Effects of elevated systolic blood pressure on ischemic heart disease: a Burden of Proof study

High systolic blood pressure (SBP) is a major risk factor for ischemic heart disease (IHD), the leading cause of death worldwide. Using data from published observational studies and controlled trials, we estimated the mean SBP–IHD dose–response function and burden of proof risk function (BPRF), and we calculated a risk outcome score (ROS) and corresponding star rating (one to five). We found a very strong, significant harmful effect of SBP on IHD, with a mean risk—relative to that at 100 mm Hg SBP—of 1.39 (95% uncertainty interval including between-study heterogeneity 1.34–1.44) at 120 mm Hg, 1.81 (1.70–1.93) at 130 mm Hg and 4.48 (3.81–5.26) at 165 mm Hg. The conservative BPRF measure indicated that SBP exposure between 107.5 and 165.0 mm Hg raised risk by 101.36% on average, yielding a ROS of 0.70 and star rating of five. Our analysis shows that IHD risk was already increasing at 120 mm Hg SBP, rising steadily up to 165 mm Hg and increasing less steeply above that point. Our study endorses the need to prioritize and strengthen strategies for screening, to raise awareness of the need for timely diagnosis and treatment of hypertension and to increase the resources allocated for understanding primordial prevention of elevated blood pressure.

3 Describe the rationale for the review in the context of existing knowledge. "Main" (intro) paragraphs 1-3 Objectives 4 Provide an explicit statement of the objective(s) or question(s) the review addresses. "Main" (intro) paragraph 5 METHODS Eligibility criteria 5 Specify the inclusion and exclusion criteria for the review and how studies were grouped for the syntheses.
Full inclusion and exclusion criteria listed in Methods section "literature review"; reasons for exclusion and number of studies excluded also provided in PRISMA flow diagram (Extended Data Figure 1) Information sources 6 Specify all databases, registers, websites, organisations, reference lists and other sources searched or consulted to identify studies. Specify the date when each source was last searched or consulted.
Methods section "systematic review"; Supplementary Information Section 2 Search strategy 7 Present the full search strategies for all databases, registers and websites, including any filters and limits used.
Methods section "literature review"; Supplementary Information Section 2.1 Selection process 8 Specify the methods used to decide whether a study met the inclusion criteria of the review, including how many reviewers screened each record and each report retrieved, whether they worked independently, and if applicable, details of automation tools used in the process.
Methods section "systematic review" Data collection process 9 Specify the methods used to collect data from reports, including how many reviewers collected data from each report, whether they worked independently, any processes for obtaining or confirming data from study investigators, and if applicable, details of automation tools used in the process.
Methods section "systematic review" Data items 10a List and define all outcomes for which data were sought. Specify whether all results that were compatible with each outcome domain in each study were sought (e.g. for all measures, time points, analyses), and if not, the methods used to decide which results to collect.
Title, abstract, methods sections 10b List and define all other variables for which data were sought (e.g. participant and intervention characteristics, funding sources). Describe any assumptions made about any missing or unclear information.
Methods section "systematic review"; Results section table 2 "Study characteristics" for each included study full list and definitions of all variables are in Supplementary Information Table 7 Study risk of bias assessment 11 Specify the methods used to assess risk of bias in the included studies, including details of the tool(s) used, how many reviewers assessed each study and whether they worked independently, and if applicable, details of automation tools used in the process.
Overview of methods for testing for bias in main text methods section "testing for bias across different study designs and characteristics" Effect measures 12 Specify for each outcome the effect measure(s) (e.g. risk ratio, mean difference) used in the synthesis or presentation of results.
Main methods "overview" and "estimating the burden of proof risk function" sections.

