The Amaranth Genome: Genome, Transcriptome, and Physical Map Assembly.

Amaranth ( L.) is an emerging pseudocereal native to the New World that has garnered increased attention in recent years because of its nutritional quality, in particular its seed protein and more specifically its high levels of the essential amino acid lysine. It belongs to the Amaranthaceae family, is an ancient paleopolyploid that shows disomic inheritance (2 = 32), and has an estimated genome size of 466 Mb. Here we present a high-quality draft genome sequence of the grain amaranth. The genome assembly consisted of 377 Mb in 3518 scaffolds with an N of 371 kb. Repetitive element analysis predicted that 48% of the genome is comprised of repeat sequences, of which -like elements were the most commonly classified retrotransposon. A de novo transcriptome consisting of 66,370 contigs was assembled from eight different amaranth tissue and abiotic stress libraries. Annotation of the genome identified 23,059 protein-coding genes. Seven grain amaranths (, , and ) and their putative progenitor () were resequenced. A single nucleotide polymorphism (SNP) phylogeny supported the classification of as the progenitor species of the grain amaranths. Lastly, we generated a de novo physical map for using the BioNano Genomics' Genome Mapping platform. The physical map spanned 340 Mb and a hybrid assembly using the BioNano physical maps nearly doubled the N of the assembly to 697 kb. Moreover, we analyzed synteny between amaranth and sugar beet ( L.) and estimated, using analysis, the age of the most recent polyploidization event in amaranth.

Implications of controlling for comorbid conditions in cost-of-illness estimates: a case study of osteoarthritis from a managed care system perspective.

OBJECTIVES: Current methods for estimating the cost of illness inconsistently control for the effect of comorbid conditions. This analysis examines the implications of controlling for comorbid conditions on the estimated cost of illness. These implications are illustrated using the cost of osteoarthritis as an example. METHODS AND DATA: Medical claims data from 1996 were obtained for inpatient, outpatient, and pharmacy services for members in four United HealthCare health plans. Total annual costs for osteoarthritis (OA) were compared to costs among an equal number of comparison members. Multivariate regression analysis was used to compare the natural log of costs between the OA and comparison groups under two alternative controls for comorbid conditions: no controls, and controls for all conditions. RESULTS: Controlling for no or all comorbid conditions resulted in estimates of the annual cost of members with OA that ranged between 261% and 151% of the cost of members without OA, respectively. CONCLUSIONS: Existing cost-of-illness estimates may seriously underestimate the true cost by including statistical controls for all comorbid conditions, or seriously overestimate the true cost by failing to control for enough comorbid conditions. In the case of OA, the range of potential bias is substantial.

One-year costs of second-line therapies for depression.

BACKGROUND: We compared patterns of medical resource utilization and costs among patients receiving a serotonin-norepinephrine reuptake inhibitor (venlafaxine), one of the selective serotonin reuptake inhibitors (SSRIs), one of the tricyclic agents (TCAs), or 1 of 3 other second-line therapies for depression. METHOD: Using claims data from a national managed care organization, we identified patients diagnosed with depression (ICD-9-CM criteria) who received second-line antidepressant therapy between 1993 and 1997. Second-line therapy was defined as a switch from the first class of antidepressant therapy observed in the data set within 1 year of a diagnosis of depression to a different class of antidepressant therapy. Patients with psychiatric comorbidities were excluded. RESULTS: Of 981 patients included in the study, 21% (N = 208) received venlafaxine, 34% (N = 332) received an SSRI, 19% (N = 191) received a TCA, and 25% (N = 250) received other second-line antidepressant therapy. Mean age was 43 years, and 72% of patients were women. Age, prescriber of second-line therapy, and prior 6-month expenditures all differed significantly among the 4 therapy groups. Total, depression-coded, and non-depression-coded 1-year expenditures were, respectively, $6945, $2064, and $4881 for venlafaxine; $7237, $1682, and $5555 for SSRIs; $7925, $1335, and $6590 for TCAs; and $7371, $2222, and $5149 for other antidepressants. In bivariate analyses, compared with TCA-treated patients, venlafaxine- and SSRI-treated patients had significantly higher depression-coded but significantly lower non-depression-coded expenditures. Venlafaxine was associated with significantly higher depression-coded expenditures than SSRIs. However, after adjustment for potential confounding covariables in multivariate analyses, only the difference in depression-coded expenditures between SSRI and TCA therapy remained significant. CONCLUSION: After adjustment for confounding patient characteristics, 1-year medical expenditures were generally similar among patients receiving venlafaxine, SSRIs, TCAs, and other second-line therapies for depression. Observed differences in patient characteristics and unadjusted expenditures raise questions as to how different types of patients are selected to receive alternative second-line therapies for depression.

