Some Thoughts on the Use of Predictive Probability in Clinical Trials.

In this short note, we express our viewpoint regarding declaring study success based on Bayesian predictive probability of study success.

Response Rate, Event-Free Survival, and Overall Survival in Newly Diagnosed Acute Myeloid Leukemia: US Food and Drug Administration Trial-Level and Patient-Level Analyses.

PURPOSE: To explore trial-level and patient-level associations between response (complete remission [CR] and CR + CR with incomplete hematologic [CRi] or platelet [CRp] recovery), event-free survival (EFS), and overall survival (OS) in newly diagnosed acute myeloid leukemia (AML) trials of intensive chemotherapy. METHODS: We identified data from eight randomized, active-controlled trials of intensive chemotherapy submitted to the US Food and Drug Administration for treatment of newly diagnosed AML (N = 4,482). Associations between trial-level odds ratios (ORs) for CR and CR + CRi or CRp, and hazard ratios (HRs) for EFS and OS were analyzed using weighted linear regression models. We performed patient-level responder analyses to compare OS by response using pooled data from all studies. RESULTS: In trial-level analyses, association between HR for OS and OR for CR was moderate (R2 = 0.49; 95% CI, 0.05 to 0.86), as was the association with OR for CR + CRi or CRp (R2 = 0.48; 95% CI, 0.05 to 0.99). For OS versus EFS, a strong association was observed (R2 = 0.87; 95% CI, 0.47 to 0.98) when EFS definitions were harmonized across trials using raw data. In the patient-level responder analyses, patients who achieved CR had better OS compared with CRi or CRp responders (0.73; 95% CI, 0.64 to 0.84) and nonresponders (HR, 0.33; 95% CI, 0.31 to 0.37). CONCLUSION: On a trial level, there is a moderate association between OS and CR rate. A strong association between EFS and OS was observed. However, CIs were wide, and results became moderate using alternative definitions for EFS. Patient-level analyses showed CR responders have better OS compared with CRi or CRp responders and nonresponders. A therapy in newly diagnosed AML with benefit in EFS or substantial benefit in CR rate would be likely to have an OS effect.

Bayesian hierarchical methods for meta-analysis combining randomized-controlled and single-arm studies.

Meta-analysis of interventions usually relies on randomized controlled trials. However, when the dominant source of information comes from single-arm studies, or when the results from randomized controlled trials lack generalization due to strict inclusion and exclusion criteria, it is vital to synthesize both sources of evidence. One challenge of synthesizing both sources is that single-arm studies are usually less reliable than randomized controlled trials due to selection bias and confounding factors. In this paper, we propose a Bayesian hierarchical framework for the purpose of bias reduction and efficiency gain. Under this framework, three methods are proposed: bivariate generalized linear mixed effects models, hierarchical power prior model and hierarchical commensurate prior model. Design difference and potential biases are considered in all models, within which the hierarchical power prior and hierarchical commensurate prior models further offer to downweight single-arm studies flexibly. The hierarchical commensurate prior model is recommended as the primary method for evidence synthesis because of its accuracy and robustness. We illustrate our methods by applying all models to two motivating datasets and evaluate their performance through simulation studies. We finish with a discussion of the advantages and limitations of our methods, as well as directions for future research in this area.

FDA Approval Summary: Midostaurin for the Treatment of Advanced Systemic Mastocytosis.

