Seeing the whole elephant: integrated advanced data analytics in support of RWE for the development and use of innovative pharmaceuticals.

INTRODUCTION: The 21st century has brought about significant technological advancement, allowing the collection of new types of data from the real world on an unprecedented scale. The healthcare industry will benefit immensely from this abundance of patient data from electronic health records (EHR), patient-reported outcomes (PROs), laboratory, demographic, social media, digital, and even climate data. AREAS COVERED: While conventional statistical methods still play a significant role in supporting the drug lifecycle, machine learning (ML) and artificial intelligence (AI) are assuming a more prominent role in the analysis of this 'big data.' Moving forward, conventional statistics and AI/ML will work together to support descriptive, diagnostic, and even predictive analytics to further revolutionize drug discovery and development, regulatory approvals, and payer acceptance. In addition, counterfactual prescriptive analytics, such as causal inference analysis using real-world data (RWD) to generate insights that have cause-and-effect conclusions, will gain momentum as a methodology that can stand up against the rigor of regulatory review. EXPERT OPINION: Our real-world evidence/health economics and outcomes research (RWE/HEOR) field has evolved in ways that require us to integrate all the methods and data into a single framework that guides a holistic analytic approach and decision-making.

A cost-effectiveness analysis of intrauterine spacers used to prevent the formation of intrauterine adhesions following endometrial cavity surgery.

AIM: To assess, from a United States (US) payer's perspective, the cost-effectiveness of gels designed to separate the endometrial surfaces (intrauterine spacers) placed following intrauterine surgery. MATERIALS AND METHODS: A decision tree model was developed to estimate the cost-effectiveness of intrauterine spacers used to facilitate endometrial repair and prevent the formation (primary prevention) and reformation (secondary prevention) of intrauterine adhesions (IUAs) and associated pregnancy- and birth-related adverse outcomes. Event rates and costs were extrapolated from data available in the existing literature. Sensitivity analyses were conducted to corroborate the base case results. RESULTS: In this model, using intrauterine spacers for adhesion prevention led to net cost savings for US payers of $2,905 per patient over a 3.5-year time horizon. These savings were driven by the direct benefit of preventing procedures associated with IUA formation ($2,162 net savings) and the indirect benefit of preventing pregnancy-related complications often associated with IUA formation ($3,002). These factors offset the incremental cost of intrauterine spacer use of $1,539 based on an assumed price of $1,800 and the related increase in normal deliveries of $931. Model outcomes were sensitive to the probability of preterm and normal deliveries. Budget impact analyses show overall cost savings of $19.96 per initial member within a US healthcare plan, translating to $20 million over a 5-year time horizon for a one-million-member plan. LIMITATIONS: There are no available data on the effects of intrauterine spacers or IUAs on patients' quality of life. Resultingly, the model could not evaluate patients' utility related to treatment with or without intrauterine spacers and instead focused on costs and events avoided. CONCLUSION: This analysis robustly demonstrated that intrauterine spacers would be cost-saving to healthcare payers, including both per-patient and per-plan member, through a reduction in IUAs and improvements to patients' pregnancy-related outcomes.

Every year, women in the United States (US) undergo surgery to treat intrauterine abnormalities to maintain or improve the uterus' ability to support fetal development and result in a term delivery. Despite the benefits of these procedures, damage caused to the endometrium (uterine lining) is associated with a risk of adherence of the endometrial cavity surfaces with scar tissue known as intrauterine adhesions (IUAs).Damage to the endometrium and the resulting IUAs may be associated with infertility, light or absent menstruation, pregnancy loss, and other pregnancy-related complications. Treating these conditions within the US healthcare system consumes resources and adds costs for healthcare payers (public and private insurance providers).To facilitate endometrial repair and to reduce or prevent IUAs, researchers have developed materials to place within the endometrial cavity following surgery to separate the endometrial surfaces during the early healing period. These intrauterine "spacers" are intended to improve patients' subsequent clinical outcomes and save money for healthcare payers. It is unknown whether these improved clinical outcomes offset the cost of the routine use of spacers following "at-risk" procedures that involve the endometrial cavity.We developed a model designed to determine the cost-effectiveness of an intrauterine spacer by quantifying improvements in clinical outcomes and the resultant cost savings for patients undergoing uterine surgeries with or without spacers. Our model predicted that routinely using such spacers following at-risk procedures would improve patient outcomes and reduce costs to US payers.