Antibiotics and Clostridium difficile diarrhea in the ambulatory care setting.

OBJECTIVE: The goal of this study was to determine the prevalence of Clostridium difficile diarrhea (CDD) and the risk for CDD associated with different oral antibiotics commonly used in the ambulatory care setting. METHODS: The prevalence of CDD was determined for enrollees in 4 UnitedHealth Group-affiliated health plans between January 1, 1992, and December 31, 1994. Cases were identified based on the presence of an inpatient or outpatient claim with a primary diagnosis of diarrhea, a pharmacy claim for a prescription drug used to treat CDD, or a physician or facility claim for the C. difficile toxin test, and were confirmed using full-text medical records. Within a retrospective cohort design, periods of risk for CDD were defined on the basis of duration of antibiotic therapy. To control for potential selection bias created by heterogeneous rates of C. difficile testing and to limit confounding due to multiple antibiotic exposures, we used a nested case-control design, restricting eligibility to subjects who underwent screening for C. difficile and who had been exposed to only 1 antibiotic risk period with a single antibiotic. RESULTS: The global prevalence of CDD in 358,389 ambulatory care enrollees was 12 per 100,000 person-years. In the nested case-control study, after controlling for other risk factors, 2 antibiotics demonstrated an increased association with CDD: cephalexin (odds ratio [OR] = 7.5, 95% CI = 1.8 to 34.7) and cefixime (OR = 6.4, 95% CI = 1.2 to 39.0). CONCLUSIONS: Although CDD is thought to occur primarily in hospitalized patients, it was found to be present in an ambulatory care population, but at a low frequency. In this population, it appeared to be associated with 2 cephalosporins but not with other types of antibiotics usually linked with nosocomial CDD. Because the frequency of C. difficile testing was shown to be more common with high-risk antibiotics, CDD may be underdiagnosed in the ambulatory care setting.

Postmarketing surveillance of medications and pregnancy outcomes: clarithromycin and birth malformations.

PURPOSE: This retrospective surveillance study used linked administrative claims data and medical records to determine the rate and types of birth malformations in infants born to women exposed to the antibiotic, clarithromycin (Biaxin), during the first trimester of pregnancy. METHODS: Pharmacy and hospital claims from eight geographically diverse health plans were used to identify women who had a delivery claim within 270 days of a clarithromycin prescription over a 5-year period (1991-1995). Hospital delivery admission medical records for 143 mothers and their 149 infants were abstracted to identify birth malformations. RESULTS: Five infants were identified with major malformations, three with minor malformations, and four with undescended testicles likely to resolve with time. The observed rate of 3.4% (95% CI, 0.5, 6.3) for major malformations was not statistically significantly different compared to an expected rate of 2.8% based on earlier national data. There was no consistency across types of major malformations. CONCLUSIONS: These results provide no evidence that clarithromycin is a likely major teratogen in humans. Use of claims data is one way to evaluate quickly and efficiently the safety of prescription medications in humans during pregnancy, especially when both exposure and outcome are rare.

Incidence of adverse oesophageal and gastric events in alendronate users.