In April 2017, the U.S. Food and Drug Administration granted regular approval to midostaurin for the treatment of adult patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia (MCL). Approval was based on results from CPKC412D2201, a single-arm trial of midostaurin (100 mg orally twice daily) in previously treated or untreated patients. For the patients with ASM and SM-AHN, efficacy was established on the basis of confirmed complete remission (CR) plus incomplete remission (ICR) by modified Valent criteria with six cycles of midostaurin. There were no CRs reported; ICR was achieved by 6 of 16 patients (38%; 95% confidence interval [CI]: 15%-65%) with ASM and by 9 of 57 patients (16%; 95% CI: 7%-28%) with SM-AHN. Within the follow-up period, the median duration of response was not reached for the patients with ASM (range, 12.1+ to 36.8+ months) or with SM-AHN (range, 6.6+ to 52.1+ months). For the patients with MCL, efficacy was established on the basis of confirmed CR using modified 2013 International Working Group-Myeloproliferative Neoplasms Research and Treatment-European Competence Network on Mastocytosis criteria. Of 21 patients with MCL, 1 (5%) achieved a CR. Of 142 patients with SM evaluated for safety, 56% had dose modifications for toxicity, and 21% discontinued treatment due to a toxicity. Over 50% reported nausea, vomiting, or diarrhea, and ≥30% reported edema, musculoskeletal pain, fatigue, abdominal pain, or upper respiratory tract infection. New or worsening grade ≥3 lymphopenia, anemia, thrombocytopenia, or neutropenia developed in ≥20%. Although midostaurin is an active drug for treatment of advanced SM, it is not clear that the optimal dose has been identified. IMPLICATIONS FOR PRACTICE: Midostaurin is the only U.S. Food and Drug Administration-approved therapy for patients with systemic mastocytosis with associated hematological neoplasm and mast cell leukemia and is the only therapy approved for patients with aggressive systemic mastocytosis regardless of KIT D816V mutation status. Based on response rate and duration, midostaurin has meaningful clinical activity in these rare, life-threatening diseases.

FDA Approval Summary: Mylotarg for Treatment of Patients with Relapsed or Refractory CD33-Positive Acute Myeloid Leukemia.

On September 2, 2017, the U.S. Food and Drug Administration approved gemtuzumab ozogamicin (GO; Mylotarg; Pfizer, New York City, NY) for treatment of relapsed or refractory (R/R) CD33-positive acute myeloid leukemia (AML) in patients 2 years of age and older. GO is a CD33-directed antibody drug conjugate linked to the cytotoxic antibiotic calicheamicin. It originally received accelerated approval for treatment of older patients with relapsed CD33-positive AML in 2000, but it was withdrawn from the market in 2010 when the confirmatory trial failed to demonstrate clinical benefit among safety concerns, such as a higher rate of induction fatalities on the GO combination arm compared with chemotherapy alone. In addition, GO was associated with hepatic veno-occlusive disease (VOD), which has substantial morbidity and mortality. Pharmacokinetic analyses suggested a lower maximum concentration of GO would result in less VOD without affecting target saturation or efficacy. A meta-analysis across dose schedules of GO in patients with R/R AML showed that a lower-dose "fractionated" schedule of 3 mg/m2 days 1, 4, and 7 was associated with less early mortality, hemorrhage, and VOD, without an apparent decrease in complete remission (CR) rate. MyloFrance 1 was a single-arm study evaluating response rates in patients with relapsed CD33-positive AML treated with the lower-dose fractionated GO regimen. The CR rate was 26% (95% confidence interval 16%-40%). Common adverse reactions were fever, infections, nausea, vomiting, constipation, bleeding, increased liver enzymes, and mucositis. There were no cases of VOD. These results supported the approval of GO as monotherapy for R/R CD33-positive AML using the lower-dose fractionated regimen. IMPLICATIONS FOR PRACTICE: Gemtuzumab ozogamicin (GO) 3 mg/m2 days 1, 4, and 7 is an active regimen for induction of remission when used to treat patients with relapsed or refractory CD33-positive acute myeloid leukemia without curative intent. The risks of hepatic veno-occlusive disease and early mortality with this regimen appear to be lower than reported previously for GO 9 mg/m2 days 1 and 15. The data were not sufficient to enable conclusions about the safety of GO in children younger than 2 years of age.

FDA Approval: Gemtuzumab Ozogamicin for the Treatment of Adults with Newly Diagnosed CD33-Positive Acute Myeloid Leukemia.

