Phylogenomic analyses reveal incongruences between divergence times and fossil records of freshwater snails in East Asia.

Fossils provide important insight into our understanding of phylogenetic history by serving as calibration points for divergence time estimation. However, uncertainties in the fossil record due to parallel evolution and convergent evolution can critically affect estimates of node ages. Here, we compare and contrast estimates of phylogenetic divergence with geologic and fossil history for two freshwater snail genera of the family Viviparidae in East Asia (Cipangopaludina and Margarya). Cipangopaludina species are commonly widely distributed species in East Asia, but extant Margarya species are endemic to the ancient lakes in Yunnan, China. According to some previous studies, parallel evolution or convergent evolution of shell morphology has occurred in the family several times which may affect divergence time estimation using fossil records. In this study, we used SNP data derived from ddRAD-seq loci to investigate population demographic history of both genera. Our results show a common pattern of lake endemic lineages diversifying from widely distributed lineages in the Miocene, and multiple colonization to a single ancient lake occurred in the Pleistocene. Our results indicate substantial incongruence among estimated phylogenomic divergence times, some fossil records, and formation ages of ancient lakes. These findings suggest some fossil records may be misidentified in these groups and highlight the need to carefully evaluate geological evidence and fossil records when using these for divergence time estimation.

Taxonomic insights and evolutionary history in East Asian terrestrial slugs of the genus Meghimatium.

East Asia, specifically the Japanese Archipelago, is a biodiversity hotspot of both vertebrates and invertebrates. Mollusks represent a burst of species diversity in this region due to the effects of biotic and abiotic factors on their morphological traits, such as shell shape and size. However, the evolutionary history of terrestrial slugs in East Asia remains unknown. In the present study, we investigated the molecular phylogeny of terrestrial slugs of the genus Meghimatium. This genus includes three described and eight undescribed species, and our study used all except for two. Based on phylogeny and the species delimitation tests, the genus Meghimatium was split into many putative species, suggesting higher species diversity than previously thought based on morphological and anatomical studies and that almost undescribed species may be inappropriate. Therefore, morphological traits, such as body size and colour, conventionally considered for classification may easily vary or be similar across geographic region. Moreover, the divergence time of this genus is almost concordant with the geographical time scale of the formation of the Japanese mainland. Our findings suggest that molecular phylogenetics helps classify Japanese Meghimatium slugs, but comprehensive taxonomic revisions using multi-locus analyses are needed.

Validation of algorithms to identify colorectal cancer patients from administrative claims data of a Japanese hospital.

BACKGROUND: Administrative claims data are a valuable source for clinical studies; however, the use of validated algorithms to identify patients is essential to minimize bias. We evaluated the validity of diagnostic coding algorithms for identifying patients with colorectal cancer from a hospital's administrative claims data. METHODS: This validation study used administrative claims data from a Japanese university hospital between April 2017 and March 2019. We developed diagnostic coding algorithms, basically based on the International Classification of Disease (ICD) 10th codes of C18-20 and Japanese disease codes, to identify patients with colorectal cancer. For random samples of patients identified using our algorithms, case ascertainment was performed using chart review as the gold standard. The positive predictive value (PPV) was calculated to evaluate the accuracy of the algorithms. RESULTS: Of 249 random samples of patients identified as having colorectal cancer by our coding algorithms, 215 were confirmed cases, yielding a PPV of 86.3% (95% confidence interval [CI], 81.5-90.1%). When the diagnostic codes were restricted to site-specific (right colon, left colon, transverse colon, or rectum) cancer codes, 94 of the 100 random samples were true cases of colorectal cancer. Consequently, the PPV increased to 94.0% (95% CI, 87.2-97.4%). CONCLUSION: Our diagnostic coding algorithms based on ICD-10 codes and Japanese disease codes were highly accurate in detecting patients with colorectal cancer from this hospital's claims data. The exclusive use of site-specific cancer codes further improved the PPV from 86.3 to 94.0%, suggesting their desirability in identifying these patients more precisely.

De novo genome assembly and genome skims reveal LTRs dominate the genome of a limestone endemic Mountainsnail (Oreohelix idahoensis).