Purpose- To estimate the incidence of adverse gastrointestinal events in alendronate users.Methods- The computerized pharmacy claims of 12 geographically dispersed United Health Group-affiliated health plans were used to identify 1421 persons who received alendronate prescriptions. The medical claims data of these individuals were searched for subsequent diagnoses of oesophagitis, ulcer of the oesophagus, oesophageal perforation, gastric ulcer, and gastritis/duodenitis. The incidence level was estimated as cumulative incidence and incidence density and their 95% confidence intervals.Results- Thirty-nine persons had a diagnostic code indicating an incident oesophageal or gastric diagnosis of interest, including 22 with oesophagitis, two with oesophageal ulcer, one with gastric ulcer, and 15 with gastritis/duodenitis. Thirteen cases (33.3%) underwent upper endoscopic examination. Five (12.8%) patients were hospitalized. Reflecting alendronate use, 95% of patients were female. The cumulative incidence of oesophageal and gastric events for alendronate users was 3.1% in females, 2.0% in males, and 3.0% overall. The incidence density of a diagnosis of oesophageal or gastric events was 9.0 per 100 woman-years of exposure. There was no significant variation in the cumulative incidence among different age groups.Conclusions- These results suggest the incidence of oesophageal and gastric diagnostic codes is high among alendronate users. Further research is needed to assess the possible association between alendronate and adverse upper gastrointestinal events. Copyright (c) 2000 John Wiley & Sons, Ltd.

Medical resource use and cost of venlafaxine or tricyclic antidepressant therapy. Following selective serotonin reuptake inhibitor therapy for depression.

OBJECTIVE: An analysis of administrative and claims data was performed to compare the resource use and costs to a managed-care organisation of venlafaxine, a serotonin and norepinephrine reuptake inhibitor (SNRI), versus tricyclic antidepressant (TCA) therapy, after switching from a selective serotonin reuptake inhibitor (SSRI). DESIGN: One-year costs and frequencies of all medical services, and of services coded for depression, were compared between patients who received venlafaxine and TCA therapy as second-line therapy using bivariate and multivariate statistical analyses. SETTING: Data were obtained from 9 individual health plans with more than 1.1 million covered lives affiliated with a national managed-care organisation. PATIENTS AND PARTICIPANTS: Health plan members were included if they had a diagnosis of depression between July 1993 and February 1997. They also had to have at least 2 months of prescriptions for SSRI therapy followed by at least 2 months of venlafaxine or TCA therapy, and continuous enrollment in the plan from at least 6 months prior to 12 months following initiation of venlafaxine or TCA therapy. 188 patients who received venlafaxine and 172 patients who received TCAs met the inclusion criteria. MAIN OUTCOME MEASURES AND RESULTS: Patients who received TCAs were slightly but significantly older (43 vs 40 years) than venlafaxine recipients and, during 6 months prior to initiating therapy, had significantly higher mean costs coded for depression ($US451 vs $US311) and costs not coded for depression ($US4500 vs $US2090). Psychiatrists prescribed a significantly higher proportion of venlafaxine than TCA prescriptions (46.3 vs 25.0%). Prior to adjusting for confounding characteristics, during 12 months following initiation of therapy, mean depression-coded costs were significantly higher for venlafaxine than TCA recipients ($US1948 vs $US1396) and mean costs not coded for depression were significantly lower ($US4595 vs $US6677). Overall costs were not significantly different ($US6543 for venlafaxine vs $US8073 for TCA). Significant cost differences were observed with primary care physicians as initial prescribers of second-line therapy but not with psychiatrists. However, costs between the 2 groups were similar after adjusting for confounding variables, including prior 6-month costs and initial prescriber of second-line therapy. CONCLUSIONS: Payer costs are similar among patients receiving venlafaxine and TCA therapy following SSRI therapy. Higher costs of venlafaxine pharmacotherapy relative to TCA therapy may be offset by lower costs of other medical services. Differences in prescribing patterns and costs between primary care physicians and psychiatrists warrant further investigation.

Financial incentives and drug spending in managed care.

This study estimates the impact of patient financial incentives on the use and cost of prescription drugs in the context of differing physician payment mechanisms. A large data set was developed that covers persons in managed care who pay varying levels of cost sharing and whose physicians are compensated under two different models: independent practice association (IPA)-model and network-model health maintenance organizations (HMOs). Our results indicate that higher patient copayments for prescription drugs are associated with lower drug spending in IPA models (in which physicians are not at risk for drug costs) but have little effect in network models (in which physicians bear financial risk for all prescribing behavior).

Financial incentives and drug spending in managed care.

Pharmaceutical costs have been rising dramatically since 1995, growing 16.6% in 1998 alone. This rate of increase is more than four times that of all health care spending. Employers, managed care organizations and consumers are looking anew for ways to stem these rising costs, without denying patients effective care. Therefore, this Issue Brief is especially timely because it investigates how patient copayments and financial incentives for physicians affect drug spending in managed care.

