Plb = 582
Notes : This table represents the pivotal/registrational trials for these oral PPA agents but does not include all studies identified in the literature review.
Abbreviations : AE, adverse event; BID, twice a day; CHD, congenital heart disease; CTD, connective tissue disease; D, diarrhea; DC, discontinuation; FC, functional class; H, headache; IPAH, idiopathic pulmonary arterial hypertension; N, nausea; NR, not reported; PAH, pulmonary arterial hypertension; Plb, placebo; Selex, selexipag; TID, three times a day; Trep, treprostinil; 6MWD, 6-minute walking distance.
The FDA-approved indication for selexipag is for treatment of PAH (World Health Organization [WHO] Group 1) to delay disease progression and reduce the risk of hospitalization. 18 This reflects findings from GRIPHON, as selexipag significantly reduced the risk of morbidity and mortality events versus placebo by 40%, 13 and resulted in a 30% risk reduction for the secondary endpoint, risk of death or hospitalization due to PAH worsening, compared with placebo (hazard ratio [HR]: 0.70; 95% confidence interval [CI]: 0.54, 0.91); 87.4% of the events for this endpoint were PAH-related hospitalizations. 13 In GRIPHON, time from diagnosis was ≤6 months in 34.9% of patients and >6 months in 65.1% of patients. The value of earlier initiation of selexipag after diagnosis (≤6 months versus >6 months) has been established in a post hoc analysis of the GRIPHON trial; patients who initiated selexipag earlier experienced a more pronounced effect on the time to first disease progression event than those who initiated later (HR: 0.45; 95% CI: 0.33, 0.63, and HR: 0.74; 95% CI: 0.57, 0.96, respectively; P = 0.0219 for interaction). 19
Oral treprostinil is indicated by the FDA for the treatment of PAH (WHO Group 1) to delay disease progression and improve exercise capacity. 20 Oral treprostinil was studied in a series of randomized, prospective, placebo-controlled clinical trials (the “FREEDOM” trials). Six-minute walk distance (6MWD) at week 12 was the primary endpoint in the FREEDOM-M trial. It showed a significant benefit compared with baseline values (median Hodges-Lehmann treatment effect of 23.0m [95% CI, 4–41 m; P = 0.0125]), leading to FDA approval of oral treprostinil for use as a monotherapy to improve exercise capacity in PAH. 15 Trials of oral treprostinil added to background therapy (FREEDOM-C and FREEDOM-C2) failed to demonstrate a significant improvement in the primary endpoint, 6MWD. 16 , 17 The primary endpoint of FREEDOM-EV was time to first adjudicated clinical worsening event. In FREEDOM-EV, 90 (26%) participants in the oral treprostinil group experienced a clinical worsening event compared with 124 (36%) of placebo participants (HR: 0.74; 95% CI: 0.56, 0.97; P = 0.028). The treatment-attributable difference in clinical worsening was driven by reduced incidence of disease progression in the oral treprostinil group (HR 0.39; 95% CI 0.23, 0.66; P < 0.001). 14 Findings from FREEDOM-EV expanded the oral treprostinil FDA label to include delay in disease progression. 20
GRIPHON was not powered to determine survival outcomes, and no statistical difference in the number of deaths among patients receiving oral selexipag (17.4%) was observed versus placebo (18.0%). 13 GRIPHON mortality data are difficult to interpret because of treatment switching following a non-fatal primary endpoint event, with many patients switching from placebo to oral selexipag. 13 Post hoc analysis of the FREEDOM-EV study found that mortality was lower at study closure in patients receiving oral treprostinil versus placebo (11% vs 17.4%, respectively; P = 0.0324). 21 However, this finding is difficult to interpret because mortality was similar between oral treprostinil and placebo at the end of randomized treatment (4.9% vs 5.2%, respectively, P = 0.9781) or open-label extension study (8.7% vs 12.2%, respectively, P = 0.43), and death status was unknown for 11% of the original FREEDOM-EV population. 21
Survival outcomes in longer term open-label studies for progressive conditions such as PAH can be impacted by variation in subsequent treatments. Long-term follow-up of patients who received selexipag in the placebo-controlled GRIPHON study and the open-label extension study showed that Kaplan–Meier estimates of overall survival at 1, 2, 5, and 7 years were 92%, 85%, 71%, and 63%, respectively. 22 Long-term follow-up of patients who received oral treprostinil in the placebo-controlled FREEDOM-EV and open-label extension study showed Kaplan–Meier estimates of overall survival at 1, 3, and 5 years were 96%, 88%, and 79% versus 95%, 80%, and 70% for placebo, respectively. 23 It is not possible to directly compare survival data between GRIPHON and FREEDOM-EV due to differences in background therapy (ie, 32.5% of patients in GRIPHON received dual-combination PAH treatment, while all patients in FREEDOM-EV received PAH monotherapy); 19 , 21 and function class with a greater proportion of FC III patients in GRIPHON compared with FREEDOM-EV (52.5% vs 33.9% respectively).
