Critical Appraisal of Published Economic Evaluation Questions for the Article- Clinical Impact & Cost Efficiency of Newborn Screening for Congenital Adrenal Hyperplasia * Read the article below and answer questions

(A) Summary: (25 points)

1-2 pages

1.- Policy/research problem is summarized (2 mks)

What is the policy/research problem in the article trying to figure out?

2.- Study rationale and main objectives are summarized (3 mks)

The primary objective is....

3.- The study design is correctly identified (2 mks), and the perspective of analysis isdescribed (3 mks)

- What study design was used in this analysis? (Cost effectiveness Analysis, Cost Benefit Analysis, or a Cost Consequence Analysis)

Was it a Social or a Public Payer Analysis?

4.- Source of model input parameters and assumptions are described (5 mks)

Where are those input parameters coming from/assumptions?

Are there any assumptions in the paper?

If the authors used cost and outcome parameters in the study and those parameters were not collected as the primary study, suppose they came from a secondary study.

The cost parameters/some of the cost parameters were obtained from other published studies, whereas the other cost parameters were already generated in the same study, like Health Economics study

-Describe assumptions if there are any assumptions in which authors used in the cost effectiveness analysis

Example of assumptions: sometimes we inflate/deflate costs by 25%, (sensitivity analysis) we assume outcomes/cost will increase/decrease

5.- Analysis and key findings are summarized (5 mks)

What is the main analysis looking at?

What are the key findings of the paper?

6.- Study strengths and limitations are summarized (5 mks)

What are the key strengths and limitations?

Were those limitations included in the paper?

If they were included, summarize

(B) Critical Appraisal table: (20 points) Highlight strengths and weakness described for each of the corresponding items on the CHEERSchecklist (see a template on page 2)

1- Title and abstract (2 mks) See CHEERS practical exercise to see what's included

Title

-Identify the study as an economic evaluation or use more specific terms such as "cost-effectiveness analysis", and describe the interventions compared.

-Looking at the title of the study, do you think the authors did a good job

Abstract

- Provide a structured summary of objectives, perspective, setting, methods (including study design and inputs), results (including base case and uncertainty analyses), and conclusions.

2- Introduction (3 mks)Background & Objectives

Background & Objectives

- Provide an explicit statement of the broader context for the study.

- Present the study question and its relevance for health policy or practice decisions.

3- Methods (5 mks)

Target population & subgroups

- Describe characteristics of the base case population and subgroups analysed, including why they were chosen.

Setting & location

- State relevant aspects of the system(s) in which the decision(s) need(s) to be made.

Study perspective

- Describe the perspective of the study and relate this to the costs being evaluated.

Comparators

- Describe the interventions or strategies being compared and state why they were chosen.

Time Horizon

- State the time horizon(s) over which costs and consequences are being evaluated and say why appropriate.

Discount rate

- Report the choice of discount rate(s) used for costs and outcomes and say why appropriate.

Choice of health outcomes

- Describe what outcomes were used as the measure(s) of benefit in the evaluation and their relevance for the type of analysis performed.

Measurement of effectiveness

- Single study-based estimates:Describe fully the design features of the single effectiveness study and why the single study was a sufficient source of clinical effectiveness data.

- Synthesis-based estimates: Describe fully the methods used for identification of included studies and synthesis of clinical effectiveness data.

Measurement & valuation of preference-based outcomes

- If applicable, describe the population and methods used to elicit preferences for outcomes.

Estimating resources & costs

- Single study-based economic evaluation:Describe approaches used to estimate resource use associated with the alternative interventions. Describe primary or secondary research methods for valuing each resource item in terms of its unit cost. Describe any adjustments made to approximate to opportunity costs.

- Model-based economic evaluation:Describe approaches and data sources used to estimate resource use associated with model health states. Describe primary or secondary research methods for valuing each resource item in terms of its unit cost. Describe any adjustments made to approximate to opportunity costs.