On September 1, 2017, the FDA granted approval for gemtuzumab ozogamicin (Mylotarg; Pfizer Inc.) in combination with daunorubicin and cytarabine and as a monotherapy for the treatment of adult patients with newly diagnosed CD33-positive acute myeloid leukemia (AML). Gemtuzumab ozogamicin is a CD33-targeted antibody-drug conjugate joined to calicheamicin. Approval of gemtuzumab ozogamicin combination treatment was based on a randomized trial of 271 patients with newly diagnosed AML treated with daunorubicin and cytarabine with or without 3 mg/m2 fractionated gemtuzumab ozogamicin, which resulted in an event-free survival (EFS) of 13.6 months for gemtuzumab ozogamicin + daunorubicin and cytarabine and 8.8 months for daunorubicin and cytarabine alone [HR = 0.68 (95% confidence interval (CI), 0.51-0.91)]. Hemorrhage, prolonged thrombocytopenia, and veno-occlusive disease were serious toxicities that were more common in patients treated with gemtuzumab ozogamicin + daunorubicin and cytarabine. Approval of gemtuzumab ozogamicin monotherapy was based on a randomized trial of 237 patients with newly diagnosed AML treated without curative intent. Median overall survival (OS) was 4.9 months with gemtuzumab ozogamicin versus 3.6 months on best supportive care [HR = 0.69 (95% CI, 0.53-0.90)]. Adverse events were similar on both arms. Postapproval, several studies are required including evaluation of fractionated gemtuzumab ozogamicin pharmacokinetics, safety of combination gemtuzumab ozogamicin in the pediatric population, immunogenicity, and the effects of gemtuzumab ozogamicin on platelet function. Clin Cancer Res; 24(14); 3242-6. ©2018 AACR.

U.S. Food and Drug Administration approval summary: Eltrombopag for the treatment of pediatric patients with chronic immune (idiopathic) thrombocytopenia.

The U.S. Food and Drug Administration (FDA) approved eltrombopag for pediatric patients with chronic immune (idiopathic) thrombocytopenia (ITP) ages ≥6 on June 11, 2015, and ages ≥1 on August 24, 2015. Approval was based on the FDA review of two randomized trials that included 159 pediatric patients with chronic ITP who had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. This manuscript describes the basis for approval of these applications. The FDA concluded that eltrombopag has shown efficacy and a favorable benefit to risk profile for pediatric patients with chronic ITP.

FDA Drug Approval: Elotuzumab in Combination with Lenalidomide and Dexamethasone for the Treatment of Relapsed or Refractory Multiple Myeloma.

On November 30, 2015, the FDA approved elotuzumab (Empliciti; Bristol-Myers Squibb) in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who received one to three prior therapies. FDA approval was based primarily on the results of a phase III, randomized, open-label, multicenter trial, CA204004, which evaluated elotuzumab in combination with lenalidomide and dexamethasone (E-Ld) compared with lenalidomide and dexamethasone (Ld) alone in patients with relapsed or refractory multiple myeloma. Coprimary endpoints were progression-free survival (PFS) and overall response rate (ORR). The key secondary endpoint was overall survival, but these data were not mature at the time of clinical database cutoff. The trial demonstrated a statistically significant improvement in PFS, with an estimated HR of 0.70 for E-Ld over Ld [95% confidence interval (CI), 0.57-0.85; P = 0.0004). Estimated median PFS was 19.4 months in the E-Ld arm and 14.9 months in the Ld arm. ORR was 75.8% in the E-Ld arm compared with 65.5% in the Ld arm. Serious adverse reactions were reported in 65% of patients in the E-Ld arm compared with 57% in the Ld arm. The FDA approved elotuzumab with the following warnings and precautions: infusion reactions, infections, second primary malignancies, hepatotoxicity, and interference with the determination of complete response. Clin Cancer Res; 23(22); 6759-63. ©2017 AACR.

FDA Approval: Blinatumomab.

