuator pair as a reference; CH1 with 8 dB, 9 dB, and 10 dB attenuator pair for attenuation cases and 3 dB and 1 dB attenuator pair for saturation cases.


Weak signal measurement with up to 20 dB attenuation: CH2 connected directly to DAC output as a reference with –16 dBFSC scaling; CH1 with 10 dB attenuator pair for <32 per cent FS signal and 20 dB attenuator pair for <10 per cent FS.


Noise measurement: CH2 with fixed 7 dB attenuator pair as reference; CH1 with 50 Ω termination.


For each test, we acquired >10 µs data and repeated the data acquisition 10 times for reproducibility check. We plotted and analysed the data in MATLAB. The 10 repeats were aligned and plotted for each test case. Figure 4 showed a single pulse in the test where CH1 is 3 dB lower than CH2. The 10 repeats were well overlapped for both channels, demonstrating high reproducibility of the data acquisition.


Table 1. Measured FWHM and SNR for the Test Case of Input at 10% FS FWHM (ns)


CH #


CH1 (20 dB) CH2 (0 dB)


SNR (dB) Mean


0.6722 0.6657


SD


0.0141 0.0056


Mean 32.07 40.98


SD


0.468 0.203


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