Currency price date & conversion

- Report the dates of the estimated resource quantities and unit costs. Describe methods for adjusting estimated unit costs to the year of reported costs if necessary. Describe methods for converting costs into a common currency base and the exchange rate.

Choice of model

- Describe and give reasons for the specific type of decision-analytical model used. Providing a figure to show model structure is strongly recommended.

Assumptions

- Describe all structural or other assumptions underpinning the decision-analytical model.

Analytical methods

- Describe all analytical methods supporting the evaluation. This could include methods for dealing with skewed, missing, or censored data; extrapolation methods; methods for pooling data; approaches to validate or make adjustments (such as half cycle corrections) to a model; and methods for handling population heterogeneity and uncertainty.

4.- Results (5 mks)

Study parameters

- Report the values, ranges, references, and, if used, probability distributions for all parameters. Report reasons or sources for distributions used to represent uncertainty where appropriate. Providing a table to show the input values is strongly recommended.

Incremental costs & outcomes

- For each intervention, report mean values for the main categories of estimated costs and outcomes of interest, as well as mean differences between the comparator groups. If applicable, report incremental cost-effectiveness ratios.

Characterizing uncertainty

- Single study-based economic evaluation: Describe the effects of sampling uncertainty for the estimated incremental cost and incremental effectiveness parameters, together with the impact of methodological assumptions (such as discount rate, study perspective).

- Model-based economic evaluation:Describe the effects on the results of uncertainty for all input parameters, and uncertainty related to the structure of the model and assumptions.

Characterizing heterogeneity

- If applicable, report differences in costs, outcomes, or cost-effectiveness that can be explained by variations between subgroups of patients with different baseline characteristics or other observed variability in effects that are not reducible by more information.

5.- Discussion (3 mks)

Study findings, limitations, generalisability, & current knowledge

- Summarise key study findings and describe how they support the conclusions reached. Discuss limitations and the generalisability of the findings and how the findings fit with current knowledge.

6.- Other (2 mks)

Source of funding

- Describe how the study was funded and the role of the funder in the identification, design, conduct, and reporting of the analysis. Describe other non-monetary sources of support.

Conflict of interest

- Describe any potential for conflict of interest of study contributors in accordance with journal policy. In the absence of a journal policy, we recommend authors comply with International Committee of Medical Journal Editors recommendations.

(C) Writing Style: (5 points) - Readability (organized, coherent, flows well) - Syntax sentence structure; spelling, grammar, punctuation - Follows guidelines (font, margins, page length, etc.)

Clinical Impact and Cost Efficacy of Newborn Screening for Congenital Adrenal Hyperplasia Danya A. Fox, MD, FRCPC, MPH1,*, Rebecca Ronsley, MD, FRCPC1,*, Asif R. Khowaja, PhD2, Alon Haim, MD3 , Hilary Vallance, MD, FRCPC, FCCMG4, Graham Sinclair, PhD, FCCMG4 , and Shazhan Amed, MD, FRCPC, MScPH1 ObjectivesTo evaluate the clinical impact of a congenital adrenal hyperplasia (CAH) newborn screening program and incremental costs relative to benefits in screened vs unscreened infants. We hypothesized that screening would lead to clinical benefits and would be cost effective. Study designThis was an ambispective cohort study at British Columbia Children's Hospital, including infants diagnosed with CAH from 1988-2008 and 2010-2018. Data were collected retrospectively (unscreened cohort) and prospectively (screened cohort). Outcome measures included hospitalization, medical transport, and resusci- tation requirements. The economic analysis was performed using a public payer perspective. ResultsForty unscreened and 17 screened infants were diagnosed with CAH (47% vs 53% male). Median days to positive screen was 6 and age at diagnosis was 5 days (range, 0-30 days) and 6 days (range, 0-13 days) in un- screened and screened populations, respectively. In unscreened newborns, 55% required transport to a tertiary care hospital, 85% required hospitalization, and 35% required a fluid bolus compared with 29%, 29%, and 12% in screened infants, respectively. The cost of care was $33 770 per case in unscreened vs $17 726 in screened new- borns. In the screened cohort, the incremental cost-effectiveness ratio was $290 in the best case analysis and $4786 in the base case analysis, per hospital day avoided. ConclusionsCompared with unscreened newborns, those screened for CAH were less likely to require medical transport and had shorter hospital stays. Screening led to a decrease in hospitalization costs. Although screening did not result in cost savings, it was assessed to be cost effective considering the clinical benefits and incremental cost-effectiveness ratio. (J Pediatr 2020;220:101-8).

