SBIR-STTR Award

The high prevalence of obesity in the US is a major public health concern, as overweight and obese individuals are at increased risk for many chronic diseases. Obesity stems from an imbalance between total caloric consumption and total energy expenditure (TEE), therefore accurate measurements of TEE play a pivotal role in understanding and ultimately reversing this epidemic. The gold standard for measuring TEE in free-living individuals is the doubly labeled water (DLW) method. The major limitations of the DLW method include high cost and precision of only 1 5% for individual measurements. In this Small Business Innovative Research (SBIR) project, Los Gatos Research (LGR) will develop, fabricate, and test a novel, laser-based analyzer to dramatically improve DLW measurements of TEE by concurrently measuring 17O/16O to correct for natural isotopic fluctuations in 18O and 2H. The Triple Isotope Water Analyzer (TIWA), which will be based on LGR's patented, laser-based Off-Axis ICOS technology, will be capable of real-time, simultaneous, high-throughput (50 samples/day) monitoring of 2H/1H, 18O/16O, and 17O/16O in H2O from human bodily fluids (e.g., blood, urine, and plasma), with a target accuracy of better than 10.60 for 2H/1H, 10.20 for 18O/16O, and 10.30 for 17O/16O at natural isotopic abundances. For enriched body waters that have been labeled with 2H and 18O, the target accuracy will be comparable to isotope ratio mass spectrometry and better than 11.50 for 2H/1H, 10.50 for 18O/16O. The TIWA will allow quantification of isotopic background fluctuation during measurements of TEE, eliminating the significant ""constant background"" assumption made during DLW experiments. Measurement of the isotopic background fluctuation will allow for much smaller isotopic doses to be used, substantially reducing the cost of TEE measurements. Alternatively, these measurements can be used to significantly increase the accuracy of the DLW technique, introducing the possibility of extending this technique from population studies to the accurate assessment of the TEE of individual subjects. During Phase I, LGR will work with Professor Edward Melanson, an established researcher of metabolic studies, and Professor John Speakman, a key developer of the DLW method, to demonstrate a prototype instrument for measurements using vacuum-distilled, clinical samples. The correlation in background fluctuations between 2H/1H, 18O/16O, and 17O/16O from 40 humans will be quantified to demonstrate the applicability of using the 17O/16O signal to correct for background fluctuations in DLW experiments. Finally, two individuals will be measured using the DLW method to directly compare the conventional double isotope measurement to the newly-developed triple isotope measurement. At the conclusion of this research project, LGR will have demonstrated the use of the TIWA for DLW measurements and empirically determined the improvement in TEE accuracy and reduction in the DLW method cost due to the measurement of background fluctuation using 17O/16O.

Public Health Relevance:
The high prevalence of obesity in the US is a major public health concern, as overweight and obese individuals are at increased risk for many chronic diseases. Obesity stems from an imbalance between total caloric consumption and total energy expenditure, therefore accurate measurements of total energy expenditure (TEE) play a pivotal role in understanding and ultimately reversing this epidemic. This Small Business Innovative Research (SBIR) project will allow direct quantification of isotopic background fluctuation during doubly-labeled water measurements of TEE, potentially reducing the cost of isotope dose for TEE measurements from approximately $400 to $80 per adult subject and thereby greatly increasing the application of TEE measurements for obesity studies.

Thesaurus Terms:
21+ Years Old;Abnormal Assessment Of Metabolism;Accounting;Adult;Adult Human;Au Element;Blood;Blood Plasma;Blood Reticuloendothelial System;Businesses;Caloric Intake;Cell Communication And Signaling;Cell Signaling;Chronic Disease;Chronic Illness;Clinical;Conduct Clinical Trials;Consumption;Cost Savings;Dose;Energy Expenditure;Energy Intake;Energy Metabolism;Epidemic;Gold;High Prevalence;Human;Hydrogen Oxide;Individual;Intracellular Communication And Signaling;Investigators;Isotopes;Label;Laboratories;Laser Electromagnetic;Laser Radiation;Lasers;Legal Patent;Life;Liquid Substance;Long-Term Effects;Longterm Effects;Man (Taxonomy);Mass Photometry/Spectrum Analysis;Mass Spectrometry;Mass Spectroscopy;Mass Spectrum;Mass Spectrum Analyses;Mass Spectrum Analysis;Measurement;Measures;Memory;Metabolic;Metabolic Studies;Metabolism Studies;Methods;Modeling;Modern Man;Monitor;Obesity;Over Weight;Overweight;Patents;Performance;Phase;Plasma;Plasma Serum;Play;Population Study;Public Health;R-Series Research Projects;R01 Mechanism;R01 Program;Research;Research Grants;Research Personnel;Research Project Grants;Research Projects;Researchers;Reticuloendothelial System, Serum, Plasma;Risk;Role;Sampling;Signal Transduction;Signal Transduction Systems;Signaling;Techniques;Technology;Testing;Time;Uncertainty;Urine;Urine Urinary System;Vacuum;Water;Work;Adiposity;Adult Human (21+);Adulthood;Base;Biological Signal Transduction;Caloric Dietary Content;Chronic Disease/Disorder;Chronic Disorder;Corpulence;Corpulency;Corpulentia;Cost;Design;Designing;Doubt;Experiment;Experimental Research;Experimental Study;Fluid;Improved;Innovate;Innovation;Innovative;Instrument;Liquid;Metabolic Abnormality Assessment;Novel;Obese;Obese People;Obese Person;Obese Population;Professor;Prototype;Public Health Medicine (Field);Research Study;Social Role;Standard Measure;Stem