Mortality outcomes are difficult to determine for oral PPAs due to the absence of comparative data, 22–24 and the short duration of clinical trials. 13–15
Based on 2022 ESC/ERS guidelines, initial triple oral combination therapy with oral PPAs is not recommended but plays a role for patients who present at intermediate-low risk of death while receiving ERA or PDE5i therapy. 6 Sequential triple therapy with selexipag is supported by post hoc analysis of patients on dual combination background therapy in GRIPHON. 24 TRITON assessed initial triple combination with selexipag versus initial dual combination with selexipag over 26 weeks; although no significant difference in pulmonary vascular resistance was observed, exploratory analyses suggested a possible signal for improved long-term outcomes. 25 Data supporting the use of oral treprostinil in triple combination therapy is lacking; additional studies will be required to evaluate the efficacy of adding oral treprostinil to dual combination therapy (see Table 2 ). 16 , 17
As illustrated in Figure 2a , real-world evidence indicates that, overall, oral selexipag is predominantly used within a triple combination regimen (31.0% to 88.0% of patients receiving selexipag); 26 , 27 newly diagnosed patients more often initiate selexipag treatment with a dual combination regimen with an ERA or a PDE5i. 26 As illustrated in Figure 2b , oral treprostinil is equally used as a monotherapy or within a dual/triple-combination regimen with an ERA and/or PDE5i. Studies from the ADAPT registry describe oral treprostinil use within triple combination (33.3% to 45.7% of patients receiving oral treprostinil). 28 , 29 However, neither of the early oral treprostinil trials, FREEDOM-C and FREEDOM-C2, demonstrated an improvement in 6MWD with the addition of oral treprostinil to double oral combination therapy (see Table 2 ). 16 , 17
Real-world evidence studies describing proportions of patient using selexipag and oral treprostinil within a combination regimen. ( a ) illustrates the proportions of patients taking selexipag as a monotherapy or within dual- or triple-combination regimens in reported studies; ( b ) illustrates the proportions of patients taking oral treprostinil as a monotherapy or within dual- or triple-combination regimens in reported studies. a This value has been calculated based on patient baseline characteristics, assuming the background therapy has been supplemented with one additional therapy rather than replaced.
As summarized in Table 3 , both oral PPAs require initial titration. Individualized dose titration is required for oral PPAs to identify an upper maintenance dose that avoids unmanageable side effects. 31
Selexipag and Oral Treprostinil Dosing in RCTs and Clinical Practice
Selexipag | Oral Treprostinil | ||||
---|---|---|---|---|---|
GRIPHON a | Up-titration by 200 µg BID per week until maintenance dose reached; if AEs occur, decrease by 200 µg in both daily doses Week 12: 23% of patients at 200–400µg BID; 31% of patients at 600–1000µg BID; 43% of patients at 1200–1600µg BID | Freedom-M c | Initiated 1.0 mg BID; dose escalation 0.25 to 0.5 mg BID every 3 days to maximum of 12 mg BID Week 12: 3.6 mg BID = 7.2 mg TDD | ||
Freedom-C b | Initiate 0.5 mg BID; changed to 0.25 mg BID Week 16: 3.0 mg BID = 6.0 mg TDD | ||||
Freedom-C2 c | Patients on background ERA and/or PDE5i initiated 0.25 mg BID; dose escalation 0.25 mg BID for 3 days; after 4 weeks dose escalations of 0.25 or 0.5 mg BID every 3 days Week 16: 3.1 mg BID = 6.2 mg TDD | ||||
Freedom-Ext b | Year 1: 7 mg TDD Year 2: 8 mg TDD Year 3: 8.25 mg TDD | ||||
Freedom-EV b | Daily up-titration in 0.125 mg increments for first 4 weeks then 0.25 mg daily to maximum of 12 mg (TID dosing with food) Week 24: Median 3.56 mg TID = 10.68 mg TDD | ||||
SPHERE Registry b (n = 500) | 1200 µg BID Median time to maintenance dose: 8.1 weeks | El-Kersh et al, 2020 b (n = 2255) | TID dosing (85% patients, n = 1917) Month 3: 5.1 mg TDD Month 6: 8.4 mg TDD Month 12: 10.8 mg TDD Month 18: 12.0 mg TDD Month 24: 12.2 mg TDD Month 36: 12.9 mg TDD | BID dosing (15% patients, n = 338) Month 3: 2.3 mg TDD Month 6: 4.3 mg TDD Month 12: 5.4 mg TDD Month 18: 5.4 mg TDD Month 24: 5.4 mg TDD Month 36: 6.4 mg TDD | |
Kung et al, 2012 c (n = 2490) | Day 83 (~12 weeks): 15.6% patients at 200–400 µg BID; 33.9% patients at 600–1000 µg BID; 50.5% patients at 1200–1600 µg BID | ||||
N/A | Rahaghi et al, 2017 b | Slow titration in 0.125 mg dose increments with 6–8 hours between doses in “stair-step” titration Month 3: Target dose: 4 mg TID = 12 mg TDD Month 6: Target dose:6 mg TID = 18 mg TDD Month 12: Target dose: 8 mg TID = 24 mg TDD |
Notes : a Percentage of patients at each dose stratification level; b median dose; c mean dose; d median time to individualized maintenance dose was measured in the first 500 patients; e TDD was calculated by multiplying individual dose by dosing frequency.