A stable isotopic approach for quantifying aquaculture-derived organic matter deposition dynamics in the sediment of a coastal fish farm.

The stable carbon and nitrogen isotopic compositions (δ13C and δ15N) of sedimentary organic matter (OM) in fish farms (FFs) were investigated to quantify the aquaculture-derived OM deposition dynamics in the sediment. The dual isotopic compositions of mixed OMs in surface sediments at FFs differed significantly (p < 0.05) from those at reference sites, indicating an increased deposition of fish feces or uneaten feed in the sediments. Furthermore, OM source apportionments revealed that the quantitative contribution of fish feces (23.3 mg g-1 dw) during farming activities was significantly higher than that of other natural OM sources (C3 plants and phytoplankton). After the disassembly of fish cages, the deposited fish feces may be preferentially degraded through processes that require a large amount of oxygen consumption (<0.1 kg C m-2 yr-1). Our isotopic approach may be helpful for assessing the impact of FF wastes and for taking measures to minimize environmental deterioration.

Estuarine dam water discharge enhances summertime primary productivity near the southwestern Korean coast.

The gate opening of estuarine dams discharge a large amount of freshwater into coastal zones during the summer monsoon in northeast Asia. We investigated seasonal and spatial variations in primary productivity (PP) and community structures of phytoplankton on a downstream macrotidal flat and examined the dam discharge effects. Our harmonic analysis of the PP revealed a clear seasonality with a unimodal peak in summer, possibly driven by high ammonium loading through internal recycling. External nitrate supply from the dam-water discharge promoted PP during July-August, generating conspicuous blooms near the discharging site. Phytoplankton community was characterized by a predominance of diatoms all year round and seasonal dominances from dinoflagellates, cryptophytes, and prasinophytes in spring to chlorophytes in summer, reflecting spatiotemporal patterns in ammonium and nitrate supply. Our findings provide new insights into the summer phytoplankton bloom linked to monsoonal rainfall in the shallow coastal seas along the Northeast Asian coast.

Significant contribution of coastal fish-farm activities to the inventory of trace elements in coastal waters: Traced by ammonia and rare earth elements.

In this study, we investigated the influence of fish-farm activities on the inventory of trace elements (Mn, Fe, Co, Ni, and Cu) in the coastal waters off the fish-farm plants on Jeju Island, Korea. NH4+ and rare earth elements (REEs) were used as tracers to examine the production and removal processes. Relatively higher concentrations of trace elements were observed in the coastal waters and significantly correlated with NH4+. Our results suggest that the excess dissolved trace elements in the coastal waters could be mainly produced inside fish farms, together with the production of NH4+ and light-REEs (La to Nd). Although dissolved trace elements were found to be partially scavenged onto particles in the fish-farm rearing waters, indicated by the significant removal of particle-reactive Ce, these particles would be eventually discharged into the coastal ocean and release the dissolved trace elements back into the water columns.

Spatial variability of water quality and sedimentary organic matter during winter season in coastal aquaculture zone of Korea.

We investigated the composition, source, and reactivity of sedimentary organic matter (OM) present in aquaculture systems along the Korean coast. A multi-isotopic approach was applied to 216 surface sediments from five sections: western (W)-1, W-2, southern (S)-1, S-2, and eastern (E)-1 sections. The 15N-enriched total nitrogen signatures in the surface sediments of the W-1 section may indicate that a substantial fraction of sedimentary OM has anthropogenic origins exported through the Han River. Simultaneously, the deposition of allochthonous OM is predominant in the S sections (Jinhae and Masan Bays). The 34S-depleted patterns at the S-2 section may indicate that sulfate reduction occurring at the sedimentary boundary contributes to active OM decomposition, depending on the increased sedimentation of the aquaculture-derived OM. Our results highlight that isotopic-based source tracking near aquaculture systems provide important information for identifying anthropogenic contamination in coastal marine sediments and for improving environmental management.

Extended Multivariate Generalizability Theory With Complex Design Structures.