Hysterectomy vs. resectoscopic endometrial ablation for the control of abnormal uterine bleeding. A cost-comparative study.

This study compared the costs of endometrial ablation using the uterine resectoscope to those of hysterectomy in a group of patients treated for abnormal uterine bleeding who were enrolled in a national managed health care organization. The cost of endometrial ablation during the periprocedural period was significantly lower than that of hysterectomy, with much of the difference coming from the hospitalization required for the latter procedure. The postprocedural cost for ablation was higher than for hysterectomy owing to the need for second ablations or hysterectomy in 13 of the 85 ablation patients. Preprocedure costs were not different between ablation and hysterectomy. A reanalysis of the data, however, that excluded patients who required a second ablation or hysterectomy suggested that these additional procedures were responsible for the higher postprocedural costs in the ablation group. Resectoscopic endometrial ablation for the treatment of abnormal uterine bleeding resulted in lower periprocedure costs and lower overall treatment costs to the health plan in the groups studied as compared with hysterectomy. Greater familiarity with the technique of resectoscopic endometrial ablation, improved patient selection for the procedure and the use of appropriate pharmacotherapy for suppressing endometrial growth prior to ablation probably substantially improve the rate of success, reduce postprocedural costs and further enhance the cost advantage of this procedure.

Healthcare resource use and costs associated with migraine in a managed healthcare setting.

OBJECTIVE: To compare healthcare use and associated costs in patients with migraine and patients without migraine headache. DESIGN: Retrospective review of a managed care organization's medical and pharmacy claims databases for claims filed between January 1, 1989 and June 30, 1990. PATIENTS: Patients between 18 and 64 years old with a 12-month minimum enrollment in the health plan, including enrollment for the prescription drug benefit. Migraine group (n = 1336) inclusion required a medical claim with the diagnosis of migraine headache and a pharmacy claim for a medication potentially used for migraine treatment. Comparison group (n = 1336) inclusion required at least one medical claim with no diagnosis of migraine; a pharmacy claim was not required. Comparison group patients were matched to migraine group patients by age, gender, enrollment status, and subscriber or dependent enrollment status. OUTCOME MEASURES: Total health services use, diagnosis-specific use of services, diagnostic procedures performed, comorbid conditions, medication use, and associated costs were tallied. RESULTS: Migraineurs generated nearly twice as many medical claims as comparison group patients, and nearly 2.5 times as many pharmacy claims. Number of claims generated and numbers of patients who generated claims within each of 19 diagnostic categories indicated greater comorbidity in the migraine group. Migraineurs used emergency services more than did patients in the comparison group. Total medical and pharmacy claims costs were $3.4 million for the migraine group and $2.1 million for the comparison group. The average amount paid per member-month of enrollment was significantly greater in the migraine group than in the comparison group. Comorbid conditions were responsible for a significant portion of costs in the migraine group. The migraine group incurred $83,537 for diagnostic procedures compared with $13,140 incurred by the comparison group. CONCLUSIONS: Patients with migraine had greater morbidity in general and incurred 64 percent greater costs in healthcare resource use compared with patients without migraine.

Pharmacoeconomics: a managed care perspective.

Managed care pharmacy organizations have the responsibility to promote high-quality cost-effective health care that provides value to their enrolled populations. Application of management interventions that reduce the inappropriate use of medications and enhance the appropriate use of medications that improve patient outcomes and the cost effectiveness of care can help meet these responsibilities. To accomplish these management objectives, managed care pharmacy organizations should aggressively apply the results of pharmacoeconomic studies and, where possible, participate in the conduct of these studies.

Patient adherence to prescribed potassium supplement therapy.