On December 3, 2014, the FDA granted accelerated approval of blinatumomab (Blincyto; Amgen, Inc.) for treatment of Philadelphia chromosome-negative relapsed or refractory precursor B-cell acute lymphoblastic leukemia (R/R ALL). Blinatumomab is a recombinant murine protein that acts as a bispecific CD19-directed CD3 T-cell engager. The basis for the approval was a single-arm trial with 185 evaluable adults with R/R ALL. The complete remission (CR) rate was 32% [95% confidence interval (CI), 26%-40%], and the median duration of response was 6.7 months. A minimal residual disease response was achieved by 31% (95% CI, 25%-39%) of all patients. Cytokine release syndrome and neurologic events were serious toxicities that occurred. Other common (>20%) adverse reactions were pyrexia, headache, edema, febrile neutropenia, nausea, tremor, and rash. Neutropenia, thrombocytopenia, and elevated transaminases were the most common (>10%) laboratory abnormalities related to blinatumomab. A randomized trial is required in order to confirm clinical benefit.

FDA approval: siltuximab for the treatment of patients with multicentric Castleman disease.

On April 22, 2014, the FDA granted full approval to siltuximab (SYLVANT for injection; Janssen Biotech, Inc.), a chimeric human-mouse monoclonal antibody to IL6, for the treatment of patients with multicentric Castleman disease (MCD) who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative. The approval was primarily based on the results of a randomized, double-blind trial in which 79 symptomatic patients with MCD were allocated (2:1) to siltuximab plus best supportive care (BSC) or to placebo plus BSC. The primary efficacy endpoint was the proportion of patients in each arm achieving a durable tumor and symptomatic response that persisted for a minimum of 18 weeks without treatment failure. Tumor response was based on independent review of CT scans using the revised Response Criteria for Malignant Lymphoma, and symptomatic response was defined as complete resolution or stabilization of 34 MCD-related signs and symptoms as reported by the investigator. Thirty-four percent of patients in the siltuximab arm and no patients in the placebo arm met the primary endpoint (P = 0.0012). The most common adverse reactions (>10% compared with placebo) during treatment with siltuximab were pruritus, increased weight, rash, hyperuricemia, and upper respiratory tract infection.

U.S. Food and drug administration approval: obinutuzumab in combination with chlorambucil for the treatment of previously untreated chronic lymphocytic leukemia.

On November 1, 2013, the U.S. Food and Drug Administration (FDA) approved obinutuzumab (GAZYVA; Genentech, Inc.), a CD20-directed cytolytic antibody, for use in combination with chlorambucil for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL). In stage 1 of the trial supporting approval, patients with previously untreated CD20-positive CLL were randomly allocated (2:2:1) to obinutuzumab + chlorambucil (GClb, n = 238), rituximab + chlorambucil (RClb, n = 233), or chlorambucil alone (Clb, n = 118). The primary endpoint was progression-free survival (PFS), and secondary endpoints included overall response rate (ORR). Only the comparison of GClb to Clb was relevant to this approval and is described herein. A clinically meaningful and statistically significant improvement in PFS with medians of 23.0 and 11.1 months was observed in the GClb and Clb arms, respectively (HR, 0.16; 95% CI, 0.11-0.24; P < 0.0001, log-rank test). The ORRs were 75.9% and 32.1% in the GClb and Clb arms, respectively, and the complete response rates were 27.8% and 0.9% in the GClb and Clb arms, respectively. The most common adverse reactions (≥10%) reported in the GClb arm were infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, and musculoskeletal disorders. Obinutuzumab was the first Breakthrough Therapy-designated drug to receive FDA approval.

U.S. Food and Drug Administration approval summary: omacetaxine mepesuccinate as treatment for chronic myeloid leukemia.