This article extends multivariate generalizability theory (MGT) to tests with different random-effects designs for each level of a fixed facet. There are numerous situations in which the design of a test and the resulting data structure are not definable by a single design. One example is mixed-format tests that are composed of multiple-choice and free-response items, with the latter involving variability attributable to both items and raters. In this case, two distinct designs are needed to fully characterize the design and capture potential sources of error associated with each item format. Another example involves tests containing both testlets and one or more stand-alone sets of items. Testlet effects need to be taken into account for the testlet-based items, but not the stand-alone sets of items. This article presents an extension of MGT that faithfully models such complex test designs, along with two real-data examples. Among other things, these examples illustrate that estimates of error variance, error-tolerance ratios, and reliability-like coefficients can be biased if there is a mismatch between the user-specified universe of generalization and the complex nature of the test.

Shifts in benthic bacterial communities associated with farming stages and a microbiological proxy for assessing sulfidic sediment conditions at fish farms.

To assess the aquaculture-induced sediment conditions associated with sulfur cycles, shifts in bacterial communities across farming stages were investigated. The sulfate reduction rate (SRR), and concentrations of acid volatile sulfide (AVS) and H2S were significantly higher at the mid- and post-farming stages than at the early stage, indicating that the aquaculture effects persist even after harvest. Incomplete organic carbon-oxidizing sulfate-reducing bacteria (IO-SRB) affiliated with Desulfobulbaceae, and gammaproteobacterial sulfur oxidizing bacteria (SOB) (Thiohalobacter, Thioprofundum, and Thiohalomonas) were dominant during the early stage, whereas fermenting bacteria (Bacteroidetes and Firmicutes) and complete oxidizing SRB (CO-SRB) belonging to Desulfobacteraceae, and epsilonproteobacterial SOB (Sulfurovum) dominated during the mid- and post-stages. The shift in SRB and SOB communities well reflected the anoxic and sulfidic conditions of farm sediment. Especially, the Sulfurovum-like SOB correlated highly and positively with H2S, AVS, and SRR, suggesting that they could be relevant microbiological proxies to assess sulfidic conditions in farm sediment.

Spatiotemporal change in coastal waters caused by land-based fish farm wastewater-borne nutrients: Results from Jeju Island, Korea.

We investigated spatiotemporal distributions of dissolved inorganic nutrients and organic carbon (DOC) and nitrogen (DON) in coastal waters and land-based fish farm wastewater to determine effects of wastewater on seawater of Jeju Island, Korea. The nutrient concentrations in seawater were lower than in wastewater with negative correlations against salinity, indicating a terrestrial source. Wastewater-derived DOC and DON were transported offshore while wastewater-derived inorganic nutrients were effectively removed, likely via biological production, and this was closely linked to decline in N:P ratios. The correlations between DOC, DON, and colored dissolved organic matter suggest that organic matters likely originate from the fish farm wastewater. Quantitatively, the estimated wastewater-derived DOC flux was equivalent to that through submarine groundwater, which is a significant water source on the island. Our results will be able to trace contaminant sources and support assessments of seawater quality for appropriate regulation of fish farm wastewater discharge into coastal zones.

Influence of intensive net cage farming on hydrodynamic and geochemical environmental conditions and the mass mortality of abalone in South Korea.

The abalone aquaculture industry in South Korea has grown rapidly since the 2000s. In this study, we investigated the sedimentary pollution at four major abalone farms responsible for ~60% of all South Korean abalone produced. We also surveyed the current statuses of cage facilities, abalone mass mortality, and current velocities within and outside farm cages. The concentrations of total organic carbon in the study area were 7.92 ± 2.09 mg g-1, indicating a mild level of sedimentary pollution. We observed higher mortality rates in rectangular-shaped shelter cages than in triangular shelters. With increases in the number and size of abalone farming facilities, current velocities inside the cages declined by an average of 45% relative to those outside the cages, leading to poor habitat conditions for farmed abalone. Our results provide insights into the current status of the benthic environments and major causes of mass mortality in the abalone farms of South Korea.

Quality of Life in Primary Open-Angle Glaucoma and Cataract: An Analysis of VFQ-25 and OSDI From the iStent inject® Pivotal Trial.

