Association of Timely Comprehensive Genomic Profiling With Precision Oncology Treatment Use and Patient Outcomes in Advanced Non-Small-Cell Lung Cancer.

PURPOSE: Timely biomarker testing remains out of reach for many patients with advanced non-small-cell lung cancer (aNSCLC). Here, we studied the quality-of-care implications of closing the gap in timely receipt of comprehensive genomic profiling (CGP) to inform first-line (1L) decisions. METHODS: Using a real-world clinicogenomic database, we studied testing and 1L treatment patterns in aNSCLC after the approval of pembrolizumab in combination with pemetrexed and carboplatin (May 10, 2017). To estimate the association of timely CGP results with therapy selection and patient outcomes, we identified patients with no previous genomic testing beyond PD-L1 immunohistochemistry and dichotomized patients by whether CGP results were available before or after 1L therapy initiation. RESULTS: In total, 2,694 patients were included in the 1L therapy decision impact assessment. Timely CGP increased matched targeted therapy use by 14 percentage points (17% with CGP v 2.8% without) and precision immune checkpoint inhibitor (ICPI) use by 14 percentage points (18% with CGP v 3.9% without). Receipt of timely CGP resulted in an estimated 31 percentage point decrease in ICPI use among ALK/EGFR/RET/ROS1-positive patients at an expected per-patient reduction in ineffective ICPI therapy cost of $13,659.37 with timely CGP to inform 1L treatment selection. Patient benefit of CGP extended to real-world time to therapy discontinuation (median time to therapy discontinuation: 3.9 v 10 months [hazard ratio, HR, 0.54 [95% CI, 0.42 to 0.70]; P = 1.9E-06; adjusted hazard ratio [aHR], 0.50 [95% CI, 0.38 to 0.67]; P = 2.0E-06) in 1L driver-positive patients. This effect was not significant for real-world overall survival (median overall survival: 32 v 29 months [HR, 1.2 [95% CI, 0.84 to 1.67]; P = .33; aHR, 1.4 [95% CI, 0.92 to 1.99]; P = .12). CONCLUSION: Timely CGP is associated with the quality of patient care as measured by 1L matched targeted therapy use, time to therapy discontinuation, and avoidance of ineffective, costly ICPIs.

Real-World Clinical Performance of a DNA-Based Comprehensive Genomic Profiling Assay for Detecting Targetable Fusions in Nonsquamous NSCLC.

BACKGROUND: Genomic fusions are potent oncogenic drivers across cancer types and many are targetable. We demonstrate the clinical performance of DNA-based comprehensive genomic profiling (CGP) for detecting targetable fusions. MATERIALS AND METHODS: We analyzed targetable fusion genes in >450 000 tissue specimens profiled using DNA CGP (FoundationOne CDx, FoundationOne). Using a de-identified nationwide (US-based) non-small cell lung cancer (NSCLC) clinico-genomic database, we assessed outcomes in patients with nonsquamous NSCLC (NonSqNSCLC) who received matched therapy based on a fusion identified using DNA CGP. Lastly, we modeled the added value of RNA CGP for fusion detection in NonSqNSCLC. RESULTS: We observed a broad diversity of fusion partners detected with DNA CGP in conjunction with targetable fusion genes (ALK, BRAF, FGFR2, FGFR3, NTRK1/2/3, RET, and ROS1). In NonSqNSCLC with oncogenic ALK, NTRK, RET, and ROS1 fusions detected by DNA CGP, patients treated with a matched tyrosine kinase inhibitor had better real-world progression-free survival than those receiving alternative treatment regimens and benefit was observed regardless of the results of orthogonal fusion testing. An estimated 1.3% of patients with NonSqNSCLC were predicted to have an oncogenic driver fusion identified by RNA, but not DNA CGP, according to a model that accounts for multiple real-world factors. CONCLUSION: A well-designed DNA CGP assay is capable of robust fusion detection and these fusion calls are reliable for informing clinical decision-making. While DNA CGP detects most driver fusions, the clinical impact of fusion detection is substantial for individual patients and exhaustive efforts, inclusive of additional RNA-based testing, should be considered when an oncogenic driver is not clearly identified.