Abbreviations : AE, adverse event; BID, twice a day; ERA, endothelin receptor antagonist; N/A, not applicable; PDE5i, phosphodiesterase 5 inhibitor; RCT, randomized controlled trial; TDD, total daily dose; TID; three times a day.
GRIPHON describes the titration regimen for selexipag of 200 µg BID increased in increments of 200 µg BID weekly until side-effects cannot be managed by adequate treatment or to the maximal dose of 1600 µg BID. Across all doses, selexipag demonstrated a reduction in the risk of morbidity and mortality, supporting individual-dose titration. For patients experiencing a prostacyclin-associated side effect that is unmanageable, the dose is reduced by 200 µg. 13
Real-world evidence (SPHERE registry) suggests that most patients (87.8%) receiving selexipag titrate more slowly than the label recommended 200 µg BID weekly, with over one-fifth of patients (21.6%) titrating at 200 µg BID every two weeks. 32 The majority of studies that reported selexipag titration described completing titration over 7–9 weeks; 33 , 39 , 40 SPHERE registry data reported a median time from selexipag initiation to an individualized maintenance dose of 8.1 weeks, 32 , 40–42 and a median maintenance dose of 1200 µg BID (n = 496). 40 SPHERE registry data indicate that the average maintenance dose continued to increase and began to stabilize at 6 months. At 18 months, 77.6% of patients enrolled in SPHERE completed the study; of the 22.4% who discontinued early, 11.4% discontinued due to adverse events (AEs) related to PAH progression and 11.2% discontinued due to AEs not related to progression (7.2% attributable to selexipag). 32
Across the FREEDOM trials, oral treprostinil titration and dosing evolved with variation in target doses ( Table 3 ). These variations arose from changes in the available tablet strength, adoption of three times daily (TID) versus BID dosing, and expert panel recommendations. 15–17 , 20 The FREEDOM-EV trial describes a higher dose than earlier trials, with daily up-titration in 0.125 mg increments for the first 4 weeks, then 0.25 mg increments daily to a maximum of 12 mg (TID dosing with food), achieving an upper median dose of 3.56 mg TID by week 24. 23
The minimum effective dose for oral treprostinil is not clear from the literature; however, the literature indicates a dose-dependent treatment effect.
The target dose across FREEDOM studies varied, as reflected in real-world studies ( Table 3 ). A study using specialty pharmacy service shipment records indicated that in the overall TID dosing group (n = 1200), the median total daily dose (TDD) varied from 5.3 mg to 10.8 mg between 3 and 18 months. In the BID dosing group (n = 400), median TDD increased from 2.5 mg to 5.5 mg between 3 and 18 months. 45 More prevalent use of TID has improved tolerability, leading to higher TDDs.
Twenty-two studies were identified reporting safety findings for selexipag and 8 studies for oral treprostinil.
The most commonly reported AEs for oral selexipag in GRIPHON were headache (65%), diarrhea (42%), nausea (34%), pain in jaw (26%), and vomiting (18%) (Table 2). 13 , 15 In FREEDOM-M, FREEDOM-C, and FREEDOM-C2 OLE, the most frequently reported AEs were headache (71%), diarrhea (55%), nausea (46%), flushing (35%), vomiting (21%), and pain in jaw (25%). 17 Findings in FREEDOM-EV were similar. 21
EXPOSURE (observational study) found that selexipag maintenance treatment at the individualized dose was well tolerated in clinical practice. 46 A registry study of oral treprostinil found that the rate of AEs decreased over time, with a large reduction in reported rates of prostacyclin-related AEs by month 6. 30
PAH is characterized by frequent hospitalizations and high medical costs. 5 Eight studies were identified that describe economic outcomes for selexipag, including two comparing outcomes with oral treprostinil. No head-to-head clinical trials have compared the impact of these two oral PPAs on hospitalization.