Congenital adrenal hyperplasia (CAH) is a group of autosomal-recessive conditions caused by an enzymatic defect in the adrenal gland leading to impaired cortisol synthesis. In Canada and the US, the incidence is estimated to be 1:15 000.1 More than 90% of cases result from a deficiency of 21-hydroxylase, an enzyme required for the synthesis of cortisol and aldosterone leading to an accumulation of steroid precursors, including 17a-hydroxyprogesterone (17OHP). CAH is subdi- vided into the salt wasting variant, defined by insufficient aldosterone production, and the simple virilizing variant, character- ized by adequate aldosterone production, with a frequency of 75% and 25%, respectively.2CAH may present in a salt wasting crisis, marked by dehydration, hyponatremia, hyperkalemia, and potentially shock. These crises generally occur in the first month of life and may be fatal if not treated promptly.3,4 In the US, newborn screening (NBS) for CAH is currently performed in all states.5In Canada, 5 provinces and at least some regions of all 3 territories include CAH in their NBS programs. Several large studies have corroborated that screening leads to earlier diagnosis of CAH, particularly for males who lack the genital ambiguity that is typically easily identifiable in females.6-9 Despite this evidence, certain regions have left CAH out of their NBS programs, most notably the United Kingdom.10Reasons include the high rate of false positives in premature newborns and the limited benefits of testing for females.11,12Determining whether screening for CAH is cost effective may help NBS programs to make informed decisions as to whether the disease should be added to their panel. However, there are few published data on the cost efficacy of this screen.13-15 The recent clinical practice guidelines for CAH highlight the paucity of knowl- edge in this field.16The 2 studies cited had strikingly different results of

$20 000 and $255 700 - $292 000 per quality-adjusted life- year, leaving it unclear as to whether screening for CAH is cost effective.13,15 In British Columbia (BC), CAH was added to the NBS program in 2010. Through this study, we sought to evaluate the clinical impact of screening for CAH and the cost effec- tiveness by comparing cohorts of screened and unscreened newborns. We hypothesized that screening would result in clinical benefits and would be cost effective.

Methods BC Children's Hospital is the only tertiary care hospital in the province of BC and is located in Vancouver, Canada. The di- vision of endocrinology at the hospital is contacted by the NBS laboratory for every positive CAH screen. The endocri- nologists at BC Children's Hospital provide care to the ma- jority of patients with CAH, although a small number of patients are managed by community endocrinologists.

NBS Program This program covers BC, as well as the Yukon Territory (72 hours) and birth weight (2500 g). The second-tier test uses the same NBS card and measures 17OHP, cortisol, androstenedione, 11- deoxycortisol, and 21-deoxycortisol via tandem mass spec- trometry (modified from Janzen et al).17Cut-off values for a positive screen over the majority of the study period were based on the algorithm suggested by Janzen et al in 2007, us- ing absolute 17OHP levels, and the ratio of (17OHP + 21- deoxycortisol)/cortisol.17In April 2017, the ratio was changed to 17OHP/11-deoxycortisol to reduce false positives from premature infants with nonspecific low cortisol levels. When the second test is above cut-off values, the newborn screen is deemed positive, and the endocrinologist on call at BC Children's Hospital is contacted. Subsequently, the endocrinologist contacts the patient's primary care provider, who, in turn communicates with the family. Depending on the clinical stability and location of the newborn, the child is either brought into a local hospital for review by a pediatri- cian or family physician, or sent directly to BC Children's Hospital for an endocrinology consult, typically within 24 hours of a positive NBS result. A serum 17OHP, cortisol, and electrolytes are drawn at that time.