BACKGROUND: Calcareous outcrops, rocky areas composed of calcium carbonate (CaCO3), often host a diverse, specialized, and threatened biomineralizing fauna. Despite the repeated evolution of physiological and morphological adaptations to colonize these mineral rich substrates, there is a lack of genomic resources for calcareous rock endemic species. This has hampered our ability to understand the genomic mechanisms underlying calcareous rock specialization and manage these threatened species. RESULTS: Here, we present a new draft genome assembly of the threatened limestone endemic land snail Oreohelix idahoensis and genome skim data for two other Oreohelix species. The O. idahoensis genome assembly (scaffold N50: 404.19 kb; 86.6% BUSCO genes) is the largest (~ 5.4 Gb) and most repetitive mollusc genome assembled to date (85.74% assembly size). The repetitive landscape was unusually dominated by an expansion of long terminal repeat (LTR) transposable elements (57.73% assembly size) which have shaped the evolution genome size, gene composition through retrotransposition of host genes, and ectopic recombination. Genome skims revealed repeat content is more than 2-3 fold higher in limestone endemic O. idahoensis compared to non-calcareous Oreohelix species. Gene family size analysis revealed stress and biomineralization genes have expanded significantly in the O. idahoensis genome. CONCLUSIONS: Hundreds of threatened land snail species are endemic to calcareous rock regions but there are very few genomic resources available to guide their conservation or determine the genomic architecture underlying CaCO3 resource specialization. Our study provides one of the first high quality draft genomes of a calcareous rock endemic land snail which will serve as a foundation for the conservation genomics of this threatened species and for other groups. The high proportion and activity of LTRs in the O. idahoensis genome is unprecedented in molluscan genomics and sheds new light how transposable element content can vary across molluscs. The genomic resources reported here will enable further studies of the genomic mechanisms underlying calcareous rock specialization and the evolution of transposable element content across molluscs.

Patterns of diversification of the operculate land snail genus Cyclophorus (Caenogastropoda: Cyclophoridae) on the Ryukyu Islands, Japan.

The Ryukyu Islands, an island chain in southwestern Japan, originated from land masses that separated from the Eurasian continent due to the formation of sea barriers about 1.55 million years ago. In this study, we investigated the phylogenetic relationships of the operculate land snail genus Cyclophorus (Caenogastropoda: Cyclophoridae) in the Ryukyu Archipelago and surrounding regions based on DNA sequence data. According to our results, all studied Cyclophorus specimens from Japan form a monophyletic group containing eight subclades. Six of these subclades were found only on the Ryukyu Islands. On most islands of the Ryukyu Archipelago, no more than one Cyclophorus subclade was recorded, which may be due to limited ecological niche space and competition. No subclade was found to occur on both sides of the Watase Line, a regional zoogeographical boundary. Divergence times were estimated based on a time-calibrated phylogeny. We found that multiple splits among the Japanese Cyclophorus subclades predate the emergence of major sea barriers in the Ryukyu Archipelago. Vicariance due to sea barrier formation, as assumed for many other taxa from the region, was thus likely not the main driver for subclade divergence in these snails. Instead, certain geographical features might have shaped the diversification of subclades prior to sea barrier formation. Given that Cyclophorus populations were also present on islands that have never been connected to other land masses, the snails must have colonized them via oversea dispersal. As not all nominal taxa corresponded to monophyletic groups, our molecular phylogenetic approach revealed that a taxonomic revision of the Japanese Cyclophorus fauna is necessary. The eight subclades may be regarded as potential species-level groups based on COI p-distances. A canonical discriminant analysis using shell morphological data revealed slight differences among the subclades.

Uncovering overlooked diversity using molecular phylogenetic approach: A case of Japanese sphaeriid clams (Bivalvia: Sphaeriidae).