Although oral treprostinil and selexipag both target the prostacyclin pathway, these medications are not clinically equivalent and have different treatment effects on specific health outcomes (eg, hospitalization) and further differences in safety profiles, titration, and maintenance management. Efficacy is also variable depending on the number of concomitant PAH therapies (one vs two) and dose level (individualized dose vs need to maximize dose). Population health decision-makers should strive to ensure that all PAH therapies are made available for patients given the risk of severe negative outcomes, including hospitalization and death in patients with poorly controlled disease, enabling expert clinicians to individualize therapy, including the choice of PPAs based on their experience, available evidence, and guidelines. To optimize outcomes with oral PPAs, careful management of initial side-effects is essential to complete titration and initiate maintenance treatment successfully. Patient tolerability is likely to improve, as side-effects are reported to decrease over time. 44
The cost for selexipag is fixed and predictable as it does not vary by dose. Oral treprostinil cost is subject to variation by dose, with increasing costs associated with higher maintenance doses, and so it is difficult to predict and model annual costs incurred with this treatment. Treatment costs should not be viewed in isolation for oral PPAs, as this is a rare fatal disease associated with significant burden on patients and the healthcare system. Oral PPAs deliver many economic benefits, including reduced healthcare costs, reduced hospitalization rates (selexipag), and delayed disease progression, offsetting costs associated with use of these medications.
Prior authorizations, step-edits, and quantity limits are common for oral PPAs due to the high treatment costs. Utilization management strategies that are too restrictive may delay initiation of therapy, resulting in poorer outcomes. Indeed, prior authorizations for life-saving medications may be a misplaced strategy when the delay can lead to worsening outcomes or incremental costs, or both. Prompt PPA therapy initiation has been associated with improved or stabilized clinical status for this rapidly progressing disease with a high mortality rate. 19
ESC/ERS guidelines recommend risk assessment every 3 to 6 months, which serves as an early signal for treatment escalation with an oral PPA. Population health decision-makers may implement risk assessments to detect patients at risk of worsening and treatment escalation.
Studies conducted on fewer than 20 patients were not included in the evidence synthesis. The heterogeneity of clinical trial design (endpoint definition, patient population – etiology, stage of disease progression) are limitations when comparing outcomes across the clinical studies describing in this literature review. The findings of the literature review reflect publications up to June 2022 and do not include subsequent publications.
The 2022 ESC/ERS guidelines describe the addition of selexipag for patients receiving PDE5i and/or ERA and oral treprostinil for patients receiving monotherapy (PDE5i or ERA) who are at risk of progression. This TLR provides population health decision-makers with important insights to evaluate the distinct profiles of oral PPA treatment options and to inform formulary and coverage decisions for the treatment of patients, with PAH ensuring access to critical PAH therapies.
This study was funded by Janssen USA and conducted in partnership with Avalere Health, UK. Janssen provided input into the initial study concept and design and Avalere Health led the study execution with input and review from the authoring team.
Dr Charles Burger reports personal fees from Janssen, personal fees from INSMED, personal fees from Merck, and non-financial support from United Therapeutics, during the conduct of the study. Yuen Tsang is a former employee and owns stock in Johnson & Johnson. Dr Marie Chivers, Nikki Atkins and Ms Riya Vekaria report employment with Avalere Health which was in receipt of payment from Janssen for this element of the study. Dr Gurinderpal Doad and Dr Sumeet Panjabi are employees and stockholders of Johnson & Johnson, the company that markets oral selexipag. The authors report no other conflicts of interest in this work.
Orphanet Journal of Rare Diseases volume 19 , Article number: 292 ( 2024 ) Cite this article
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Ankyrin repeat domain containing-protein 11 (ANKRD11), a transcriptional factor predominantly localized in the cell nucleus, plays a crucial role in the expression regulation of key genes by recruiting chromatin remodelers and interacting with specific transcriptional repressors or activators during numerous biological processes. Its pathogenic variants are strongly linked to the pathogenesis and progression of multisystem disorder known as KBG syndrome. With the widespread application of high-throughput DNA sequencing technologies in clinical medicine, numerous pathogenic variants in the ANKRD11 gene have been reported. Patients with KBG syndrome usually exhibit a broad phenotypic spectrum with a variable degree of severity, even if having identical variants. In addition to distinctive dental, craniofacial and neurodevelopmental abnormalities, patients often present with skeletal anomalies, particularly postnatal short stature. The relationship between ANKRD11 variants and short stature is not well-understood, with limited knowledge regarding its occurrence rate or underlying biological mechanism involved. This review aims to provide an updated analysis of the molecular spectrum associated with ANKRD11 variants, investigate the prevalence of the short stature among patients harboring these variants, evaluate the efficacy of recombinant human growth hormone in treating children with short stature and ANKRD11 variants, and explore the biological mechanisms underlying short stature from both scientific and clinical perspectives. Our investigation indicated that frameshift and nonsense were the most frequent types in 583 pathogenic or likely pathogenic variants identified in the ANKRD11 gene. Among the 245 KBGS patients with height data, approximately 50% displayed short stature. Most patients showed a positive response to rhGH therapy, although the number of patients receiving treatment was limited. ANKRD11 deficiency potentially disrupts longitudinal bone growth by affecting the orderly differentiation of growth plate chondrocytes. Our review offers crucial insights into the association between ANKRD11 variants and short stature and provides valuable guidance for precise clinical diagnosis and treatment of patients with KBG syndrome.