On October 26, 2012, the U.S. Food and Drug Administration (FDA) granted accelerated approval to omacetaxine mepesuccinate (Synribo; Teva Pharmaceuticals USA, Inc., North Wales, PA, http://www.tevausa.com) for the treatment of adult patients with chronic phase (CP) or accelerated phase (AP) chronic myeloid leukemia (CML) with resistance and/or intolerance to two or more tyrosine kinase inhibitors (TKIs). The approval was based on the FDA review of data from 111 patients with CML in CP or in AP who had received two or more prior TKIs, including imatinib. Major cytogenetic response was achieved in 18% of patients with CP, with a median response duration of 12.5 months. Major hematologic response was achieved in 14% of patients with AP, with a median response duration of 4.7 months. The FDA safety evaluation was based on submitted data from 163 patients with CP or AP CML who had received at least one dose of omacetaxine mepesuccinate. The safety evaluation was limited by the single-arm design of the clinical trials as conducted in a small number of previously treated patients. The most common (≥20%) adverse reactions of any grade in enrolled patients included thrombocytopenia, anemia, neutropenia, diarrhea, nausea, fatigue, asthenia, injection site reaction, pyrexia, and infection. The FDA concluded that omacetaxine mepesuccinate has shown activity and a favorable benefit-to-risk profile for the studied population of adult patients with CML (CP or AP) with resistance and/or intolerance to two or more TKIs. Further evidence of response durability to verify clinical benefit is pending.

Relationship Between Progression-Free Survival and Overall Survival Benefit: A Simulation Study.

This study evaluated the circumstances under which the observed progression-free survival (PFS) benefit may translate into an overall survival (OS) benefit. METHODS: A simulation study, based on PFS and OS joint model decomposition, was conducted to evaluate the impact of crossover rates, survival post progression (SPP) lengths, and magnitudes of difference in median PFS on OS. Under different simulation scenarios, the degree of impact was investigated based on the probability of observing a significant OS benefit given an observed PFS benefit. RESULTS: Using simulation parameters defined based on historical NDA datasets, the probability of detecting an OS benefit given the observed PFS benefit depends largely on crossover rate and SPP length (ie, SPP median times). Compared to no crossover, a crossover rate of ≤ 50% decreases the probability of detecting an OS benefit by at most 15% regardless of the SPP length. A crossover rate of > 50% decreases the probability of detecting an OS benefit much further, and the extent of decrease is proportional to the length of SPP. CONCLUSION: Crossover rate and SPP length are important factors affecting the benefit translating from PFS to OS. This simulation study identified a threshold, of 50%, for crossover rate that is likely to confound OS effect. With a greater than 50% crossover rate, longer SPP further decreases the probability of translating a PFS benefit to OS.

A systematic comparison of cockcroft-gault and modification of diet in renal disease equations for classification of kidney dysfunction and dosage adjustment.

BACKGROUND: The dosing of drugs in patients with kidney dysfunction is often based on the estimates of kidney function. OBJECTIVE: To systematically compare the performance of the Modification of Diet in Renal Disease (MDRD) and Cockcroft-Gault (CG) equations for dosage adjustment. METHODS: We assessed agreement (concordance, kappa statistics [κ,κ(ω)]) between CG and MDRD using a Food and Drug Administration database to evaluate the effect of renal function on the pharmacokinetics of 36 approved drugs. Across the approved drugs, we compared the correlation between these 2 equations for renal drug clearance (Cl(ren)) and area under the concentration-time curve. For 26 approved drugs that require renal dose adjustment, we also compared dosing regimens and expected exposure using these equations. Sensitivity analyses were performed by adjusting the MDRD estimates for individualized body surface area and/or range of serum creatinine assay calibration errors. RESULTS: In the pharmacokinetic database with 973 subjects (age 18-95 years, weight 35-153 kg, female 33%), we found that the CG and the MDRD classification of renal function generally agreed (64.2%, κ = 0.54, κ(ω) = 0.73). Among the subjects studied for drugs requiring renal dose adjustment, dosages in 12% were changed to a higher or lower dosing category by the MDRD compared to the CG equation. In particular, using MDRD in place of CG for dosage modification yielded higher dosing recommendations for subjects with a combination of age >80 years, weight <55 kg, and serum creatinine >0.7 and ≤1.5 mg/dL; the coefficient of determination was also higher by CG than MDRD in trials that enrolled these or similar patients. CONCLUSIONS: For patients with advanced age, low weight, and modestly elevated serum creatinine, further work is needed before the MDRD equations can replace the CG equation for dose adjustment in the labeling.

The influence of body size descriptors on the estimation of kidney function in normal weight, overweight, obese, and morbidly obese adults.