Revealing the species and lineage diversity of a taxon is important for many biological studies of wildlife. In recent decades, DNA-based approaches have been widely utilised to elucidate the diversity of taxa, especially those that are difficult to distinguish based on morphological traits. This study focused on freshwater clams (Sphaeriidae) in Japan, a biodiversity hotspot of freshwater molluscs. Molecular phylogenetic approaches, including divergence time estimation, species delimitation, rarefaction, and biogeographic area estimation, were used to reveal the nature of the species diversity and its formation process, which are largely unknown. Our delimitation and rarefaction analyses suggest that Japanese sphaeriid clams consist of at least 18 delimitated lineages. This lineage diversity is relatively high compared to other Japanese freshwater molluscs, and in addition, the majority of the Japanese lineage appears to have high endemicity despite the possibility of long-distance dispersal in sphaeriid clams. Our biogeographical analyses suggest that this diversity may be due to the combination of colonisation, during the period when Japan was connected to the continent, and the relatively recent dispersal. Our results highlight the overlooked biodiversity of Japan and provide a basis for further Japanese sphaeriid research, including conservation perspectives.

Resolving species-level diversity of Beringiana and Sinanodonta mussels (Bivalvia: Unionidae) in the Japanese archipelago using genome-wide data.

Accurate species identification is of primary importance in ecology and evolutionary biology. For a long time, the unionid mussels Beringiana and Sinanodonta have puzzled researchers trying to unravel their diversity because of their poorly discernible morphologies. A recent study conducted species delineation of unionid mussels based on mitochondrial DNA variation, opening up a new avenue to grasp species diversity of the mussels. However, mtDNA-based classification may not align with species boundaries because mtDNA is prone to introgression and incomplete lineage sorting that cause discordance between species affiliation and gene phylogeny. In this study, we evaluated the validity of the mtDNA-based classification of unionid mussels Beringiana and Sinanodonta in Japan using mitochondrial sequence data, double digest restriction site-associated DNA library (ddRAD) sequencing, and morphological data. We found significant inconsistencies in the mitochondrial and nuclear DNA phylogenies, casting doubt on the reliability of the mtDNA-based classification in this group. In addition, nuclear DNA phylogeny revealed that there are at least two unionid lineages hidden in the mtDNA phylogeny. Although molecular dating technique indicates that Beringiana and Sinanodonta diverged >35 million years ago, their shell morphologies are often indistinguishable. Specifically, morphological analyses exhibited the parallel appearance of nearly identical ball-like shell forms in the two genera in Lake Biwa, which further complicates species identification and the morphological evolution of unionid mussels. Our study adds to a growing body of literature that accurate species identification of unionid mussels is difficult when using morphological characters alone. Although mtDNA-based classification is a simple and convenient way to classify unionid mussels, considerable caution is warranted for its application in ecological and evolutionary studies.

Structure-activity relationship studies on an antitumor marine macrolide using aplyronine a-swinholide A hybrid.

An aplyronine A-swinholide A hybrid, consisting of the macrolactone part of aplyronine A and the side chain part of swinholide A, was designed, synthesized, and biologically evaluated. This hybrid induced protein-protein interactions between two major cytoskeletal proteins actin and tubulin in the same manner as aplyronine A, and exhibited potent cytotoxicity and actin-depolymerizing activity. The importance of the methoxy group in the N,N,O-trimethylserine ester was clarified by the structure-activity relationship studies of the amino acid moiety by using the hybrid analogs. Furthermore, the comparison of the actin-depolymerizing activities between the side chain analogs of aplyronine A and swinholide A showed that the side chain analog of swinholide A had much weaker actin-depolymerizing activity than that of aplyronine A.

Tolerability of the Intravenously Administered Tolvaptan Prodrug, OPC-61815, in Patients With Congestive Heart Failure Who Have Difficulty With, or Are Incapable of, Oral Intake (TRITON-HF)　- A Phase III, Multicenter, Open-Label Trial.

