A simple method to combine multiple molecular biomarkers for dichotomous diagnostic classification

BACKGROUND: In spite of the recognized diagnostic potential of biomarkers, the quest for squelching noise and wringing in information from a given set of biomarkers continues. Here, we suggest a statistical algorithm that – assuming each molecular biomarker to be a diagnostic test – enriches the diagnostic performance of an optimized set of independent biomarkers employing established statistical techniques. We validated the proposed algorithm using several simulation datasets in addition to four publicly available real datasets that compared i) subjects having cancer with those without; ii) subjects with two different cancers; iii) subjects with two different types of one cancer; and iv) subjects with same cancer resulting in differential time to metastasis. RESULTS: Our algorithm comprises of three steps: estimating the area under the receiver operating characteristic curve for each biomarker, identifying a subset of biomarkers using linear regression and combining the chosen biomarkers using linear discriminant function analysis. Combining these established statistical methods that are available in most statistical packages, we observed that the diagnostic accuracy of our approach was 100%, 99.94%, 96.67% and 93.92% for the real datasets used in the study. These estimates were comparable to or better than the ones previously reported using alternative methods. In a synthetic dataset, we also observed that all the biomarkers chosen by our algorithm were indeed truly differentially expressed. CONCLUSION: The proposed algorithm can be used for accurate diagnosis in the setting of dichotomous classification of disease states

Divergent trends in ischaemic heart disease and stroke mortality in India from 2000 to 2015: a nationally representative mortality study.

INTRODUCTION: India accounts for about a fifth of cardiovascular deaths globally, but nationally representative data on mortality trends are not yet available. In this nationwide mortality study, we aimed to assess the trends in ischaemic heart disease and stroke mortality over 15 years using the Million Death Study. METHODS: We determined national and subnational cardiovascular mortality rates and trends by sex and birth cohort using cause of death ascertained by verbal autopsy from 2001 to 2013 among 2·4 million households. We derived mortality rates for ischaemic heart disease and stroke by applying mortality proportions to UN mortality estimates for India and projected the rates from 2000 to 2015. FINDINGS: Cardiovascular disease caused more than 2·1 million deaths in India in 2015 at all ages, or more than a quarter of all deaths. At ages 30-69 years, of 1·3 million cardiovascular deaths, 0·9 million (68·4%) were caused by ischaemic heart disease and 0·4 million (28·0%) by stroke. At these ages, the probability of dying from ischaemic heart disease increased during 2000-15, from 10·4% to 13·1% in men and 4·8% to 6·6% in women. Ischaemic heart disease mortality rates in rural areas increased rapidly and surpassed those in urban areas. By contrast, the probability of dying from stroke decreased from 5·7% to 5·0% in men and 5·0% to 3·9% in women. A third of premature stroke deaths occurred in the northeastern states, inhabited by a sixth of India's population, where rates increased significantly and were three times higher than the national average. The increased mortality rates of ischaemic heart disease nationally and stroke in the northeastern states were higher in the cohorts of adults born in the 1970s onwards, than in earlier decades. A large and growing proportion of the ischaemic heart disease nationally and stroke deaths in high-burden states reported earlier diagnosis of cardiovascular disease, but low medication use. INTERPRETATION: The unexpectedly diverse patterns of cardiovascular mortality require investigation to identify the role of established and new cardiovascular risk factors. Secondary prevention with effective and inexpensive long-term treatment and adult smoking cessation could prevent substantial numbers of premature deaths. Without progress against the control of cardiovascular disease in India, global goals to reduce non-communicable diseases by 2030 will be difficult to achieve. FUNDING: Fogarty International Center of the US National Institutes of Health, Dalla Lana School of Public Health, University of Toronto, Indian Council of Medical Research, and the Disease Control Priorities

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation

Specialist involvement and referral patterns in ambulatory medical care for patients with dementia in Germany: results of a claims data based case-control study

<p>Abstract</p> <p>Background</p> <p>To analyze the referral processes from general practitioners to specialists and among specialists for dementia patients in the time periods before, during and after the diagnosis in Germany.</p> <p>Methods</p> <p>In this case-control study claims data from 1,848 insurants with incident dementia aged 65 years and more and 7,392 matched controls were compared over a two-year period covering the pre-incidence, incidence and post-incidence time periods.</p> <p>Results</p> <p>We found an increase in referrals of 30% in the incidence quarter, mainly from general practice to neuropsychiatry and from there to radiology. Referrals to clinical chemistry and other disciplines for dementia-specific reasons were negligible in amount. 34% of incident cases had at least one contact with a neuropsychiatrist during the year of incidence, and the majority of them visited this specialist repeatedly during that year. Only a minority (13.5%) of patients was referred to radiology for imaging. Referrals to other specialists declined whereas self-referrals did not increase.</p> <p>Conclusions</p> <p>The referral rates to relevant specialists (neuropsychiatry, radiology and clinical chemistry) are far less frequent than proposed in German guidelines. More research is needed to explain the gape between guidelines and daily care and to find ways for a better implementation of guidelines in ambulatory care. Guidelines should not only deal with diagnostic procedures and therapeutic options but also consider questions of applicability in daily clinical practice and propose effective organizational models of care provision.</p