The ANKRD11 gene (OMIM#611192) is mapped to human chromosome 16q24.3 and encodes an ankyrin repeat domain-containing protein 11 that belongs to a member of the ankyrin repeats-containing cofactor family (ANCO). It is relatively conserved across species and ubiquitously expressed in multiple organs and tissues, particularly in the brain and ovary [ 1 , 2 ]. The ANKRD11 protein, consisting of 2,663 amino acid residues, structurally includes the ankyrin domain (ANK), transcriptional activation domain (AD), transcriptional repression domains (RD1 and RD2), and multiple putative nuclear localization signals (NLSs) [ 3 ]. The N-terminal ANK domain follows the canonical helix-loop-helix-β-hairpin/loop configuration and is comprised of five consecutive ankyrin repeat motifs. Each motif contains a 33-residue sequence and facilitates protein-protein interaction to coordinate subsequent transcriptional regulatory processes [ 4 , 5 , 6 ]. The ANKRD11 protein binds to the conserved N-terminal Per-Arnt-Sim (PAS) region of p160 coactivator via its ANK domain, concurrently, recruits histone deacetylases (HDACs) through its RD1 or RD2 domain. When p160 coactivator binds to the hydrophobic cleft within the C-terminal ligand-binding domain (LBD) of nuclear receptors (NRs) through its LXXLL motifs, the assembly of p160/ANKRD11/HDACs complex suppresses NRs-mediated ligand-dependent transactivation [ 7 ]. The ANKRD11 protein also interacts with the N-terminal 84 amino acids of ADA3 (alteration/deficiency in activation 3), which is an essential part of the p300/CBP [cAMP-response-element binding protein-binding protein]-associated factor (P/CAF) complex. This complex connects coactivators to histone acetylation and basal transcription machinery, resulting in the recruitment of the P/CAF complex and the specific regulation of ADA3 coactivator in a transcription factor-dependent manner [ 8 ]. Moreover, the ANKRD11 protein is capable of amplifying p53 activity through the enhancement of P/CAF-mediated acetylation [ 6 ]. Overall, the ANKRD11 protein, through its various functional domains, collectively facilitates the formation of a molecular bridge between coactivators or corepressors and histone deacetylases (HDACs) or histone acetyltransferases (HATs), thereby precisely regulating the transcription of target genes.
Initially, ANKRD11 has been recognized as a tumor suppressor gene in breast cancer due to its location within the chromosomal region 16q24.3, which is widely acknowledged for its frequent loss of heterozygosity (LOH) among patients suffering from breast cancer [ 9 , 10 ]. Under normal physiological conditions, the estrogen receptor (ER)/amplified in breast cancer 1 (AIB1)/ANKRD11/HDACs or transcriptional enhanced associate domain (TEAD)/yes-associated protein (YAP)/AIB1/ANKRD11 complex functions to suppress the transcriptional activation of oncogenes in breast cancer [ 11 , 12 ]. However, aberrant DNA methylation of three CpGs within a 19-base pair region of the ANKRD11 promoter leads to its down-regulation, thereby disrupting the assembly of the complex and consequently promoting breast tumorigenesis [ 13 ]. ANKRD11 haploinsufficiency was later identified in KBG syndrome (KBGS) patient-focused clinical and molecular studies, confirming the dominant pathogenic mechanism responsible for this condition (OMIM#148050). KBGS was initially reported by Herrmann and colleagues in 1975 and characterized by macrodontia of the upper central incisors, distinctive craniofacial findings, postnatal short stature, skeletal anomalies and, neurodevelopmental disorders, sometimes with seizures and electroencephalogram (EEG) abnormalities [ 14 , 15 , 16 ]. Patients harboring ANKRD11 pathogenic variants exhibit overlapping features between KBGS and Cornelia de Lange syndrome or Coffin-Siris-like syndrome, particularly neurological and skeletal anomalies [ 17 , 18 ]. KBGS typically presents with a wide range of phenotypic manifestations, each varying in severity [ 19 ]. The biological function and cellular mechanism of ANKRD11 variants associated with the KBGS features have garnered significant interest and attention within the academic community. Previous study has established the pivotal role of the ANKRD11 gene in proliferation, neurogenesis and neuronal localization of cortical neural precursor cells by utilizing a Yoda mice model harboring a point mutation within the ANKRD11-HDAC interaction region, and the underlying mechanism was linked to alterations in the acetylation patterns of specific lysine residues (H3K9, H4K5, H4K8, H4K16) on the target genes regulated by ANKRD11 [ 20 ]. Further investigation has revealed that ANKRD11 regulates pyramidal neuron migration and dendritic differentiation of mouse cerebral cortex through the coordination of P/CAF to facilitate the acetylation of both p53 and Histone H3, which subsequently leads to the activation of brain-derived neurotrophic factor (BDNF)/tyrosine receptor kinase B (TrkB) signaling pathway [ 21 ]. Moreover, Roth and their colleagues developed a heterozygous neural crest-specific ANKRD11-mutant mice model, and revealed that multiple ossification centers in the middle facial bone of mice failed to expand or fuse properly, leading to a significant delay in bone maturation and a severe restriction in bone remodeling [ 22 ]. Recent research has uncovered that conditional knockout of the ANKRD11 gene within murine embryonic neural crest leads to severe congenital cardiac malformations and the underlying mechanism was linked to a reduction in Sema3C expression levels, coupled with diminished mTOR and BMP signaling within the cardiac neural crest cells of the outflow tract [ 23 ]. Based on the accumulating evidence from ongoing research into gene functions, the relationship between ANKRD11 pathogenic variants and the clinical features of KBGS is better understood than ever before. However, the role of ANKRD11 variants in inducing short stature has not received sufficient attention, particularly regarding its frequency of occurrence and the underlying biological mechanisms of action.