BACKGROUND: OPC-61815, a prodrug of tolvaptan, is an injectable aquaretic drug. This study evaluated the tolerability of OPC-61815 in patients with congestive heart failure (CHF) who had difficulty with, or were incapable of, oral intake in a multicenter, uncontrolled, open-label Phase III study.Methods and Results: Forty-five patients were enrolled at 30 Japanese sites. OPC-61815 infusion was administered once daily; the 8 mg initial dose could be increased to 16 mg if the dose escalation criteria were met. Patients were treated for up to 5 days. Thirty-eight patients maintained the 8-mg dose and 7 had a dose increase to 16 mg; 41 completed the trial (34 completed early). One patient had mild hypernatremia. No significant safety concerns were observed with OPC-61815 administration at a starting dose of 8 mg and with dose escalation in accordance with the protocol-specified criteria. Treatment resulted in weight decrease (-3.01 kg); improvement or disappearance rates for other CHF symptoms (including edema, dyspnea, orthopnea, pulmonary congestion, and rales) indicated that treatment was effective. Urine excretion was increased 0-1 h after OPC-61815 administration and reached a maximum level at 1-2 h. CONCLUSIONS: The tolerability of once daily (up to 5 days) intravenous OPC-61815 (8 mg or 16 mg) was confirmed in patients with CHF who had difficulty with, or were incapable of, oral intake.

Pharmacokinetics, Pharmacodynamics, Efficacy, and Safety of OPC-61815, a Prodrug of Tolvaptan for Intravenous Administration, in Patients With Congestive Heart Failure　- A Phase II, Multicenter, Double-Blind, Randomized, Active-Controlled Trial.

BACKGROUND: Tolvaptan is an orally administered aquaretic drug indicated for patients with congestive heart failure (CHF) to remove excess fluid. OPC-61815, a prodrug of tolvaptan with improved water solubility, is considered suitable for intravenous (IV) administration. This Phase II study investigated the OPC-61815 dose that would result in an exposure equivalent to tolvaptan 15 mg.Methods and Results:We conducted a multicenter, randomized study in Japanese patients aged 20-85 years with CHF and volume overload despite treatment with diuretics other than vasopressin antagonists. Patients received IV OPC-61815 2 mg (n=13), 4 mg (n=12), 8 mg (n=12), 16 mg (n=11), or oral tolvaptan 15 mg (n=12). The primary endpoint was tolvaptan exposure on treatment Day 1; efficacy and safety were also assessed. Tolvaptan exposure increased in a dose-dependent manner following a single IV administration of OPC-61815; the exposure following an IV dose of OPC-61815 16 mg was similar to that of a tolvaptan 15-mg tablet, with no marked differences in safety or tolerability. OPC-61815 increased urine volume from baseline, resulting in decreased body weight and improved lower limb edema. No notable safety concerns were observed. CONCLUSIONS: In this first study of OPC-61815 in patients with CHF, exposure following a single IV administration of OPC-61815 16 mg was comparable with a single oral administration of tolvaptan 15 mg, with no safety concerns.

Real-world hospital mortality of liver cirrhosis inpatients in Japan: a large-scale cohort study using a medical claims database: Prognosis of liver cirrhosis.

AIM: Prognosis of liver cirrhosis patients is poor when ascites is present and liver function is impaired, but such up-to-date information from a large-scale, real-world setting is limited in Japan. We aimed to investigate the hospital mortality of Japanese liver cirrhosis inpatients. METHODS: This retrospective cohort study included data on liver cirrhosis inpatients between January 2011 and September 2018 extracted from an administrative claims database. The outcome was in-hospital mortality. The 1- and 3-year cumulative survival rates were examined for liver cirrhosis etiology, Child-Pugh classification, or ascites presence/absence using Kaplan-Meier analysis. The survival up to 1 year for tolvaptan prescription/nonprescription was examined. RESULTS: We analyzed the data of 57 769 inpatients. Survival rates did not substantially differ among etiologies, with a better prognosis for alcohol etiology and poorer prognosis for hepatitis C virus. According to the Child-Pugh classification, the 1- and 3-year survival rates were 90.2% and 75.3% for grade A, 73.5% and 53.9% for grade B, and 41.9% and 28.9% for grade C, respectively. Patients without ascites had a higher survival rate (83.2% and 67.0% at 1 and 3 years, respectively) than those with ascites (51.9% and 36.3%, respectively). Based on examining matched patients with ascites using a propensity score, prognosis was poor in general but was better at 6 months (58.1%) or similar at 1 year (47.1%) in patients prescribed tolvaptan compared to those not prescribed tolvaptan (54.8% and 47.5%, respectively). CONCLUSIONS: Poorer prognosis was suggested in inpatients with cirrhosis who had a worse Child-Pugh grade and ascites.