Racial and Ethnic Inequities at the Practice and Physician Levels in Timely Next-Generation Sequencing for Patients With Advanced Non-Small-Cell Lung Cancer Treated in the US Community Setting.

PURPOSE: Racial/ethnic inequities in next-generation sequencing (NGS) were examined for patients with advanced non-small-cell lung cancer (aNSCLC) at the practice and physician levels to inform policies to improve equitable quality of care. METHODS: This retrospective study used a nationwide electronic health record-derived deidentified database for patients with aNSCLC diagnosed between April 2018 and March 2022 in the community setting. Timely NGS was an NGS result between initial diagnosis and ≤60 days after advanced diagnosis. We studied how inequities were driven by (1) non-Latinx Black (Black) and Latinx patient under-representation at high testing practices versus (2) Black and Latinx patients being tested at lower rates than non-Latinx White (White) patients, even at the same practice. We defined these two concepts as across inequity and within inequity, respectively, with total inequity as their summation. Mean percentage point inequities were estimated using a Bayesian approach. RESULTS: A total of 12,045 patients (9,981 White; 1,528 Black; 536 Latinx) met study criteria. At the practice level, versus White patients, the mean percentage point difference in NGS testing total inequity was 7.49 for Black and 8.26 for Latinx. Within- and across-practice inequities contributed to total inequity in NGS testing for Black (48% v 52%) and Latinx patients (60% v 40%). At the physician level, versus White patients, the mean percentage point difference in total inequity was 7.73 for Black and 8.81 for Latinx patients. Within- versus across-physician inequities contributed to total inequity for Black and Latinx patients (77% v 23% and 67% v 33%). CONCLUSION: Within-practice, across-practice, and across-physician inequities were main contributors to total inequity in NGS testing, requiring a suite of interventions to effectively address inequities.

A Novel HRD Signature Is Predictive of FOLFIRINOX Benefit in Metastatic Pancreatic Cancer.

BACKGROUND: Pancreatic cancer (PC) represents an aggressive disease with median overall survival (OS) of less than 1 year in the front-line setting. FOLFIRINOX and gemcitabine and paclitaxel (GP) are standard of care options for these patients; however, optimal selection of therapy is challenging. METHODS: Comprehensive genomic profiling was performed on 8358 PC patients. Outcomes were available for 1149 metastatic PC patients treated with 1L FOLFIRINOX or GP. A scar-based measure of HRD was called using a machine learning-based algorithm incorporating copy number and indel features. RESULTS: A scar-based HRD signature (HRDsig) was identified in 9% of patients. HRDsig significantly co-occurred with biallelic alterations in BRCA1/2, PALB2, BARD1, and RAD51C/D, but encompassed a larger population than that defined by BRCA1/BRCA2/PALB2 (9% vs. 6%). HRDsig was predictive of 1L FOLFIRNOX chemotherapy benefit with doubled OS relative to gemcitabine and paclitaxel (GP) (rwOS aHR 0.37 [0.22-0.62]), including 25% of the population with long-term (2 year+) survival in a real-world cohort of patients. Less benefit from FOLFIRINOX was observed in the HRDsig(-) population. Predictive value was seen in both the BRCA1/2/PALB2 mutant and wildtype populations, suggesting additional value to mutational profiling. CONCLUSION: A scar-based HRD biomarker was identified in a significant fraction of PC patients and is predictive of FOLFIRINOX benefit. Incorporating a biomarker like HRDsig could identify the right patients for platinum chemotherapy and potentially reduce FOLFIRINOX use by over 40%, minimizing toxicities with similar survival outcomes. Confirmatory studies should be performed.

Quantifying the Value of Multigene Testing in Resected Early Stage Lung Adenocarcinoma.