Synthesis methods
13a Describe the processes used to decide which studies were eligible for each synthesis (e.g. tabulating the study intervention characteristics and comparing against the planned groups for each synthesis (item #5)).
Broad description of processes available in methods "literature reviews" 13b Describe any methods required to prepare the data for presentation or synthesis, such as handling of missing summary statistics, or data conversions.
Methods section "literature review" 13c Describe any methods used to tabulate or visually display results of individual studies and syntheses.
Methods sections "literature reviews", "estimating the shape of the risk-outcome relationship"; Figure 1 13d Describe any methods used to synthesize results and provide a rationale for the choice(s). If meta-analysis was performed, describe the model(s), method(s) to identify the presence and extent of statistical heterogeneity, and software package(s) used.
Methods sections "Estimating the shape of the risk-outcome relationship," "quantifying between-study heterogeneity...," "estimating the burden of proof risk function". Software packages described in "code availability" section of the manuscript 13e Describe any methods used to explore possible causes of heterogeneity among study results (e.g. subgroup analysis, meta-regression).
Methods section "quantifying between-study heterogeneity" and results of sensitivity analyses Extended Data Figures 3-10 13f Describe any sensitivity analyses conducted to assess robustness of the synthesized results. Supplementary Information Section 3: sensitivity results (reference to these results found in the main text of the methods and results sections "sensitivity analysis" and Extended Data Figures 3-10 Reporting bias assessment 14 Describe any methods used to assess risk of bias due to missing results in a synthesis (arising from reporting biases).
Methods for detecting publication or reporting bias found in methods section "evaluating publication and reporting bias" Certainty assessment 15 Describe any methods used to assess certainty (or confidence) in the body of evidence for an outcome.
Methods section "quantifying between-study heterogeneity" RESULTS Study selection 16a Describe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram.
PRISMA flow diagram Extended Data Figure 1 16b Cite studies that might appear to meet the inclusion criteria, but which were excluded, and explain why they were excluded.

Not applicable
Study characteristics 17 Cite each included study and present its characteristics. Results Table 2 ("study characteristics"); Supplemental Information Table S3 ("study name and citation for all input data sources") citations also provided in the online viz tool. Risk of bias in studies 18 Present assessments of risk of bias for each included study.
Results section "burden of proof risk function" Results of individual studies 19 For all outcomes, present, for each study: (a) summary statistics for each group (where appropriate) and (b) an effect estimates and its precision (e.g. confidence/credible interval), ideally using structured tables or plots.
No, we do not present this information in the present manuscript. Results of syntheses 20a For each synthesis, briefly summarise the characteristics and risk of bias among contributing studies.
Results section "burden of proof risk function" and methods section "testing and adjusting for bias related to study attributes" 20b Present results of all statistical syntheses conducted. If meta-analysis was done, present for each the summary estimate and its precision (e.g. confidence/credible interval) and Results, Figure 1; Supplemental Information Relative risk based on the mean relative risk function (95% UI accounting for between-study heterogeneity), presented at every 10 mmHg of systolic blood pressure from 100 to 200 mmHg. The mean RRs are calculated in comparison to a reference SBP level of 100 mmHg. IHD = ischemic heart disease. RR = relative risk. UI = uncertainty interval. Supplementary Table 5. Burden of proof risk function for high systolic blood pressure exposure and ischemic heart disease.
Burden of proof risk function defined as the 5th quantile risk curve (closest to null)-inclusive of between-study heterogeneity, providing a conservative estimate of effect size and evidence strength-averaged across the data dense 15th-85th percentile range (107.5 to 165 mmHg) of systolic blood pressure (SBP) exposure. The BPRF is calculated in comparison to a reference SBP level of 100 mmHg. Risk outcome score (ROS) calculated as the average log relative risk of the BPRF over the 15th-85th percentile of the SBP exposure range. Star rating summary measure of risk and evidence strength: ROS<0 yields 1 star, 0-15% risk increase yields 2 stars, >15-50% risk increase yields 3 stars, >50-85% risk increase yields 4 stars, and >85% risk increase yields 5 stars. BPRF = burden of proof risk function, ROS = risk outcome score, SBP = Systolic blood pressure. Define the indicator(s), populations (including age, sex, and geographic entities), and period(s) for which estimates were made.
Main text (methods and results section); Supplemental Information Section 3 2 List the funding sources for the work.