Stroke in India: a systematic review of the incidence, prevalence and case fatality

Background: The burden of stroke is increasing in India; stroke is now the fourth leading cause of death and the fifth leading cause of disability. Previous research suggests that the incidence of stroke in India ranges between 105 and 152/100,000 people per year. However, there is a paucity of available data and a lack of uniform methods across published studies. Aim: To identify high-quality prospective studies reporting the epidemiology of stroke in India. Summary of review: A search strategy was modified from the Cochrane Stroke Strategy and adapted for a range of bibliographic databases from January 1997 to August 2020. From 7,717 identified records, nine studies were selected for inclusion; three population-based registries, a further three population-based registries also using community-based ascertainment and three community-based door-to-door surveys. Studies represented the four cities of Mumbai, Trivandrum, Ludhiana, Kolkata, the state of Punjab and 12 villages of Baruipur in the state of West Bengal. The total population denominator was 22,479,509 and 11,654 (mean 1,294 SD 1,710) people were identified with incident stroke. Crude incidence of stroke ranged from 108 to 172/100,000 people per year, crude prevalence from 26 to 757/100,000 people per year and one-month case fatality rates from 18% to 42%. Conclusions: Further high-quality evidence is needed across India to guide stroke policy and inform the development and organisation of stroke services. Future researchers should consider the World Health Organisation STEPwise approach to Surveillance (STEPS) framework, including longitudinal data collection, the inclusion of census population data and a combination of hospital-registry and comprehensive community ascertainment strategies to ensure complete stroke identification

The effect of multiple adverse childhood experiences on health: a systematic review and meta-analysis

Background A growing body of research identifies the harmful effects that adverse childhood experiences (ACEs; occurring during childhood or adolescence; eg, child maltreatment or exposure to domestic violence) have on health throughout life. Studies have quantified such effects for individual ACEs. However, ACEs frequently co-occur and no synthesis of findings from studies measuring the effect of multiple ACE types has been done. Methods In this systematic review and meta-analysis, we searched five electronic databases for cross-sectional, case-control, or cohort studies published up to May 6, 2016, reporting risks of health outcomes, consisting of substance use, sexual health, mental health, weight and physical exercise, violence, and physical health status and conditions, associated with multiple ACEs. We selected articles that presented risk estimates for individuals with at least four ACEs compared with those with none for outcomes with sufficient data for meta-analysis (at least four populations). Included studies also focused on adults aged at least 18 years with a sample size of at least 100. We excluded studies based on high-risk or clinical populations. We extracted data from published reports. We calculated pooled odds ratios (ORs) using a random-effects model. Findings Of 11 621 references identified by the search, 37 included studies provided risk estimates for 23 outcomes, with a total of 253 719 participants. Individuals with at least four ACEs were at increased risk of all health outcomes compared with individuals with no ACEs. Associations were weak or modest for physical inactivity, overweight or obesity, and diabetes (ORs of less than two); moderate for smoking, heavy alcohol use, poor self-rated health, cancer, heart disease, and respiratory disease (ORs of two to three), strong for sexual risk taking, mental ill health, and problematic alcohol use (ORs of more than three to six), and strongest for problematic drug use and interpersonal and self-directed violence (ORs of more than seven). We identified considerable heterogeneity (I 2 of > 75%) between estimates for almost half of the outcomes. Interpretation To have multiple ACEs is a major risk factor for many health conditions. The outcomes most strongly associated with multiple ACEs represent ACE risks for the next generation (eg, violence, mental illness, and substance use). To sustain improvements in public health requires a shift in focus to include prevention of ACEs, resilience building, and ACE-informed service provision. The Sustainable Development Goals provide a global platform to reduce ACEs and their life-course effect on health. Funding Public Health Wales. © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 licens

Statistical analysis plan for the family-led rehabilitation after stroke in India (ATTEND) trial: A multicenter randomized controlled trial of a new model of stroke rehabilitation compared to usual care