Open-label, multicenter, dose-titration study to determine the efficacy and safety of tolvaptan in Japanese patients with hyponatremia secondary to syndrome of inappropriate secretion of antidiuretic hormone.

The purpose of this study was to determine the efficacy and safety of tolvaptan in Japanese patients with hyponatremia secondary to syndrome of inappropriate secretion of antidiuretic hormone (SIADH). This multicenter, open-label, dose-escalation, phase III study enrolled Japanese patients (20-85 years old) with hyponatremia secondary to SIADH who were unresponsive to fluid restriction. Oral tolvaptan was administered for up to 30 days, initially at 7.5 mg/day, but escalated daily as necessary, based on the serum sodium concentration and safety, over the first 10 days until the optimal maintenance dose was determined for each patient (maximum 60 mg/day). The primary endpoint was the proportion of patients with normalized serum sodium concentration on the day after the final tolvaptan dose. Secondary endpoints included the mean change in serum sodium concentration from baseline on the day after the final dose. Sixteen patients (male, 81.3%; mean ± standard deviation age 71.9 ± 6.1 years) received tolvaptan treatment and 11 patients completed the study with one patient re-administered tolvaptan in the treatment period. Serum sodium concentrations normalized in 13 of 16 (81.3%) patients on the day after the final tolvaptan dose. The mean change in serum sodium concentration from baseline on the day after the final dose was 11.0 ± 4.3 mEq/L. Adverse events considered related to tolvaptan (10 [62.5%] patients) were generally of mild to moderate severity. Oral tolvaptan corrects hyponatremia in Japanese patients with SIADH with a similar efficacy and safety profile as that noted in non-Japanese patients.

Role of ancient lakes in genetic and phenotypic diversification of freshwater snails.

Endemic organisms of ancient lakes have been studied as models to understand processes of speciation and adaptive radiation. However, it remains unclear how ancient lakes play roles in genetic and phenotypic diversity of freshwater mollusks. In the present study, we focus on viviparid freshwater snails in the ancient lakes of East and Southeast Asia (Japan and China) to address this question. Using molecular phylogenetic analyses based on mitochondrial (COI, 16S) and nuclear genes (18S, 28S, H3), we show that patterns of species diversification in viviparid lineages. Colonization to ancient lakes occurred independently in China and Japan at least four times, with subsequent diversification into more than two species within each lake group. Morphological analyses of fossil related viviparids suggest parallel phenotypic evolution occurred in the different lakes and ages. Each lake contained a single lineage which was phenotypically diversified relative to those from other sites. Using genome-wide SNPs obtained by MIG-seq, we also examined the genetic structure of three Japanese viviparids, including two endemic species of ancient Lake Biwa. The results suggest that these two species diversified from the population of the third species living in wetlands surrounding the lake. These findings suggest that rapid diversification of lineages and phenotypic divergence can occur in ancient lakes compared to other habitats. Formation of large lakes probably promotes speciation and phenotypic divergence as a result of adaptation into different microhabitats. High numbers of ancient lakes could be a driver of species diversity in Asian viviparid snails.

Phylogeography of freshwater planorbid snails reveals diversification patterns in Eurasian continental islands.

BACKGROUND: Islands have traditionally been the centre of evolutionary biological research, but the dynamics of immigration and differentiation at continental islands have not been well studied. Therefore, we focused on the Japanese archipelago, the continental islands located at the eastern end of the Eurasian continent. While the Japanese archipelago is characterised by high biodiversity and rich freshwater habitats, the origin and formation mechanisms of its freshwater organisms are not clear. In order to clarify the history of the planorbid gastropod fauna, we conducted phylogenetic analysis, divergence time estimation, ancestral state reconstruction, and lineage diversity estimations. RESULTS: Our analyses revealed the formation process of the planorbid fauna in the Japanese archipelago. Most lineages in the Japanese archipelago have closely related lineages on the continent, and the divergence within the Japanese lineages presumably occurred after the late Pliocene. In addition, each lineage is characterised by different phylogeographical patterns, suggesting that immigration routes from the continent to the Japanese archipelago differ among lineages. Furthermore, a regional lineage diversity plot showed that the present diversity in the Japanese archipelago potentially reflects the differentiation of lineages within the islands after the development of the Japanese archipelago. CONCLUSIONS: Although additional taxon sampling and genetic analysis focused on each lineage are needed, our results suggest that immigration from multiple routes just prior to the development of the Japanese archipelago and subsequent diversification within the islands are major causes of the present-day diversity of the Japanese planorbid fauna.