We investigated publicly available online resources including published literature in Web of Science, PubMed, Google Scholar, and Wanfang database by searching keywords “KBGS”, “ANKRD11”, “Short stature” and “Intellectual disability” as well as genetic testing records in ClinVar database between July 2011 and March 2024. In this review, we included a total of 78 published papers that encompassed cohort studies, case series or single-case reports, and gathered 583 ANKRD11 variants, which were classified as pathogenic or likely pathogenic according to the American College of Medical Genetics and Genomics (ACMG)-Association for Molecular Pathology (AMP) guideline (Supplemental material 1 ). Among these variants, 202 were reported in published papers and 381 were described in the ClinVar database. Certain large deletions or duplications of the ANKRD11 gene were not considered in this analysis, as the complexity of their impact on the amino acid sequence of the encoded protein posed challenges for interpretation. We have also excluded patients with 16q24.3 microdeletions, 16q24.3 microduplications and dual molecular diagnosis involving ANKRD11 and/or flanking genes, as the role of other genes in contributing to the height phenotype remains uncertain. Furthermore, hotspot variants within ANKRD11 were analyzed in 838 patients, comprising 457 derived from the literature and 381 derived from the ClinVar database (Supplemental material 2 ). ANKRD11 allele frequency below 1% in the general poulation was obtained from gnomAD ( http://gnomad-sg.org/ ). 245 patients were reported to have height data, of which 112 had a height SDS. The differences in height SDS among patients with short stature carrying various ANKRD11 variants were further analyzed (Supplemental material 3 ). Data was described as mean ± SDS, and analyzed with one-way analysis of variance (ANOVA) followed by Tukey’s multiple comparisons test. A significant difference was considered when the p -value was less than 0.05.
Since ANKRD11 was identified as the causal gene for KBGS in 2011, more than 340 KBGS patients have been reported worldwide [ 24 ]. Considering the variant data documented in the ClinVar database, it is projected that the number of patients with ANKRD11 variants exceeds 800. Despite the global prevalence of KBGS worldwide remaining unknown, its prevalence is underestimated due to a limited understanding of the disease phenotype and molecular underpinning. Consequently, establishing the spectrum of genetic variation in the ANKRD11 gene holds the promise of not only enhancing our understanding of disease’s pathogenesis but also enabling clinicians to render a precise molecular diagnosis for KBGS. A total of 583 ANKRD11 variants encompassed nearly the entire sequence of amino acids [ 1 , 2 , 15 , 17 , 18 , 19 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 ] (Fig. 1 ). All identified ANKRD11 variants were present in a heterozygous state, aligning with early embryonic lethality of Yoda mice observed in homozygotes, as demonstrated by Barbaric et al. [ 3 ]. This review encapsulates the up-to-date molecular landscape of ANKRD11 variants, nevertheless, in light of the continual discovery of patients with newly identified ANKRD11 variants, it needs to be supplemented and updated in time.