Study Methodology This was an ambispective cohort study (including both retro- spective and prospective components) and was approved by BC Children & Women's Hospital Clinical Research Ethics Boards (H10-03225). Screening for CAH began in November 2010. Data were collected retrospectively on an unscreened cohort of infants diagnosed with CAH and followed by the BC Children's Hospital Division of Endocrinology from 1988 to 2008. From November 2010 to March 2018, a screened cohort of all newly diagnosed cases of classic CAH were recruited to the study and clinical data were collected prospectively with written, informed consent from the fam- ilies. When involved in patient care, community endocrinol- ogists also contributed to data collection. Clinical data were collected from electronic and paper re- cords. Age at diagnosis was defined as the age at the time of the first endocrine consult or telephone call where medical advice was provided. In the screened cohort, we recorded the time from birth to reporting of the positive screen (referred to as age at time of positive screen). The recall rate was defined as true-positive plus false-positive cases, divided by the total number of newborn screens performed.

Statistical and Economic Analyses The unscreened cohort and screened cohort were compared using descriptive statistics. Variables were compared usingt tests andc2tests for linear and categorical variables, respec- tively. Costs to the health system included the NBS, patient trans- fers to BC Children's Hospital (via ambulance or plane), hos- pitalization, and inpatient or outpatient consultation with the endocrinologist. Specific costs related to investigation of cases (ie, imaging, further blood tests) and treatment were not included. The cost of tier 1 screening included 170HP kits, Autodelfia instrument, and personnel time, and tier 2 screening included reagents, Tandem mass spec- trometry (XEVO, Bellevue, Washington) instrument and personnel time. For false-positive cases, costs included the cost of serum steroid levels from a venipuncture sample

Table I. Infant demographics and physical examination and investigations at presentation Variables Screened cohort (n = 17) Unscreened cohort (n = 40) P value Subject demographics Male sex 8 (47) 21 (53) 787 Reason for suspected CAH Ambiguous genitalia 6 (35) 19 (48) 289 Family history 1 (6) 9 (22) <.001 salt wasting crisis positive cah screen n abnormal electrolytes age at time of diagnosis for males fluid bolus .005 physical examination and investigations presentation systolic blood pressure diastolic .047 ug .018 cortisol .695 sodium meq mmol potassium .302 data are number or median bolded values significant the level sample size in screened unscreened respectively: bp iii. comparing financial costs cases vs group total no. days average frequency consults cost incremental variables use unit trips case inpatient hospitalization any neonatal icu general ward both pediatric outpatient consultation endocrine consult mode hospital transfers transfer plane road ambulance sum tt infant transport team. children hospitalized i weighted length stay icu. minus savings per case.table iv. model input screening base range epidemiologic incidence probability death newborns identified with na test characteristics sensitivity tier fp health facility-level resource admission canadian dollars year costing direct medical care specimen repeat bloodspot card ambulatory endoconsultation nonmedical outcomes mean false not applicable. plus transferred ambulance.table v. cost-effectiveness analysis classic only day avoided scenarios base-case best worst iii probabilistic one-way scenario to represents most favorable such as: highest specificity lowest costs. approach address uncertainties across all parameters applied using monte carlo simulations treeage pro software williamstown mas- sachusetts confirmed phospscreen psenst t1 pt1abnormal present normal o ti healthy child pfalsepositive decision phospunscreen figure tree analytic screening. screened.hospitalized peenst t-2 pt2abnormal il pt1 ive pfalsepositive_12 pfalsepositive_t1 t2 rate screened.table ii. male demographics cohort reason suspected ambiguous genitalia family history ohp>