Main text (acknowledgement section) Data Inputs
For all data inputs from multiple sources that are synthesized as part of the study:

3
Describe how the data were identified and how the data were accessed. Main text (step 1 in methods); Extended Data Provide information on all included data sources and their main characteristics. For each data source used, report reference information or contact name/institution, population represented, data collection method, year(s) of data collection, sex and age range, diagnostic criteria or measurement method, and sample size, as relevant.
Main Identify and describe any categories of input data that have potentially important biases (e.g., based on characteristics listed in item 5).

Main text (methods and results sections)
For data inputs that contribute to the analysis but were not synthesized as part of the study: 7 Describe and give sources for any other data inputs. Not applicable For all data inputs: 8 Provide all data inputs in a file format from which data can be efficiently extracted (e.g., a spreadsheet rather than a PDF), including all relevant meta-data listed in item 5. For any data inputs that cannot be shared because of ethical or legal reasons, such as third-party ownership, provide a contact name or the name of the institution that retains the right to the data.
See Data Availability statement. Data sources and citations can be downloaded from the Burden of Proof visualization tool: http://vizhub.healthdata.org/burden-of-proof

Data analysis 9
Provide a conceptual overview of the data analysis method. A diagram may be helpful.
Main text (methods overview)

10
Provide a detailed description of all steps of the analysis, including mathematical formulae. This description should cover, as relevant, data cleaning, data pre-Main text (methods section) processing, data adjustments and weighting of data sources, and mathematical or statistical model(s).

11
Describe how candidate models were evaluated and how the final model(s) were selected.
Main text ("model validation" in methods)

12
Provide the results of an evaluation of model performance, if done, as well as the results of any relevant sensitivity analysis.
Main text ("sensitivity analysis" in methods); Supplementary Information Section 3. Extended Data Figures 3-9 13 Describe methods for calculating uncertainty of the estimates. State which sources of uncertainty were, and were not, accounted for in the uncertainty analysis.
Main text (methods section)

14
State how analytic or statistical source code used to generate estimates can be accessed.

15
Provide published estimates in a file format from which data can be efficiently extracted.
Risk-outcome scores; star ratings; risk curves with all data points, trimmed data points, and conventional and conservative uncertainty intervals; and an interpretation of the findings are available for all risk-outcome pairs at http://vizhub.healthdata.org/burden-of-proof

16
Report a quantitative measure of the uncertainty of the estimates (e.g. uncertainty intervals).

17
Interpret results in light of existing evidence. If updating a previous set of estimates, describe the reasons for changes in estimates.
Main text (discussion)

18
Discuss limitations of the estimates. Include a discussion of any modelling assumptions or data limitations that affect interpretation of the estimates. Exposure exp_assess_level Level of exposure assessment: The exposure was assessed… exp_instrument Exposure assessment instrument: Specify the name of the exposure assessment instrument. For self-reported exposures, please specify the name of the questionnaire e.g., International Physical Activity Questionnaire (IPAQ). If more than one instrument specify all exp_assess_period