OBJECTIVE: To assess quality of life (QOL) as measured by patient-reported outcomes (PRO) within the iStent inject® pivotal trial. DESIGN: Randomized controlled trial analysis of secondary outcomes. METHODS: The Vision Function Questionnaire (VFQ-25) and Ocular Surface Disease Index (OSDI) questionnaire were administered at baseline and at months 1, 6, 12, and 24. PRO responders were defined as patients reaching improvement based on minimally important differences. RESULTS: A total of 505 patients were randomized (386 iStent inject® [Glaukos], 119 surgery alone). The iStent inject® group exhibited a greater percentage of PRO responders across all follow-up visits over 24 months, averaging 58.0% vs 45.8%; P < .05 for VFQ-25 composite scores and 56.7% vs 48.9%; P < .05 for OSDI composite scores. Odds of being a responder in the iStent inject® group was 60% (P < .05) higher for the VFQ-25 and 32% (P > .05) higher for the ODSI. Driving (49.0% vs 28.8%; P < .05), ocular pain (59.3% vs 47.2%; P < .05), and general vision (71.8% vs 60.0%; P < .05) were the VFQ-25 subscales responsible for differences between treatment groups. At month 24, 76.5% of VFQ-25 responders and 62.5% of nonresponders were medication free regardless of treatment group (P < .05). CONCLUSIONS: Exploratory analysis suggests that by reducing medication dependence, implantation with the micro-scale iStent inject® device with cataract surgery may improve QOL vs cataract surgery alone over 24 months, with improvements influenced by ocular symptoms and vision-related activities.

Interval estimation procedures for true scores of a test composed of polytomous items: An application of the multinomial error model.

When a person takes alternative forms of the same test across replications of the testing procedure, the test taker's observed scores on the alternative forms are rarely identical. In educational and psychological measurement, inconsistencies in a test taker's scores that are irrelevant to the construct being measured are attributed to errors of measurement. Typically, errors of measurement are summarized as the standard deviation of a test taker's observed scores over replication of the same testing procedure. Assuming that errors of measurement follow a multinomial distribution (i.e., multinomial error model), the main goal of this study was to propose two interval estimation procedures, which are referred to as the score-like and Perks procedures, for true scores of a test with polytomous items. The performance of the score-like and Perks procedures was compared with that of two normal approximation procedures under the multinomial error model and a procedure based on item response theory (IRT) through simulation. In general, the score-like and Perks procedures outperformed the other three procedures when data were generated under the multinomial error theory framework and showed reasonable results when data were generated under the IRT framework. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Simple-Structure Multidimensional Item Response Theory Equating for Multidimensional Tests.

A theoretical and conceptual framework for true-score equating using a simple-structure multidimensional item response theory (SS-MIRT) model is developed. A true-score equating method, referred to as the SS-MIRT true-score equating (SMT) procedure, also is developed. SS-MIRT has several advantages over other complex multidimensional item response theory models including improved efficiency in estimation and straightforward interpretability. The performance of the SMT procedure was examined and evaluated through four studies using different data types. In these studies, results from the SMT procedure were compared with results from four other equating methods to assess the relative benefits of SMT compared with the other procedures. In general, SMT showed more accurate equating results compared with the traditional unidimensional IRT (UIRT) equating when the data were multidimensional. More accurate performance of SMT over UIRT true-score equating was consistently observed across the studies, which supports the benefits of a multidimensional approach in equating for multidimensional data. Also, SMT performed similarly to a SS-MIRT observed score method across all studies.

Impact of finfish aquaculture on biogeochemical processes in coastal ecosystems and elemental sulfur as a relevant proxy for assessing farming condition.

We conducted experiments to investigate the effects of finfish aquaculture and to propose appropriate proxies for assessing their environmental impact. Due to enhanced fish feed input, sulfate reduction (SR) and the resulting metabolic products (H2S, NH4+, PO43-) were significantly greater at the farm than at the control site. Benthic release of dissolved inorganic nitrogen (DIN) and phosphorus (DIP) from farm sediment accounted for 52-837% and 926-1048%, respectively, of the potential DIN and DIP demand for phytoplankton production. The results suggest that excess organic loading in fish farms induces deleterious eutrophication and algal blooms in coastal ecosystems via benthic-pelagic coupling. Direct SR measurement provided the most useful information of all the parameters on organic contamination in fish farms. However, given its abundance, relatively lower chemical reactivity and relative ease of analysis, elemental sulfur was regarded as the most appropriate proxy for assessing the environmental impacts of finfish aquaculture.