INTRODUCTION: Tyrosine kinase inhibitors and immune checkpoint inhibitors (ICIs), each requiring testing for precision biomarkers, have recently been approved in the adjuvant setting. We assessed the potential value of multigene testing in early lung adenocarcinoma (LUAD). METHODS: Using a real-world clinicogenomic database linking deidentified electronic health record-derived clinical data to genomic data, we selected patients with LUAD who underwent tissue comprehensive genomic profiling (CGP). Using a probabilistic decision tree, we estimated the cost implications of the avoidance of adjuvant ICI in patients with programmed death-ligand 1-positive (PD-L1+) LUAD and an ALK, ROS1 or RET driver. RESULTS: The CGP was performed on a specimen collected before advanced disease in 20% (1320 of 6697) of cases and ordered before advanced diagnosis for 12.6% (847 of 6697) of patients. The prevalence of driver alterations in early and advanced-stage specimens was similar, though KRAS mutations were enriched in early disease and drivers including ALK rearrangements in advanced disease. Patients who had CGP results obtained before versus after recurrence had less time between recurrence and the start of any first-line treatment (median 3.6 versus 6 wk, p < 0.001). Through avoidance of ICI in programmed death-ligand 1-positive early LUAD with an ALK, ROS1 or RET driver, we estimated that the universal CGP could reduce expected costs by $1597.23 per patient relative to EGFR single-gene testing. CONCLUSIONS: The CGP can identify driver alterations and accelerate the start of first-line therapy at recurrence. It may also represent a cost-effective approach for avoiding futile adjuvant ICI in patients with drivers that have historically lacked activity with ICI in metastatic disease.

Complementary Roles for Tissue- and Blood-Based Comprehensive Genomic Profiling for Detection of Actionable Driver Alterations in Advanced NSCLC.

Introduction: Whereas tumor biopsy is the reference standard for genomic profiling of advanced NSCLC, there are now multiple assays approved by the Food and Drug Administration for liquid biopsy testing of circulating tumor DNA. Here, we study the incremental value that liquid biopsy comprehensive genomic profiling (CGP) adds to tissue molecular testing. Methods: Patients with metastatic NSCLC were enrolled in a prospective diagnostic study to receive circulating tumor DNA CGP; tissue CGP was optional in addition to their standard tissue testing. Focusing on nine genes listed per the National Comprehensive Cancer Network (NCCN) guidelines, liquid CGP was compared with available tissue testing results across three subcohorts: tissue CGP, standard-of-care testing of up to five biomarkers, or no tissue testing. Results: A total of 515 patients with advanced nonsquamous NSCLC received liquid CGP. Among 131 with tissue CGP results, NCCN biomarkers were detected in 86 (66%) with tissue CGP and 56 (43%) with liquid CGP (p < 0.001). Adding liquid CGP to tissue CGP detected no additional patients with NCCN biomarkers, whereas tissue CGP detected NCCN biomarkers in 30 patients (23%) missed by liquid CGP. Studying 264 patients receiving tissue testing of up to five genes, 102 (39%) had NCCN biomarkers detected in tissue, with an additional 48 (18%) detected using liquid CGP, including 18 with RET, MET, or ERBB2 drivers not studied in tissue. Conclusions: For the detection of patients with advanced nonsquamous NSCLC harboring 9 NCCN biomarkers, liquid CGP increases detection in patients with limited tissue results, but does not increase detection in patients with tissue CGP results available. In contrast, tissue CGP can add meaningfully to liquid CGP for detection of NCCN biomarkers and should be considered as a follow-up when an oncogenic driver is not identified by liquid biopsy.

Estimating maternity ward birth attendant time use in India: a microcosting study.

OBJECTIVES: Despite global concern over the quality of maternal care, little is known about the time requirements to complete the essential birth practices. Using three microcosting data collection methods within the BetterBirth trial, we aimed to assess time use and the specific time requirements to incorporate the WHO Safe Childbirth Checklist into clinical practice. SETTING: We collected detailed survey data on birth attendant time use within the BetterBirth trial in Uttar Pradesh, India. The BetterBirth trial tested whether the peer-coaching-based implementation of the WHO Checklist was effective in improving the quality of facility-based childbirth care. PARTICIPANTS: We collected measurements of time to completion for 18 essential birth practices from July 2016 through October 2016 across 10 facilities in five districts (1559 total timed observations). An anonymous survey asked about the impact of the WHO Checklist on birth attendants at every intervention facility (15 facilities, 83 respondents) in the Lucknow hub. Additionally, data collectors visited facilities to conduct a census of patients and birth attendants across 20 facilities in seven districts between June 2016 and November 2016 (six hundred and ten 2-hour facility observations). PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome measure of this study is the per cent of staff time required to complete the essential birth practices included in the WHO Checklist. RESULTS: When birth attendants were timed, we found practices were completed rapidly (18 s to 2 min). As the patient load increased, time dedicated to clinical care increased but remained low relative to administrative and downtime. On average, WHO Checklist clinical care accounted for less than 7% of birth attendant time use per hour. CONCLUSIONS: We did not find that a coaching-based implementation of the WHO Checklist was a burden on birth attendant's time use. However, questions remain regarding the performance quality of practices and how to accurately capture and interpret idle and break time. TRIAL REGISTRATION NUMBER: NCT02148952.