R-warfarin clearances from plasma associated with polymorphic cytochrome P450 2C19 and simulated by individual physiologically based pharmacokinetic models for 11 cynomolgus monkeys.

1. Cynomolgus monkey cytochrome P450 2C19 (formerly known as P450 2C75), homologous to human P450 2C19, has been identified as R-warfarin 7-hydroxylase. In this study, simulations of R-warfarin clearance in individual cynomolgus monkeys genotyped for P450 2C19 p.[(Phe100Asn; Ala103Val; Ile112Leu)] were performed using individual simplified physiologically based pharmacokinetic (PBPK) modeling. 2. Pharmacokinetic parameters and absorption rate constants, volumes of the systemic circulation, and hepatic intrinsic clearances for individual PBPK models were estimated for eleven cynomolgus monkeys. 3. One-way ANOVA revealed significant effects of the genotype (p < 0.01) on the observed elimination half-lives and areas under the curves of R-warfarin among the homozygous mutant, heterozygous mutant, and wild-type groups. R-Warfarin clearances in individual cynomolgus monkeys genotyped for P450 2C19 were simulated by simplified PBPK modeling. The modeled hepatic intrinsic clearances were significantly associated with the P450 2C19 genotypes. The liver microsomal elimination rates of R-warfarin for individual animals after in vivo administration showed significant reductions associated with the genotype (p < 0.01). 4. This study provides important information to help simulate clearances of R-warfarin and related medicines associated with polymorphic P450 2C19 in individual cynomolgus monkeys, thereby facilitating calculation of the fraction of hepatic clearance.

Substantial incongruence among the morphology, taxonomy, and molecular phylogeny of the land snails Aegista, Landouria, Trishoplita, and Pseudobuliminus (Pulmonata: Bradybaenidae) occurring in East Asia.

Analyses of molecular phylogeny have revealed that phenotypically identified taxa do not reflect phylogenetic relationships. Such taxa often are not evolutionary significant and are misleading in describing and evaluating biological diversity. Herein, we investigated the molecular phylogeny of the East Asian bradybaenid land snail genera Aegista, Landouria, Trishoplita, and Pseudobuliminus to test whether morphology and current taxonomy reflect phylogenetic relationships. Our results document extensive parallel evolution and substantial incongruence between taxonomy and molecular phylogeny. Species with an elongated turret shell evolved independently five times, and hair-like ornamentation of the shell was independently gained or lost in a number of lineages. Although genital anatomy reveals phylogenetic conservatism to some extent, love dart and dart-related organs were lost independently at least three times in these genera. Accordingly, classification of these genera based on morphological traits did not reflect phylogenetic relationships, and, overall, these genera except for a few species should be tentatively assigned to a single genus as Aegista. The present findings suggest that radical revision is required for the taxonomy of bradybaenid land snails.

Tele-education by an orthopedic specialist increased the confidence in orthopedics of a general practitioner at a rural solo-practice clinic.

Objective: General practitioners in rural clinics are required to deal with musculoskeletal problems, but they often lack the confidence. We aim to confirm changes in their confidence in orthopedic practices after using tele-education. Materials and Methods: We conducted tele-education in orthopedic practices from June 1, 2022, to November 30, 2022. Using a teleconference system, the first author, an orthopedic specialist, provided tele-education training to an independent general practitioner in a rural clinic. We adopted a 7-point Likert scale to assess the general practitioner's confidence levels. In pre- and post-research, the counts and confidence levels in the scale were assessed for 18 types of orthopedic practices each month. Furthermore, we interviewed the general practitioner to examine the factors influencing their confidence. Results: The confidence levels increased for all measurement items. The most experienced orthopedic practice was "Advising on daily care for musculoskeletal problems", with confidence levels increasing from 3 to 6. The least experienced orthopedic practice was "Manipulative reduction of radial head subluxation", with confidence levels increasing from 4 to 5. The factors that influenced the change in confidence levels were regular feedback and unrestricted availability of consultations. Conclusion: Tele-education in orthopedics may enhance general practitioners' confidence in orthopedic practices.