Background In low- and middle-income countries, few patients receive organized rehabilitation after stroke, yet the burden of chronic diseases such as stroke is increasing in these countries. Affordable models of effective rehabilitation could have a major impact. The ATTEND trial is evaluating a family-led caregiver delivered rehabilitation program after stroke. Objective To publish the detailed statistical analysis plan for the ATTEND trial prior to trial unblinding. Methods Based upon the published registration and protocol, the blinded steering committee and management team, led by the trial statistician, have developed a statistical analysis plan. The plan has been informed by the chosen outcome measures, the data collection forms and knowledge of key baseline data. Results The resulting statistical analysis plan is consistent with best practice and will allow open and transparent reporting. Conclusions Publication of the trial statistical analysis plan reduces potential bias in trial reporting, and clearly outlines pre-specified analyses

Primary stroke prevention worldwide : translating evidence into action

Funding Information: The stroke services survey reported in this publication was partly supported by World Stroke Organization and Auckland University of Technology. VLF was partly supported by the grants received from the Health Research Council of New Zealand. MOO was supported by the US National Institutes of Health (SIREN U54 HG007479) under the H3Africa initiative and SIBS Genomics (R01NS107900, R01NS107900-02S1, R01NS115944-01, 3U24HG009780-03S5, and 1R01NS114045-01), Sub-Saharan Africa Conference on Stroke Conference (1R13NS115395-01A1), and Training Africans to Lead and Execute Neurological Trials & Studies (D43TW012030). AGT was supported by the Australian National Health and Medical Research Council. SLG was supported by a National Heart Foundation of Australia Future Leader Fellowship and an Australian National Health and Medical Research Council synergy grant. We thank Anita Arsovska (University Clinic of Neurology, Skopje, North Macedonia), Manoj Bohara (HAMS Hospital, Kathmandu, Nepal), Denis ?erimagi? (Poliklinika Glavi?, Dubrovnik, Croatia), Manuel Correia (Hospital de Santo Ant?nio, Porto, Portugal), Daissy Liliana Mora Cuervo (Hospital Moinhos de Vento, Porto Alegre, Brazil), Anna Cz?onkowska (Institute of Psychiatry and Neurology, Warsaw, Poland), Gloria Ekeng (Stroke Care International, Dartford, UK), Jo?o Sargento-Freitas (Centro Hospitalar e Universit?rio de Coimbra, Coimbra, Portugal), Yuriy Flomin (MC Universal Clinic Oberig, Kyiv, Ukraine), Mehari Gebreyohanns (UT Southwestern Medical Centre, Dallas, TX, USA), Ivete Pillo Gon?alves (Hospital S?o Jos? do Avai, Itaperuna, Brazil), Claiborne Johnston (Dell Medical School, University of Texas, Austin, TX, USA), Kristaps Jurj?ns (P Stradins Clinical University Hospital, Riga, Latvia), Rizwan Kalani (University of Washington, Seattle, WA, USA), Grzegorz Kozera (Medical University of Gda?sk, Gda?sk, Poland), Kursad Kutluk (Dokuz Eylul University, ?zmir, Turkey), Branko Malojcic (University Hospital Centre Zagreb, Zagreb, Croatia), Micha? Maluchnik (Ministry of Health, Warsaw, Poland), Evija Migl?ne (P Stradins Clinical University Hospital, Riga, Latvia), Cassandra Ocampo (University of Botswana, Princess Marina Hospital, Botswana), Louise Shaw (Royal United Hospitals Bath NHS Foundation Trust, Bath, UK), Lekhjung Thapa (Upendra Devkota Memorial-National Institute of Neurological and Allied Sciences, Kathmandu, Nepal), Bogdan Wojtyniak (National Institute of Public Health, Warsaw, Poland), Jie Yang (First Affiliated Hospital of Chengdu Medical College, Chengdu, China), and Tomasz Zdrojewski (Medical University of Gda?sk, Gda?sk, Poland) for their comments on early draft of the manuscript. The views expressed in this article are solely the responsibility of the authors and they do not necessarily reflect the views, decisions, or policies of the institution with which they are affiliated. We thank WSO for funding. The funder had no role in the design, data collection, analysis and interpretation of the study results, writing of the report, or the decision to submit the study results for publication. Funding Information: The stroke services survey reported in this publication was partly supported by World Stroke Organization and Auckland University of Technology. VLF was partly supported by the grants received from the Health Research Council of New Zealand. MOO was supported by the US National Institutes of Health (SIREN U54 HG007479) under the H3Africa initiative and SIBS Genomics (R01NS107900, R01NS107900-02S1, R01NS115944-01, 3U24HG009780-03S5, and 1R01NS114045-01), Sub-Saharan Africa Conference on Stroke Conference (1R13NS115395-01A1), and Training Africans to Lead and Execute Neurological Trials & Studies (D43TW012030). AGT was supported by the Australian National