Advancing digital health applications: priorities for innovation in real-world evidence generation.

In 2019, Germany passed the Digital Healthcare Act, which, among other things, created a "Fast-Track" regulatory and reimbursement pathway for digital health applications in the German market. The pathway explicitly provides for flexibility in how researchers can present evidence for new digital products, including the use of real-world data and real-world evidence. Against this backdrop, the Digital Medicine Society and the Health Innovation Hub of the German Federal Ministry of Health convened a set of roundtable discussions to bring together international experts in evidence generation for digital medicine products. This Viewpoint highlights findings from these discussions with the aims of (1) accelerating and stimulating innovative approaches to digital medical product evaluation, and (2) promoting international harmonisation of best evidentiary practices. Advancing these topics and fostering international agreement on evaluation approaches will be vital to the safe, effective, and evidence-based deployment and acceptance of digital health applications globally.

Trends in Use of Next-Generation Sequencing in Patients With Solid Tumors by Race and Ethnicity After Implementation of the Medicare National Coverage Determination.

Importance: In March 2018, Medicare issued a national coverage determination (NCD) for next-generation sequencing (NGS) to facilitate access to NGS testing among Medicare beneficiaries. It is unknown whether the NCD affected health equity issues for Medicare beneficiaries and the overall population. Objective: To examine the association between the Medicare NCD and NGS use by insurance types and race and ethnicity. Design, Setting, and Participants: A retrospective cohort analysis was conducted using electronic health record data derived from a real-world database. Data originated from approximately 280 cancer clinics (approximately 800 sites of care) in the US. Patients with advanced non-small cell lung cancer (aNSCLC), metastatic colorectal cancer (mCRC), metastatic breast cancer (mBC), or advanced melanoma diagnosed from January 1, 2011, through March 31, 2020, were included. Exposure: Pre- vs post-NCD period. Main Outcomes and Measures: Patients were classified by insurance type and race and ethnicity to examine patterns in NGS testing less than or equal to 60 days after diagnosis. Difference-in-differences models examined changes in average NGS testing in the pre- and post-NCD periods by race and ethnicity, and interrupted time-series analysis examined whether trends over time varied by insurance type and race and ethnicity. Results: Among 92 687 patients with aNSCLC, mCRC, mBC, or advanced melanoma, mean (SD) age was 66.6 (11.2) years, 51 582 (55.7%) were women, and 63 864 (68.9%) were Medicare beneficiaries. The largest racial and ethnic categories according to the database used and further classification were Black or African American (8605 [9.3%]) and non-Hispanic White (59 806 [64.5%]). Compared with Medicare beneficiaries, changes in pre- to post-NCD NGS testing trends were similar in commercially insured patients (odds ratio [OR], 1.03; 95% CI, 0.98-1.08; P = .25). Pre- to post-NCD NGS testing trends increased at a slower rate among patients in assistance programs (OR, 0.93; 95% CI, 0.87-0.99; P = .03) compared with Medicare beneficiaries. The rate of increase for patients receiving Medicaid was not statistically significantly different compared with those receiving Medicare (OR, 0.92; 95% CI, 0.84-1.01; P = .07). The NCD was not associated with statistically significant changes in NGS use trends by racial and ethnic groups within Medicare beneficiaries alone or across all insurance types. Compared with non-Hispanic White individuals, increases in average NGS use from the pre-NCD to post-NCD period were 14% lower (OR, 0.86; 95% CI, 0.74-0.99; P = .04) among African American and 23% lower (OR, 0.77; 95% CI, 0.62-0.96; P = .02) among Hispanic/Latino individuals; increases among Asian individuals and those with other races and ethnicities were similar. Conclusions and Relevance: The findings of this study suggest that expansion of Medicare-covered benefits may not occur equally across insurance types, thereby further widening or maintaining disparities in NGS testing. Additional efforts beyond coverage policies are needed to ensure equitable access to the benefits of precision medicine.