BACKGROUND: Dosing adjustments for patients with impaired kidney function are often based on estimated creatinine clearance (eCrCl) because measuring kidney function is not always possible for dose adjustment. However, there is no consensus on the body size descriptor that should be used in the estimation equations. OBJECTIVE: To compare the use of alternative body size descriptors (ABSDs) on the performance of kidney function estimation equations compared with measured CrCl (mCrCl). METHODS: We combined 2 DATA SOURCES: a Food and Drug Administration clinical trial database that includes subjects with body mass index (BMI) less than 40 kg/m(2) and published data from those 40 kg/m(2) or more. The 3 parent equations (Cockcroft-Gault [CG], Modification of Diet in Renal Disease [MDRD], Chronic Kidney Disease-Epidemiology Collaboration [CKDEPI]), and 14 ABSD-modified equations were compared with mCrCl for accuracy, bias, agreement, goodness of fit (R(2)), and prediction error. These equations were also compared across mCrCl and BMI strata. RESULTS: Subjects (n = 590) were aged 19-80 years; 33.9% were female and BMI ranged from 17.2 to 95.6 kg/m(2). Compared with mCrCl, the use of total weight in the CG equation yielded low accuracy (12.5%) and significant bias (-107 mL/min) in the morbidly obese group. In contrast, the use of lean body weights (BMI ≥40 kg/m(2)) and total ± adjusted weights (BMI <40 kg/m(2)) with the CG equation yielded higher accuracy, greater than or equal to 60.7% across all BMI strata, and was unbiased. Transforming the MDRD or CKDEPI equations with body surface area improved accuracy only at mCrCl of 30-80 mL/min and increased the overall prediction error. CONCLUSIONS: No kidney function equation was consistently accurate and unbiased across weight, mCrCl, and estimate ranges. The accuracy and overestimation bias of the CG equation in obese subjects was improved through the selective use of total, adjusted, and lean body weight by BMI strata.

Hearing threshold levels at age 70 years (65-74 years) in the unscreened older adult population of the United States, 1959-1962 and 1999-2006.

OBJECTIVES: To provide hearing threshold percentiles from unscreened older adults for creating new Annex B reference standards. DESIGN: Percentiles are calculated, and 95% confidence intervals for medians from two U.S. surveys are compared graphically. RESULTS: Median thresholds are lower (better) in the 1999-2006 National Health and Nutrition Examination Survey for men across all frequencies except 1 kHz. Results for women are similar; however, there is more overlap in confidence intervals across frequencies. CONCLUSIONS: The prevalence of hearing impairment in older adults, age 70 years (65-74 years), is lower in 1999-2006 compared with 1959-1962, consistent with our earlier findings for younger adults.

Term pregnancy: a period of heterogeneous risk for infant mortality.

OBJECTIVE: To estimate the trend of maternal racial and ethnic differences in mortality for early-term (37 0/7 to 38 6/7 weeks of gestation) compared with full-term births (39 0/7 to 41 6/7 weeks of gestation). METHODS: We analyzed 46,329,018 singleton live births using the National Center for Health Statistics U.S. period-linked birth and infant death data from 1995 to 2006. Infant mortality rates, neonatal mortality rates, and postneonatal mortality rates were calculated according to gestational age, race and ethnicity, and cause of death. RESULTS: Overall, infant mortality rates have decreased for early-term and full-term births between 1995 and 2006. At 37 weeks of gestation, Hispanics had the greatest decline in infant mortality rates (35.4%; 4.8 per 1,000 to 3.1 per 1,000) followed by 22.4% for whites (4.9 per 1,000 to 3.8 per 1,000); blacks had the smallest decline (6.8%; 5.9 per 1,000 to 5.5 per 1,000) as a result of a stagnant neonatal mortality rate. At 37 weeks compared with 40 weeks of gestation, neonatal mortality rates increase. For Hispanics, the relative risk is 2.6 (95% confidence interval [CI] 2.0-3.3); for whites, the relative risk is 2.6 (95% CI 2.2-3.1); and for blacks, the relative risk is 2.9 (95% CI 2.2-3.8). Neonatal mortality rates are still increased at 38 weeks of gestation. At both early- and full-term gestations, neonatal mortality rates for blacks are 40% higher than for whites and postneonatal mortality rates 80% higher, whereas Hispanics have a reduced postneonatal mortality rate when compared with whites. CONCLUSION: Early-term births are associated with higher neonatal, postneonatal, and infant mortality rates compared with full-term births with concerning racial and ethnic disparity in rates and trends.