Physiological responses of the abalone Haliotis discus hannai to daily and seasonal temperature variations.

Organisms inhabiting tidal mixing-front zones in shallow temperate seas are subjected to large semidiurnal temperature fluctuations in summer. The ability to optimize energy acquisition to this episodic thermal oscillation may determine the survival, growth and development of these ectotherms. We compared the physiological and molecular responses of Haliotis discus hannai cultivated in suspended cages to fluctuating or stable temperature conditions. Several physiological indicators (respiration, excretion rates and O:N) were measured in both conditions, and alterations in the proteome during thermal fluctuations were assessed. No summer mortality was observed in abalone cultivated in fluctuating temperatures compared with that at stable high temperatures. Metabolic rates increased sharply during stable warm summer conditions and fluctuated in accordance with short-term temperature fluctuations (20-26 °C). Ammonia excretion rates during acute responses were comparable in both conditions. When abalone were exposed to fluctuating temperatures, enzyme activities were downregulated and structure-related protein expression was upregulated compared with that at an acclimation temperature (26 °C), highlighting that exposure to low temperatures during fluctuations alters molecular processes. Our results reveal that modulation of physiological traits and protein expression during semidiurnal thermal fluctuations may buffer abalone from the lethal consequences of extreme temperatures in summer.

Physiological processes and gross energy budget of the submerged longline-cultured Pacific oyster Crassostrea gigas in a temperate bay of Korea.

Physiological processes and gross energy budget of the longline-cultured Pacific oyster Crassostrea gigas were investigated in Geoje-Hansan Bay, Korea during two entire culturing periods. Based on physiological measurements of food consumption, feces production, ammonium excretion, and respiration from July 2008 to February 2009 and from July 2013 to February 2014, scope for growth appeared to be positive during most of the culturing period, except for one period with extremely high temperatures (up to 25°C). Estimates of physiological energy production matched well with tissue energy increment measured by gross biochemical composition during the culturing period, suggesting that the oysters might adjust their physiological performance to relatively low concentrations of suspended particulate matter in the bay to optimize energy acquisition. Such an adaptive adjustment includes an increased absorption of energy and a reduced loss of metabolic and excretory energy, resulting in positive production under high culturing density. Using physiological measurements, we further assessed the feedback effects of the longline aquaculture of oysters on the bay system. Ecological efficiency, estimated by a series of energetic efficiencies at the whole bay level, was low compared with Lindeman's law of trophic efficiency. Biodeposition and ammonia excretion rates in this study were relatively low compared with other intertidal plastic bag cultures. These results indicate that the cultured oysters might have only minor effects on benthic and pelagic environments of the bay. Overall, our results suggest that the adaptive physiological performance of oysters and consequently weak feedback effects on ambient habitats should facilitate sustainable longline aquaculture in the bay for a prolonged period without severe habitat deterioration.

"Real-World" Comparison of Prasugrel With Ticagrelor in Patients With Acute Coronary Syndrome Treated With Percutaneous Coronary Intervention in the United States.

OBJECTIVES: The 30-day clinical outcomes with prasugrel or ticagrelor were compared using a US payer database in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). BACKGROUND: Prasugrel and ticagrelor demonstrated superior efficacy with increased non-coronary artery bypass graft major bleeding compared with clopidogrel in randomized clinical trials. No direct randomized or observational studies have compared clinical outcomes between prasugrel and ticagrelor. METHODS: Patients hospitalized for ACS-PCI between August 1, 2011 and April 30, 2013 and prescribed prasugrel or ticagrelor were selected. Drug treatment cohorts were propensity matched based upon demographic and clinical characteristics. The primary objective compared 30-day net adverse clinical events (NACE) in prasugrel- and ticagrelor-treated patients using a prespecified 20% noninferiority margin. Secondary objectives included comparisons of major adverse cardiovascular events (MACE) and major bleeding. RESULTS: Data were available for 16,098 patients (prasugrel, n = 13,134; ticagrelor, n = 2,964). In unmatched cohorts, prasugrel-treated patients were younger with fewer comorbidities than ticagrelor-treated patients, and 30-day NACE rates were 5.6 and 9.3%, respectively (P < 0.001). Following propensity matching, NACE was noninferior (P < 0.001) and 22% lower in prasugrel-treated than in ticagrelor-treated patients (RR, 0.78; 95% CI, 0.64-0.94). A 30-day adjusted MACE (RR, 0.80; 95% CI, 0.64-0.98) and major bleeding (RR, 0.65; 95% CI, 0.45-0.95) were also lower in prasugrel-treated patients compared with ticagrelor-treated patients. CONCLUSIONS: In this "real-world," retrospective, observational study, physicians appear to preferentially use prasugrel in younger patients with lower risk of bleeding or comorbidities compared with ticagrelor. Following adjustment, clinical outcomes associated with prasugrel use appear as good, if not better, than those associated with ticagrelor in ACS-PCI patients. © 2015 Wiley Periodicals, Inc.