The high prevalence of obesity in the US is a major public health concern, as overweight and obese individuals are at increased risk for many chronic diseases. Obesity stems from an imbalance between total caloric consumption and total energy expenditure (TEE), therefore accurate measurements of TEE play a pivotal role in understanding and ultimately reversing this epidemic. The gold standard for measuring TEE in free-living individuals is the doubly labeled water (DLW) method; major limitations of the method include high cost and precision of only ¿ 7% for individual measurements. In this Small Business Innovative Research (SBIR) project, Los Gatos Research (LGR) will develop, fabricate, and test a novel, laser-based analyzer based on LGR's patented, laser-based Off-Axis Integrated Cavity Output Spectroscopy technology to dramatically improve DLW measurements of TEE by measuring 17O/16O to correct for natural isotopic fluctuations in 18O and 2H. The Triple Isotope Water Analyzer (TIWA) will be capable of real-time, simultaneous, high-throughput (45 samples/day) monitoring of 2H/1H, 18O/16O, and 17O/16O in H2O from human bodily fluids, with a target accuracy and precision of better than ¿0.6% for 2H/1H, ¿0.15% for 18O/16O, and ¿0.2% for 17O/16O at natural isotopic abundances. For enriched body waters that have been labeled with 2H and 18O, the accuracy and precision will be comparable to IRMS and better than ¿1.0% for 2H/1H and ¿0.2% for 18O/16O. By measuring 17O/16O, the TIWA will allow quantification of isotopic background fluctuation in 18O/16O and 2H/1H during DLW measurements of TEE, thus eliminating the significant "constant background" assumption made during DLW experiments, and thereby improving measurement precision and significantly reducing the cost of TEE experiments. Based on the excellent correlation measured during Phase I, we estimate that measurement of the isotopic background fluctuation will result in a 40% increase in the precision of DLW tests of TEE, allowing for smaller study sizes while maintaining the statistical power of the measurements and reducing study costs by an estimated 72%! Additionally, the improved precision introduces the possibility of extending this technique from population studies to the accurate assessment of the TEE of a single subject. During Phase II, LGR will continue to work with Prof. Edward Melanson and Prof. John Speakman to demonstrate and apply an improved instrument for simultaneous isotope measurements using minimally prepared, human urine samples. TEE will be measured using the improved, triple isotope method and the results compared with simultaneous, gold-standard measurement of TEE in a metabolic chamber, standard DLW as measured by IRMS, and standard DLW as measured using laser-based isotope analysis. At the conclusion of this research project, LGR will have demonstrated the use of the TIWA for triple-isotope DLW measurements and empirically determined the improvement in TEE accuracy and reduction in the DLW method cost due to the measurement of background fluctuation using 17O/16O.

Public Health Relevance Statement:


Public Health Relevance:
The high prevalence of obesity in the US is a major public health concern, as overweight and obese individuals are at increased risk for many chronic diseases. Obesity stems from an imbalance between total caloric consumption and total energy expenditure (TEE), therefore accurate measurements of TEE play a pivotal role in understanding and ultimately reversing this epidemic. This Small Business Innovative Research (SBIR) project will develop a new, triple-isotope method for doubly labeled water (DLW) measurements of TEE which will reduce existing barriers to widespread use of the DLW method by improving precision, reducing costs, reducing the technical expertise required to perform the analysis, and increasing throughput.

Project Terms:
Accounting; Algorithms; base; Blood; Businesses; Calibration; Chronic Disease; Clinical; Computer software; Conduct Clinical Trials; Consumption; cost; Cost Savings; Data Analyses; design; Development; Energy Metabolism; Epidemic; Funding; Gold; High Prevalence; Housing; Human; improved; Individual; innovation; instrument; Isotopes; Label; Laboratories; Lasers; Legal patent; Life; Liquid substance; Marketing; Mass Spectrum Analysis; Measurement; Measures; Medical; Medicine; Memory; Metabolic; metabolic abnormality assessment; Methods; Modeling; Monitor; novel; Obesity; Output; Overweight; Phase; Plasma; Play; Population Study; professor; public health medicine (field); public health relevance; Research; Research Personnel; Research Project Grants; research study; Risk; Role; Sampling; Secure; Source; Spectrum Analysis; standard measure; stem; Technical Expertise; Techniques; Technology; Testing; Time; treatment center; Urine; Water; water testing;