Balancing health and financial protection in health benefit package design.

Policymakers face difficult choices over which health interventions to publicly finance. We developed an approach to health benefits package design that accommodates explicit tradeoffs between improvements in health and provision of financial risk protection (FRP). We designed a mathematical optimization model to balance gains in health and FRP across candidate interventions when publicly financed. The optimal subset of interventions selected for inclusion was determined with bi-criterion integer programming conditional on a budget constraint. The optimal set of interventions to publicly finance in a health benefits package varied according to whether the objective for optimization was population health benefits or FRP. When both objectives were considered jointly, the resulting optimal essential benefits package depended on the weights placed on the two objectives. In the Sustainable Development Goals era, smart spending toward universal health coverage is essential. Mathematical optimization provides a quantitative framework for policymakers to design health policies and select interventions that jointly prioritize multiple objectives with explicit financial constraints.

The cost-effectiveness of preimplantation genetic testing for aneuploidy in the United States: an analysis of cost and birth outcomes from 158,665 in vitro fertilization cycles.

BACKGROUND: A controversial and unresolved question in reproductive medicine is the utility of preimplantation genetic testing for aneuploidy as an adjunct to in vitro fertilization. Infertility is prevalent, but its treatment is notoriously expensive and typically not covered by insurance. Therefore, cost-effectiveness is critical to consider in this context. OBJECTIVE: This study aimed to analyze the cost-effectiveness of preimplantation genetic testing for aneuploidy for the treatment of infertility in the United States. STUDY DESIGN: As reported to the Society for Assisted Reproductive Technology Clinic Outcomes Reporting System, a national data registry, in vitro fertilization cycles occurring between 2014 and 2016 in the United States were analyzed. A probabilistic decision tree was developed using empirical outputs to simulate the events and outcomes associated with in vitro fertilization with and without preimplantation genetic testing for aneuploidy. The treatment strategies were (1) in vitro fertilization with intended preimplantation genetic testing for aneuploidy and (2) in vitro fertilization with transfers of untested embryos. Patients progressed through the treatment model until they achieved a live birth or 12 months after ovarian stimulation. Clinical costs related to both treatment strategies were extracted from the literature and considered from both the patient and payer perspectives. Outcome metrics included incremental cost (measured in 2018 US dollars), live birth outcomes, incremental cost-effectiveness ratio, and incremental cost per live birth between treatment strategies. RESULTS: The study population included 114,157 first fresh in vitro fertilization stimulations and 44,508 linked frozen embryo transfer cycles. Of the fresh stimulations, 16.2% intended preimplantation genetic testing for aneuploidy and 83.8% did not. In patients younger than 35 years old, preimplantation genetic testing for aneuploidy was associated with worse clinical outcomes and higher costs. At age 35 years and older, preimplantation genetic testing for aneuploidy led to more cumulative births but was associated with higher costs from both perspectives. From a patient perspective, the incremental cost per live birth favored the no preimplantation genetic testing for aneuploidy strategy from the <35 years age group to the 38 years age group and beginning at age 39 years favored preimplantation genetic testing for aneuploidy. From a payer perspective, the incremental cost per live birth favored preimplantation genetic testing for aneuploidy regardless of patient age. CONCLUSION: The cost-effectiveness of preimplantation genetic testing for aneuploidy is dependent on patient age and perspective. From an economic perspective, routine preimplantation genetic testing for aneuploidy should not be universally adopted; however, it may be cost-effective in certain scenarios.

Global, regional, and national levels of neonatal, infant, and under-5 mortality during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013.