Species-specific accumulation of methyl and total mercury in sharks from offshore and coastal waters of Korea.

Limited information is available on mercury (Hg) levels in various shark species consumed in Korea. The methyl-Hg (Me-Hg) and total Hg concentrations in all shark species ranged from 0.08 to 4.5 (mean: 1.2) mg/kg wet weight and from 0.1 to 7.0 (mean: 1.4) mg/kg wet weight, respectively. Inter-species differences in Hg accumulation were found among the species; however, Hg accumulation was homogenous between dorsal and pectoral fins within species. The highest Hg levels were found in aggressive carnivore shark species. Trophic position was important in determining Hg accumulation for aggressive carnivore sharks. Approximately 80% of shark species exceeded the safety limits for Me-Hg established by domestic and international authorities. The mean estimated daily intake of Me-Hg (1.3 µg/kg body weight/day) for Korean populations consuming various sharks was higher than the guidelines proposed by international regulatory authorities, suggesting that excessive shark fin consumption may pose potential health risks for Koreans.

A retrospective study of persistence, adherence, and health economic outcomes of fixed-dose combination vs. loose-dose combination of oral anti-diabetes drugs.

OBJECTIVE: To compare outcomes between patients with type 2 diabetes mellitus (T2DM) using fixed-dose combination (FDC) and loose-dose combination (LDC) products. METHODS: This retrospective cohort study used MarketScan Commercial and Medicare Supplemental data from January 1, 2009-December 31, 2013. The identified population included patients with T2DM and ≥1 additional oral anti-diabetic prescription (of the same regimen [FDC/LDC] as the index prescription) within 12 months following the fill date. Persistence (no ≥30-day gap) and adherence (medication possession ratio [MPR] ≥0.8) were assessed as primary end-points; secondary end-points included hypoglycemia, healthcare resource utilization, and costs. RESULTS: Of 23,361 patients identified, 12,590 (53.9%) were on FDC therapy and 10,771 (46.1%) were on LDC therapy. FDC patients had a significantly lower rate of non-persistence (67.9% vs. 73.4%, p < 0.0001) and a significantly higher rate of adherence to therapy (57.0% vs. 50.7%, p < 0.0001) when compared to LDC patients. Average time to non-persistence was significantly longer among FDC vs. LDC patients (207.1 vs. 186.3 days, p < 0.0001). After adjusting for baseline characteristics, the odds of non-persistence were 21% lower with FDC vs. LDC therapy (OR = 0.79, 95% CI = 0.74-0.85, p < 0.0001), with a 28% higher odds of adherence (OR = 1.28, 95% CI = 1.20-1.36, p < 0.0001). Differences in most secondary outcomes significantly favored FDC therapy, including total predicted monthly all-cause costs ($1008 vs. $1053; p = 0.006) and T2DM-related costs ($142 vs. $155; p < 0.001). LIMITATIONS: Cohort classification was based on prescription claims data. The lack of clinical data limits assessment of potential influencers of FDC vs. LDC decisions, residual confounding was possible, and diabetes-related medical costs only captured claims with a primary diagnosis for diabetes. The results may not be generalizable to populations such as Medicaid. CONCLUSION: Management of T2DM using FDC therapies provides a compliance benefit relative to LDC therapies that may translate to reductions in healthcare utilization and costs.