Molecular spectrum of ANKRD11 variants. A total of 583 ANRKD11 (likely) pathogenic variants were collected through literature review and ClinVar database. ANKRD11 variants were shown by frameshift, nonsense, missense, splice and inframe deletion, respectively. ANK: ankyrin repeat domain, RD1: repression domain 1, AD: activation domain, RD2: repression domain 2
All ANKRD11 variants in the map were classified into five types: frameshift variants (340/583, 58.32%), nonsense variants (163/583, 27.96%), missense variants (54/583, 9.26%), splicing variants (21/583, 3.60%) and inframe deletion variants (5/583, 0.86%) (Fig. 2 ). Variants occurring in ANK, RD1, AD, RD2 and non-domain region accounted for 3.60%, 10.12%, 9.09%, 15.10% and 62.09% of the total variant pool, respectively (Fig. 2 ). Multiple putative NLSs within the interval between the RD1 and AD regions were categorized as part of the non-domain segment, primarily due to the absence of definitive and evidence-based localization data [ 3 , 5 , 15 , 48 ]. Specific variants occurring within these NLSs may impair the nuclear targeting of the ANKRD11 protein. Notably, the most common variants were frameshift and nonsense variants, which give rise to prematurely truncated forms of the ANKRD11 protein. 62.96% (34/54) of ANKRD11 missense variants were found to cluster within C-terminal RD2 region. The majority of these missense variants, particularly those impacting arginine residues, were reported to impair protein stability or transcriptional activity, however, they did not produce an obvious impact on the protein’s subcellular localization [ 61 , 66 ]. Additionally, alternative splicing events predominantly affected the C-terminal RD2 (13/21) and N-terminal region (8/21). It is not surprising that those affecting 5’ and 3’ splice sites are commonly implicated as the underlying cause of hereditary disorders [ 97 ]. Nonetheless, how these hypothesized splicing variants impact the encoded protein requires an in-depth examination of splicing patterns by cDNA analysis, and frequently involves a Mini-gene assay. Other types of ANKRD11 variants were relatively uncommon including p.Lys1347del, p.Thr2471_Gly2474del, p.Glu2524_Lys2525del, p.Q2350del, and p.R595_A2663delinsS. Interestingly, p.Lys1347del has been demonstrated to significantly disrupt the transcriptional activation of downstream p21 gene but did not influence the levels of ANKRD11 mRNA or protein [ 2 , 15 , 19 , 61 ]. Theoretically, protein-truncating variants (PTVs) cause a more detrimental effect on protein function compared to the consequences of amino acid deletions (≥ 1) and single amino acid substitution [ 98 , 99 ]. The impact of various types of genetic variants on the ANKRD11 protein function requires further investigation by a range of functional analyses.
The percentage of different types of ANKRD11 variants located in different functional domains. The pie chart indicates the percentage of variants within different domains. 10 X 10 dot plot represents the percentage of different variant types. The column shows the the proportion of five mutation types within different domains of ANKRD11. ANK: ankyrin repeat domain, RD1: repression domain 1, AD: activation domain, RD2: repression domain 2
Mutation rates vary significantly along nucleotide sequences such that variants often concentrate at certain positions called hotspots [ 100 ]. DNA sequences prone to variation are highly dependent of gene sequence and structure as well as its chromosomal location, such as GC-rich region, microsatellites, meiotic recombination, nonallelic homologous recombination, centromeric rearrangements, telomeres and subtelomeric regions, replication timing and common fragile sites [ 101 , 102 ]. Therefore, hotspot variants are indicative of the structural and functional properties of DNA sequence. Within the spectrum of ANKRD11 variants, over two dozen distinct variants have been identified in at least three patients. Beyond a few variants that have been vertically inherited within a single family, the majority of variants were discovered in multiple sporadic patients, underscoring the propensity for these genetic variants to arise independently in unrelated individuals. Four hotspot variants of ANKRD11 protein were observed including p.Glu461Glnfs*48, p.Lys635Glnfs*26, p.Glu800Asnfs*62 and p.Lys803Argfs*5 (Fig. 3 A). These four variants are frameshift variants generated by c.1381_1384delGAAA, c.1903_1907delAAACA, c.2395_2398delAAAG and c.2408_2412delAAAAA, respectively. Two additional prevalent frameshift variants were traced back to analogous genomic alterations including p.Asn725Lysfs*23 and p.Thr462Lysfs*47 arising from c.2175_2178delCAAA and c.1385_1388delCAAA, respectively. The propensity for short deletions within AAA-type-containing sequences may be associated with polymerase slippage events induced by tandem repeats, a well-established mechanism for indels [ 100 ]. Nonetheless, it should be highlighted that CCC-type-containing sequences exhibit a heightened vulnerability to this form of genetic variation [ 103 , 104 ]. RD2 domain located at the C-terminus of ANKRD11 seemed to be particularly vulnerable to a range of variant events in KBGS patients, with missense variants being notably prevalent (Fig. 3 A). Conversely, the missense variants occuring in RD2 domain were relatively rare in general population (Fig. 3 B). This was consistent with the results of in vitro cellular assays, which showed that missense variants occurring in the RD2 domain impaired the protein function of ANKRD11 [ 66 ]. Some frameshift and nonsense variants of ANKRD11 have been identified in general population, such as p.Glu2082Argfs*20, p.Ser2180Phefs*6, p.Glu1075* and p.Gln2507*, indicating a pattern of variable expressivity and incomplete penetrance associated with ANKRD11 variants [ 2 ]. Taken together, the presence of hotspot variants offers valuable insights into the inherent vulnerability of specific DNA sequence to abnormal DNA repair, replication, and modification or environmental exposures. These findings warrant in-depth exploration at the molecular level to unravel the underlying mechanisms and implications.
Frequency of ANKRD11 variants in a total of 838 KBGS patients ( A ) and ANKRD11 allele frequency in general population ( B ). ANKRD11 allele frequency below 1% in general poulation was obtained from gnomAD ( http://gnomad-sg.org/ ). The abscissa represents the full-length amino acid sequence of ANKRD11, and the ordinate represents the frequency
Frequency of occurrence of short stature in patients with ankrd11 variants.