BACKGROUND: Remarkable financial and political efforts have been focused on the reduction of child mortality during the past few decades. Timely measurements of levels and trends in under-5 mortality are important to assess progress towards the Millennium Development Goal 4 (MDG 4) target of reduction of child mortality by two thirds from 1990 to 2015, and to identify models of success. METHODS: We generated updated estimates of child mortality in early neonatal (age 0-6 days), late neonatal (7-28 days), postneonatal (29-364 days), childhood (1-4 years), and under-5 (0-4 years) age groups for 188 countries from 1970 to 2013, with more than 29,000 survey, census, vital registration, and sample registration datapoints. We used Gaussian process regression with adjustments for bias and non-sampling error to synthesise the data for under-5 mortality for each country, and a separate model to estimate mortality for more detailed age groups. We used explanatory mixed effects regression models to assess the association between under-5 mortality and income per person, maternal education, HIV child death rates, secular shifts, and other factors. To quantify the contribution of these different factors and birth numbers to the change in numbers of deaths in under-5 age groups from 1990 to 2013, we used Shapley decomposition. We used estimated rates of change between 2000 and 2013 to construct under-5 mortality rate scenarios out to 2030. FINDINGS: We estimated that 6·3 million (95% UI 6·0-6·6) children under-5 died in 2013, a 64% reduction from 17·6 million (17·1-18·1) in 1970. In 2013, child mortality rates ranged from 152·5 per 1000 livebirths (130·6-177·4) in Guinea-Bissau to 2·3 (1·8-2·9) per 1000 in Singapore. The annualised rates of change from 1990 to 2013 ranged from -6·8% to 0·1%. 99 of 188 countries, including 43 of 48 countries in sub-Saharan Africa, had faster decreases in child mortality during 2000-13 than during 1990-2000. In 2013, neonatal deaths accounted for 41·6% of under-5 deaths compared with 37·4% in 1990. Compared with 1990, in 2013, rising numbers of births, especially in sub-Saharan Africa, led to 1·4 million more child deaths, and rising income per person and maternal education led to 0·9 million and 2·2 million fewer deaths, respectively. Changes in secular trends led to 4·2 million fewer deaths. Unexplained factors accounted for only -1% of the change in child deaths. In 30 developing countries, decreases since 2000 have been faster than predicted attributable to income, education, and secular shift alone. INTERPRETATION: Only 27 developing countries are expected to achieve MDG 4. Decreases since 2000 in under-5 mortality rates are accelerating in many developing countries, especially in sub-Saharan Africa. The Millennium Declaration and increased development assistance for health might have been a factor in faster decreases in some developing countries. Without further accelerated progress, many countries in west and central Africa will still have high levels of under-5 mortality in 2030. FUNDING: Bill & Melinda Gates Foundation, US Agency for International Development.

Age-specific and sex-specific mortality in 187 countries, 1970-2010: a systematic analysis for the Global Burden of Disease Study 2010.