Health and Medical Research Council. SLG was supported by a National Heart Foundation of Australia Future Leader Fellowship and an Australian National Health and Medical Research Council synergy grant. We thank Anita Arsovska (University Clinic of Neurology, Skopje, North Macedonia), Manoj Bohara (HAMS Hospital, Kathmandu, Nepal), Denis Čerimagić (Poliklinika Glavić, Dubrovnik, Croatia), Manuel Correia (Hospital de Santo António, Porto, Portugal), Daissy Liliana Mora Cuervo (Hospital Moinhos de Vento, Porto Alegre, Brazil), Anna Członkowska (Institute of Psychiatry and Neurology, Warsaw, Poland), Gloria Ekeng (Stroke Care International, Dartford, UK), João Sargento-Freitas (Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal), Yuriy Flomin (MC Universal Clinic Oberig, Kyiv, Ukraine), Mehari Gebreyohanns (UT Southwestern Medical Centre, Dallas, TX, USA), Ivete Pillo Gonçalves (Hospital São José do Avai, Itaperuna, Brazil), Claiborne Johnston (Dell Medical School, University of Texas, Austin, TX, USA), Kristaps Jurjāns (P Stradins Clinical University Hospital, Riga, Latvia), Rizwan Kalani (University of Washington, Seattle, WA, USA), Grzegorz Kozera (Medical University of Gdańsk, Gdańsk, Poland), Kursad Kutluk (Dokuz Eylul University, İzmir, Turkey), Branko Malojcic (University Hospital Centre Zagreb, Zagreb, Croatia), Michał Maluchnik (Ministry of Health, Warsaw, Poland), Evija Miglāne (P Stradins Clinical University Hospital, Riga, Latvia), Cassandra Ocampo (University of Botswana, Princess Marina Hospital, Botswana), Louise Shaw (Royal United Hospitals Bath NHS Foundation Trust, Bath, UK), Lekhjung Thapa (Upendra Devkota Memorial-National Institute of Neurological and Allied Sciences, Kathmandu, Nepal), Bogdan Wojtyniak (National Institute of Public Health, Warsaw, Poland), Jie Yang (First Affiliated Hospital of Chengdu Medical College, Chengdu, China), and Tomasz Zdrojewski (Medical University of Gdańsk, Gdańsk, Poland) for their comments on early draft of the manuscript. The views expressed in this article are solely the responsibility of the authors and they do not necessarily reflect the views, decisions, or policies of the institution with which they are affiliated. We thank WSO for funding. The funder had no role in the design, data collection, analysis and interpretation of the study results, writing of the report, or the decision to submit the study results for publication. Funding Information: VLF declares that the PreventS web app and Stroke Riskometer app are owned and copyrighted by Auckland University of Technology; has received grants from the Brain Research New Zealand Centre of Research Excellence (16/STH/36), Australian National Health and Medical Research Council (NHMRC; APP1182071), and World Stroke Organization (WSO); is an executive committee member of WSO, honorary medical director of Stroke Central New Zealand, and CEO of New Zealand Stroke Education charitable Trust. AGT declares funding from NHMRC (GNT1042600, GNT1122455, GNT1171966, GNT1143155, and GNT1182017), Stroke Foundation Australia (SG1807), and Heart Foundation Australia (VG102282); and board membership of the Stroke Foundation (Australia). SLG is funded by the National Health Foundation of Australia (Future Leader Fellowship 102061) and NHMRC (GNT1182071, GNT1143155, and GNT1128373). RM is supported by the Implementation Research Network in Stroke Care Quality of the European Cooperation in Science and Technology (project CA18118) and by the IRIS-TEPUS project from the inter-excellence inter-cost programme of the Ministry of Education, Youth and Sports of the Czech Republic (project LTC20051). BN declares receiving fees for data management committee work for SOCRATES and THALES trials for AstraZeneca and fees for data management committee work for NAVIGATE-ESUS trial from Bayer. All other authors declare no competing interests. Publisher Copyright: © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licenseStroke is the second leading cause of death and the third leading cause of disability worldwide and its burden is increasing rapidly in low-income and middle-income countries, many of which are unable to face the challenges it imposes. In this Health Policy paper on primary stroke prevention, we provide an overview of the current situation regarding primary prevention services, estimate the cost of stroke and stroke prevention, and identify deficiencies in existing guidelines and gaps in primary prevention. We also offer a set of pragmatic solutions for implementation of primary stroke prevention, with an emphasis on the role of governments and population-wide strategies, including task-shifting and sharing and health system re-engineering. Implementation of primary stroke prevention involves patients, health professionals, funders, policy makers, implementation partners, and the entire population along the life course.publishersversionPeer reviewe