We have investigated whether patient adherence ratios calculated from prescription refill data for potassium supplement medications differ depending on the type of supplement. By using automated pharmacy claims records from a large managed care organization, an index of adherence to prescribed therapy was calculated for each patient as a ratio of total days of drug supplied to the total number of days between prescription refills. The mean patient adherence to prescribed therapy ratios were compared among different potassium drug regimens. There were 2289 patients eligible for analysis; 65.9% were women, and the mean age was 57.6 years. The mean patient adherence ratio for one brand of extended-release tablet, K-DUR, was 0.81 (a majority of the patients were receiving 20 mEq/day). This was higher than the combined mean patient adherence ratio for all other supplements (0.73); the combined mean ratio for all other extended-release tablets (0.74); the combined mean ratio for all other tablets and capsules (0.74); the combined mean ratio for liquids (0.50); the combined mean ratio for liquids and powders (0.63); and equivalent to the ratio for another extended tablet, Micro-K (0.82). Regression analysis showed that increased patient adherence was seen among patients taking K-DUR tablets as compared with those taking other potassium supplements. Increased adherence among patients taking K-DUR remained statistically significant after controlling for number of prescriptions filled, dose, age, sex, and health plan location. Pharmacy claims data can be used effectively to measure patient adherence with potassium supplement therapy. Future research should relate patient adherence ratios to clinical outcomes.

Using claims data for epidemiologic research. The concordance of claims-based criteria with the medical record and patient survey for identifying a hypertensive population.

In this study, a method was developed to identify health plan members with hypertension from insurance claims, using medical records and a patient survey for validation. A sample of 2,079 patients from two study sites with medical service or pharmacy claims indicating a diagnosis of essential hypertension were surveyed, and the medical records of 182 of the 1,275 survey respondents were reviewed. Where the criteria to identify hypertensive patients used both the medical and pharmacy claims, there was 96% agreement with either the medical record or the patient survey. Where the criteria relied on medical claims alone, the agreement rate decreased to 74% with the medical record and 64% with the patient survey. Where the criteria relied on the pharmacy claims alone, the agreement rate was 67% with the medical record and 75% with the patient survey. Combined evidence from medical service and pharmacy claims yielded a high level of agreement with alternative, more costly sources of data in identifying patients with essential hypertension. As it is more thoroughly investigated, claims data should become a more widely accepted resource for epidemiologic research.

Treatment of comorbid generalized anxiety in a recently detoxified alcoholic population with a selective serotonergic drug (buspirone).

Recent literature has addressed a common dyad: alcoholism and anxiety. Both disorders have been interdigitated with the brain amine serotonin. We investigated 51 dually diagnosed patients (generalized anxiety/alcohol abuse:dependence) in a randomized, double-blind, placebo-controlled trial of the serotonin partial agonist buspirone. Buspirone was superior to placebo as an anxiolytic, was well tolerated, and was associated with both a reduction in the number of days desiring alcohol and an overall clinical global improvement.

The association of buspirone and its metabolite 1-pyrimidinylpiperazine in the remission of comorbid anxiety with depressive features and alcohol dependency.

Recent literature has addressed a frequent comorbidity between alcoholism and anxiety/depression. These disorders have been interdigitated with the brain amines serotonin (5-HT) and norepinephrine. We investigated 51 dually diagnosed patients (generalized anxiety disorder with depressive features plus alcohol abuse/dependency) under a randomized, double-blind, placebo-controlled trial employing the 5-HT1A compound buspirone. Buspirone was superior to placebo as an anxiolytic. It was well tolerated and reduced the number of days patients desired alcohol. At the final study dose, the buspirone metabolite 1-pyrimidinylpiperazine (1-PP) was significantly related to improvement in anxiety, global depressive symptoms, and number of days not using alcohol. Analysis using the Hamilton Rating Scale for Depression and its retardation cluster revealed significant improvement secondary to anxiolysis. Thus, buspirone (especially via its 1-PP metabolite) may be an effective treatment strategy in the anxious or mixed anxious-depressive patient with comorbid alcoholism when other conventional anxiolytics may be contraindicated.

The relationship of serum anticholinergic activity to mental status performance in an elderly nursing home population.

Adverse drug reactions among elderly patients pose a significant clinical problem. The authors used a serum radioreceptor assay [RRA] to quantify drug-induced muscarinic blockade in 34 randomly selected nursing home residents. A random intervention group and the nonintervention control subjects were then retested 4 weeks later. The reduction of serum antimuscarinic activity (as determined by RRA) did relate to changes on several measures of cognitive function. A calculated "antimuscarinic index" lost significance with the RRA following intervention and may have overestimated the impact of a dosage reduction.