BACKGROUND: Estimation of the number and rate of deaths by age and sex is a key first stage for calculation of the burden of disease in order to constrain estimates of cause-specific mortality and to measure premature mortality in populations. We aimed to estimate life tables and annual numbers of deaths for 187 countries from 1970 to 2010. METHODS: We estimated trends in under-5 mortality rate (children aged 0-4 years) and probability of adult death (15-59 years) for each country with all available data. Death registration data were available for more than 100 countries and we corrected for undercount with improved death distribution methods. We applied refined methods to survey data on sibling survival that correct for survivor, zero-sibling, and recall bias. We separately estimated mortality from natural disasters and wars. We generated final estimates of under-5 mortality and adult mortality from the data with Gaussian process regression. We used these results as input parameters in a relational model life table system. We developed a model to extrapolate mortality to 110 years of age. All death rates and numbers have been estimated with 95% uncertainty intervals (95% UIs). FINDINGS: From 1970 to 2010, global male life expectancy at birth increased from 56·4 years (95% UI 55·5-57·2) to 67·5 years (66·9-68·1) and global female life expectancy at birth increased from 61·2 years (60·2-62·0) to 73·3 years (72·8-73·8). Life expectancy at birth rose by 3-4 years every decade from 1970, apart from during the 1990s (increase in male life expectancy of 1·4 years and in female life expectancy of 1·6 years). Substantial reductions in mortality occurred in eastern and southern sub-Saharan Africa since 2004, coinciding with increased coverage of antiretroviral therapy and preventive measures against malaria. Sex-specific changes in life expectancy from 1970 to 2010 ranged from gains of 23-29 years in the Maldives and Bhutan to declines of 1-7 years in Belarus, Lesotho, Ukraine, and Zimbabwe. Globally, 52·8 million (95% UI 51·6-54·1 million) deaths occurred in 2010, which is about 13·5% more than occurred in 1990 (46·5 million [45·7-47·4 million]), and 21·9% more than occurred in 1970 (43·3 million [42·2-44·6 million]). Proportionally more deaths in 2010 occurred at age 70 years and older (42·8% in 2010 vs 33·1% in 1990), and 22·9% occurred at 80 years or older. Deaths in children younger than 5 years declined by almost 60% since 1970 (16·4 million [16·1-16·7 million] in 1970 vs 6·8 million [6·6-7·1 million] in 2010), especially at ages 1-59 months (10·8 million [10·4-11·1 million] in 1970 vs 4·0 million [3·8-4·2 million] in 2010). In all regions, including those most affected by HIV/AIDS, we noted increases in mean ages at death. INTERPRETATION: Despite global and regional health crises, global life expectancy has increased continuously and substantially in the past 40 years. Yet substantial heterogeneity exists across age groups, among countries, and over different decades. 179 of 187 countries have had increases in life expectancy after the slowdown in progress in the 1990s. Efforts should be directed to reduce mortality in low-income and middle-income countries. Potential underestimation of achievement of the Millennium Development Goal 4 might result from limitations of demographic data on child mortality for the most recent time period. Improvement of civil registration system worldwide is crucial for better tracking of global mortality. FUNDING: Bill & Melinda Gates Foundation.

Progress towards Millennium Development Goals 4 and 5 on maternal and child mortality: an updated systematic analysis.

BACKGROUND: With 4 years until 2015, it is essential to monitor progress towards Millennium Development Goals (MDGs) 4 and 5. Although estimates of maternal and child mortality were published in 2010, an update of estimates is timely in view of additional data sources that have become available and new methods developed. Our aim was to update previous estimates of maternal and child mortality using better data and more robust methods to provide the best available evidence for tracking progress on MDGs 4 and 5. METHODS: We update the analyses of the progress towards MDGs 4 and 5 from 2010 with additional surveys, censuses, vital registration, and verbal autopsy data. For children, we estimate early neonatal (0-6 days), late neonatal (7-28 days), postneonatal (29-364 days), childhood (ages 1-4 years), and under-5 mortality. We use an improved model for estimating mortality by age under 5 years. For maternal mortality, our updated analysis includes greater than 1000 additional site-years of data. We tested a large set of alternative models for maternal mortality; we used an ensemble model based on the models with the best out-of-sample predictive validity to generate new estimates from 1990 to 2011. FINDINGS: Under-5 deaths have continued to decline, reaching 7·2 million in 2011 of which 2·2 million were early neonatal, 0·7 million late neonatal, 2·1 million postneonatal, and 2·2 million during childhood (ages 1-4 years). Comparing rates of decline from 1990 to 2000 with 2000 to 2011 shows that 106 countries have accelerated declines in the child mortality rate in the past decade. Maternal mortality has also continued to decline from 409,100 (uncertainty interval 382,900-437,900) in 1990 to 273,500 (256,300-291,700) deaths in 2011. We estimate that 56,100 maternal deaths in 2011 were HIV-related deaths during pregnancy. Based on recent trends in developing countries, 31 countries will achieve MDG 4, 13 countries MDG 5, and nine countries will achieve both. INTERPRETATION: Even though progress on reducing maternal and child mortality in most countries is accelerating, most developing countries will take many years past 2015 to achieve the targets of the MDGs 4 and 5. Similarly, although there continues to be progress on maternal mortality the pace is slow, without any overall evidence of acceleration. Immediate concerted action is needed for a large number of countries to achieve MDG 4 and MDG 5. FUNDING: Bill & Melinda Gates Foundation.