36 research outputs found

    A Milestoning Study of the Kinetics of an Allosteric Transition: Atomically Detailed Simulations of Deoxy Scapharca Hemoglobin

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    Atomically detailed simulations are used to compute the kinetics of the R-to-T transition in deoxy Scapharca hemoglobin. A computational approach called milestoning is utilized that combines 1), an efficient reaction path algorithm; and 2), a “fragment and glue” approach for classical trajectories. Milestoning computes the R-to-T transition kinetics on the microsecond timescale based on atomically detailed trajectories that rarely exceed a nanosecond. Eleven reference hypersurfaces (milestones) are constructed along the reaction coordinate, which is computed with a global path optimization algorithm. Two-hundred classical trajectories are calculated for each of the milestones to collect local distributions of first passage times. These local distributions are used in a non-Markovian theory to compute the overall timescale. Exponential enrichment of reactive trajectories, an important component of the milestoning approach, makes these calculations possible. The overall timescale of the reaction is estimated as 10 ± 9 μs, in accord with available experimental data. The barrier is not sharp and is spread over four milestones. Even after the most significant structural changes are completed (phenylalanine F4 ring flips), highly collective and activated motions continue. The calculations suggest an additional late free energy barrier

    Cross-sectional validation of the PROMIS-Preference scoring system.

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    ObjectivesThe PROMIS-Preference (PROPr) score is a recently developed summary score for the Patient-Reported Outcomes Measurement Information System (PROMIS). PROPr is a preference-based scoring system for seven PROMIS domains created using multiplicative multi-attribute utility theory. It serves as a generic, societal, preference-based summary scoring system of health-related quality of life. This manuscript evaluates construct validity of PROPr in two large samples from the US general population.MethodsWe utilized 2 online panel surveys, the PROPr Estimation Survey and the Profiles-Health Utilities Index (HUI) Survey. Both included the PROPr measure, patient demographic information, self-reported chronic conditions, and other preference-based summary scores: the EuroQol-5D (EQ-5D-5L) and HUI in the PROPr Estimation Survey and the HUI in the Profiles-HUI Survey. The HUI was scored as both the Mark 2 and the Mark 3. Known-groups validity was evaluated using age- and gender-stratified mean scores and health condition impact estimates. Condition impact estimates were created using ordinary least squares regression in which a summary score was regressed on age, gender, and a single health condition. The coefficient for the health condition is the estimated effect on the preference score of having a condition vs. not having it. Convergent validity was evaluated using Pearson correlations between PROPr and other summary scores.ResultsThe sample consisted of 983 respondents from the PROPr Estimation Survey and 3,000 from the Profiles-HUI survey. Age- and gender-stratified mean PROPr scores were lower than EQ-5D and HUI scores, with fewer subjects having scores corresponding to perfect health on the PROPr. In the PROPr Estimation survey, all 11 condition impact estimates were statistically significant using PROPr, 8 were statistically significant by the EQ-5D, 7 were statistically significant by HUI Mark 2, and 9 were statistically significant by HUI Mark 3. In the Profiles-HUI survey, all 21 condition impact estimates were statistically significant using summary scores from all three scoring systems. In these samples, the correlations between PROPr and the other summary measures ranged from 0.67 to 0.70.ConclusionsThese results provide evidence of construct validity for PROPr using samples from the US general population

    Age- and gender-stratified mean scores in the PROPr Estimation sample.

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    <p>HUI 2 is the Health Utilities Index Mark 2, HUI 3 is the Health Utilities Index Mark 3, EQ-5D US Mapped is the Euroqol-5D-5L mapped to the US valuation set, PROPr is the PROMIS-Preference score.</p
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