Supplementary
What was the frequency of exposure assessment? exp_assess_num If multiple, specify the number of times that exposure was assessed (excluding baseline) exp_method_1 Please specify the method of exposure assessment. If there are more than 1, please add in the next columns labeled "exp_method_2". exp_method_2 Please specify the method of exposure assessment. If there are more than 2, please add in the next columns labeled "exp_method_3". exp_method_3 Please specify the method of exposure assessment. exp_recall_period This field describes the unit of exposure recall used in data collection ONLY for self-report. Select the correct option from the drop-down menu. If the unit is days, weeks, months, or years, please enter the number in exp_recall_period_value (next column). If the unit is 'lifetime', nothing needs to be entered in exp_recall_period_value. For example, if the study said the recall period was 4 weeks, enter 4 in exp_recall_period_value, and 'weeks' in the field exp_recall_period. If 'other' is selected, please describe in exp_recall_period_other exp_recall_period_value If you entered days, weeks, months, or years in the field 'exp_recall_period', please enter the corresponding integer in this field. For example, if the study said the recall period was 4 weeks, enter 4 in exp_recall_period_value, and 'weeks' in the field exp_recall_period. exp_recall_period_other If 'other' was selected in exp_recall_period, please describe the exposure recall period that the study specified (e.g., recall of exposure from 12 to 18 years). exp_type Which form of the exposure was included in relative risk estimation analysis?
Outcome outcome_def Outcome definition: Provide a brief description of the outcome as reported in the study. outcome_type Outcome type: please specify if the outcome definition included incidence of or mortality from a disease endpoint outcome_assess_1 Method of outcome assessment: Specify the method of assessment of the study outcome. If more than 1 are appropriate, enter additional methods in the next column labeled "outcome_assess_2" outcome_assess_2 Method of outcome assessment: Specify the method of assessment of the study outcome. If more than 2 are appropriate, enter additional methods in the next column labeled "outcome_assess_3" outcome_assess_3 Method of outcome assessment: Specify the method of assessment of the study outcome. Mark with a 1 if no uncertainty is reported, if some sort of uncertainty is reported, mark 0 subgroup_analysis 1 if RR is from main analysis (all participants), 0 if sub-analysis (only males, or among a specific age group, etc.) subgroup_analysis_free_text If a sub-analysis, describe it (i.e., age, sex, etc.) effect_size_multi_location 1 if the reported effect size is from a multi-country study and only one effect size has been reported for all locations, otherwise 0 effect_size_multi_location_specify Which geography level is the RR for pooled_cohort 1 if the reported effect size is from a pooled analysis and only pooled effect size has been reported, otherwise 0 dose_response Does the study support a dose-response relationship between the exposure and the outcome? (1= yes, 0=no) dose_response_detail If "1" was specified in the dose_response field, please specify in this field the type of evidence supporting the dose-response relationship. For example, "statistically significant p value for linear trend". Cohorts cohort_person_years_exp Please specify the person-years of follow up in the exposed group cohort_person_years_unexp Please specify the person-years of follow up in the unexposed group cohort_person_years_total Enter the total person-years of follow-up if person-years of follow up in exposed and unexposed not reported cohort_number_events_exp Please specify the number of events in the exposed group cohort_number_events_unexp Please specify the number of events in the unexposed group cohort_number_events_total Enter the total number of events/cases if number of events in exposed and unexposed not reported cohort_sample_size_exp Please specify the number of people in the exposed group if personyears of follow up in exposed not reported

Category Variable Definition cohort_sample_size_unexp
Please specify the number of people in the unexposed group if personyears of follow up in unexposed not reported cohort_sample_size_total Please specify the number of people included in the analysis if total person-years of follow up is not reported cohort_dropout_rate Dropout rate: Specify the dropout rate (%) at the end of the study. Enter on a "per 1" basis. For example: 23% is entered as .23. cohort_dropout_assess Specify how dropout rate was defined in the study. cohort_exposed_def Exposed group definition: Provide a brief description of the exposed group (i.e., the comparison group) as used in estimation of the relative risk (e.g., never smokers) cohort_exp_unit_rr Exposure unit (for continuous risks): Specify the unit of exposure (e.g., grams/day). cohort_exp_level_rr Exposure level in the exposed group (for continuous risks): Specify the mean/median level of exposure in the exposed group. cohort_unexp_def unexposed group definition: Provide a brief description of the unexposed group (i.e., the comparison group) as used in estimation of the relative risk (e.g., never smokers) cohort_unexp_unit_rr Exposure unit ( Exposed group definition: Provide a brief description of the exposed group for which the relative risk is reported (e.g., current smokers) cc_exp_unit_rr Exposure unit (for continuous risks): Specify the unit of exposure (e.g., grams/day). cc_exp_level_rr Exposure level in the exposed group (for continuous risks): Specify the mean/median level of exposure in the exposed group. cc_unexposed_def Unexposed group definition: Provide a brief description of the unexposed group (i.e., the comparison group) as used in estimation of the relative risk (e.g., never smokers) cc_unexp_unit_rr Unexposed unit ( Section 2: Data source identification The data used for this study includes randomized control trials (RCTs) and pooled cohort studies. More detailed information on data inputs is provided in the online viz tool: http://vizhub.healthdata.org/burdenof-proof.