Americans hear as well or better today compared with 40 years ago: hearing threshold levels in the unscreened adult population of the United States, 1959-1962 and 1999-2004.

OBJECTIVES: (1) To present hearing threshold data from a recent nationally representative survey in the United States (National Health and Nutrition Examination Survey, 1999-2004) in a distributional format that might be appropriate to replace Annex B in international (ISO-1999) and national (ANSI S3.44) standards and (2) to compare these recent data with older survey data (National Health Examination Survey I, 1959-1962) on which the current Annex B is based. DESIGN: Better-ear threshold distributions (selected percentiles and their confidence intervals) were estimated using linear interpolation. The 95% confidence intervals for the medians for the two surveys were compared graphically for each of the four age groups and for both men and women. In addition, we calculated odds ratios comparing the prevalences of better-ear hearing impairment (thresholds > 25 dB HL) between the two surveys, for 500, 1000, 2000, and 4000 Hz, and for their four-frequency average. RESULTS: Across age and sex groups, median thresholds were lower (better) in the 1999-2004 survey at 500, 3000, 4000, and 6000 Hz (8000 Hz was not tested in the 1959-1962 survey). For both men and women, the prevalence of hearing impairment was significantly lower in 1999-2004 at 500, 2000, and 4000 Hz, but not at 1000 Hz. CONCLUSIONS: For men and women of a specific age, high-frequency hearing thresholds were lower (better) in 1999-2004 than in 1959-1962. The prevalences of hearing impairment were also lower in the recent survey. Differences seen at 500 Hz may be attributable at least in part to changes in standards for ambient noise in audiometry. The National Health and Nutrition Examination Survey 1999-2004 distributions are offered as a possible replacement for Annex B in ISO-1999 and ANSI S3.44.

Vision, hearing, balance, and sensory impairment in Americans aged 70 years and over: United States, 1999-2006.

KEY FINDINGS: Sensory impairments are a substantial problem for older Americans: One out of six has impaired vision; one out of four has impaired hearing; one out of four has loss of feeling in the feet; and three out of four have abnormal postural balance testing. Sensory impairments increase with age: Vision and hearing impairments each double, and loss of feeling in the feet increases by 40% in persons aged 80 years and over compared with persons aged 70-79 years. One in five Americans below the poverty threshold has impaired vision: 50% higher than other Americans. Balance problems are also common among the poor. Over one-half of those with impaired vision could improve their eyesight by using glasses or by getting a corrected prescription. For those with hearing problems, 72% might benefit from a hearing aid but do not use one.

Racial disparities in stillbirth risk across gestation in the United States.

OBJECTIVE: We sought to determine factors associated with racial disparities in stillbirth risk. STUDY DESIGN: Stillbirth hazard was analyzed using 5,138,122 singleton gestations from the National Center of Health Statistics perinatal mortality and birth files, 2001-2002. RESULTS: Black women have a 2.2-fold increased risk of stillbirth compared with white women. The black/white disparity in stillbirth hazard at 20-23 weeks is 2.75, decreasing to 1.57 at 39-40 weeks. Higher education reduced the hazard for whites more than for blacks and Hispanics. Medical, pregnancy, and labor complications accounted for 30% of the hazard in blacks and 20% in whites and Hispanics. Congenital anomalies and small for gestational age contributed more to preterm stillbirth risk among whites than blacks. Pregnancy and labor conditions contributed more to preterm stillbirth risk among blacks than whites. CONCLUSION: The excess stillbirth risk for blacks was greatest at preterm gestations, and factors contributing to stillbirth risk vary by race and gestational age.