An Attempt to Replicate Randomized Trials of Diabetes Treatments Using a Japanese Administrative Claims and Health Checkup Database: A Feasibility Study.

BACKGROUND: Use of real-world evidence (RWE) has been limited for evaluating effectiveness because of the lack of confidence in its reliability. Examining whether a rigorously designed observational study using real-world data (RWD) can reproduce the results of a randomized controlled trial (RCT) will provide insights into the implementation of high-quality RWE studies that can produce valid conclusions. OBJECTIVE: We aimed to replicate published RCTs using a Japanese claims and health checkup database and examine whether the emulated RWE studies' results agree with those of the original RCTs. METHODS: We selected three RCTs on diabetes medications for replication in patients with type 2 diabetes. The study outcome was either the change or percentage change in HbA1c levels from baseline. We designed three observational studies using the RWD to mimic the critical study elements of the respective RCTs as closely as possible. We performed 1:1 propensity score nearest-neighbor matching to balance the groups for potential confounders. The differences in outcomes between the groups and their 95% confidence intervals (CIs) were calculated in each RWE study, and the results were compared with those of the RCT. RESULTS: Patient characteristics, such as age, sex, and duration of diabetes, differed between the RWE studies and RCTs. In Trial 1 emulation, the percentage changes in HbA1c levels were larger in the treatment group than in the comparator group (difference -6.21, 95% confidence interval (CI) -11.01 to -1.40). In Trial 2, the change in HbA1c level was larger in the treatment group (difference -0.01; 95% CI -0.25 to 0.23), and in Trial 3, it was smaller in the treatment group (difference 0.46; 95% CI -0.01 to 0.94). These results did not show regulatory or estimate agreement with the RCTs. CONCLUSIONS: None of the three emulated RWE studies using this claims and health checkup database reproduced the same conclusions as the RCTs. These discrepancies could largely be attributed to design differences between RWE studies and RCTs, primarily due to the lack of necessary data in the database. This particular RWD source may not be the best fit for evaluating treatment effects using laboratory data as the study outcome.

Validation of Algorithms to Identify Bone Metastases Using Administrative Claims Data in a Japanese Hospital.

BACKGROUND: Validated coding algorithms are essential to generate high-quality, real-world evidence from claims data studies. OBJECTIVE: We aimed to evaluate the validity of the algorithms to identify patients with bone metastases using claims data from a Japanese hospital. PATIENTS AND METHODS: This study used administrative claims data and electronic medical records at Juntendo University Hospital from April 2017 to March 2019. We developed two candidate claims-based algorithms to detect bone metastases, one based on diagnosis codes alone (Algorithm 1) and the other based on the combination of diagnosis and imaging test codes (Algorithm 2). Of the patients identified by Algorithm 1, 100 patients were randomly sampled. Among these 100 patients, 88 patients met the conditions of Algorithm 2; further, 12 additional patients were randomly sampled from those identified by Algorithm 2, thus obtaining a total of 100 patients for Algorithm 2. They were evaluated for their true diagnosis using the patient chart review as the gold standard. The positive predictive value (PPV) was calculated to assess the accuracy of each algorithm. RESULTS: For Algorithm 1, 82 patients were analyzed after excluding 18 patients without diagnostic imaging reports. Of these, 69 patients were true positive by chart review, resulting in a PPV of 84.1% (95% confidence interval (CI) 74.5-90.6). For Algorithm 2, 92 patients were analyzed after excluding eight patients whose diagnoses were not judged by chart review. Of these, 76 patients were confirmed positive by chart review, yielding a PPV of 82.6% (95% CI 73.4-89.1). CONCLUSION: Both claims-based algorithms yielded high PPVs of approximately 85%, with no improvement in PPV by adding imaging test conditions. The diagnosis code-based algorithm is sufficient and valid for identifying bone metastases in this Japanese hospital.