Short stature is defined as height less than − 2 standard deviation (SD) or below the third percentile of corresponding mean height for age-, gender- and race-matched populations [ 105 , 106 ]. As widely recognized, height is a highly heritable characteristic, and is classically influenced by hundreds of common variants pinpointed by genome-wide association studies (GWAS) [ 107 , 108 ]. By comparison, the impact of rare and low-frequency monogenic variants on height is more pronounced, yielding a larger effect size compared to single nucleotide polymorphisms (SNPs) [ 109 , 110 ]. Finding new genes with rare deleterious variants relating to growth is of considerable significance. Case series and individual reports serve as valuable sources of evidence for investigating the frequency of occurrence of short stature among patients harboring ANKRD11 variants. In 121 patients reported with height SDS, a significant proportion, amounting to 48.76% (59/121), exhibited a height below the − 2 SDS (Fig. 4 A). This prevalence was observed with nearly equal frequency across genders, with female patients exhibiting a rate of 46.43% (26/56) and male patients exhibiting a rate of 49.02% (25/51). The height SDS of females and males were − 1.80 ± 1.27 and − 1.85 ± 1.28 SDS, respectively. Upon incorporating additional patients recorded with height percentile values into the analysis, the proportion of patients with short stature was found to be 47.35% (116/245). Moreover, while some patients did not exhibit short stature, their adult height SDS or growth percentile might be lower than expected if their genetic potential (mid-parental height) was taken into account. However, most studies did not report patients’ genetic potential for height, making it challenging to extract this specific information from the published literature. Overall, approximately half of the patients with ANKRD11 variants exhibited short stature, consequently, this characteristic stand as an important manifestation of KBGS attributable to ANKRD11 variants. Certainly, compared to other features, the incidence of short stature was less frequent than that of craniofacial anomalies (100%), dental anomalies (80%) and intellectual disability (77%) [ 48 ]. Notably, patients with ANKRD11 variants displayed a variable height phenotype ranging from as low as -4.9 SDS to as high as + 1.5 SDS. It can be ascribed to several factors, including genetic context of the gene, modified penetrance, variant type and variant location [ 111 , 112 ]. There was no significant difference in height SDS among patients with ANKRD11 variants located in different regions or with different ANKRD11 variant types ( p > 0.05) (Fig. 4 B&C). Previous investigation has revealed that terminations close to the C-terminus of the ANKRD11 protein tended to have less severe short stature, but the research did not yield a statistically significant difference or a clear trend in the severity of short stature among the various types of ANKRD11 variants [ 39 ]. The findings of the current study indicated that no genotype-phenotype correlation was established. Certainly, a limited number of patients with ANKRD11 variants across different domains present a significant constraint on this conclusion.
Distribution of gender and height SDS of patients having ANKRD11 variants ( A ) and comparison of height SDS of patients having ANKRD11 variants within different domain ( B ) or having different ANKRD11 variant types ( C ). ANK: ankyrin repeat domain, RD1: repression domain 1, AD: activation domain, RD2: repression domain 2
Functional variants in the ANKRD11 gene have been identified through exome sequencing or gene panels in multiple short-stature cohorts (Table 1 ). The frequency of pathogenic variants was estimated to be between 0.35% and 0.55% [ 43 , 68 , 79 , 113 ]. These variants were identified in patients initially diagnosed as having syndromic short stature, however, subsequent molecular diagnosis facilitated a more precise diagnosis of KBG syndrome. Syndromic short stature represents a phenotypic and genetically heterogeneous disease, and it accounts for a large part of the etiology of short stature. Considering the wide range of phenotypic manifestations and variable degree of severity, certain patients with short stature suffering from KBGS may not be accurately diagnosed in clinical practice. Consequently, it is likely that these patients harbor rare pathogenic variants in the ANKRD11 gene, which may elude detection and result in their classification within the vast and enigmatic group of short stature with undetermined etiologies. Genetic testing should be factored into precise diagnosis of syndromic short stature in the future. Based on previous studies estimating the occurrence of short stature at approximately 3% [ 114 , 115 , 116 ], the prevalence of ANKRD11 variants in the general population could be roughly calculated to be in the range of 0.0105–0.0165%. Nevertheless, given the limited sample sizes and the variability among different cohorts studied for short stature, the frequency of ANKRD11 variants remains uncertain and requires a more accurate assessment. This evaluation should ideally be conducted through large-scale population screenings, employing artificial intelligence-enhanced phenotyping in conjunction with genetic testing [ 117 ]. Despite the growing awareness and attention this condition has recently garnered in the clinical and genetic research communities, there remains a significant gap in the identification and management of KBGS patients. Therefore, the development of international consensus guidelines for the diagnosis of KBGS is of paramount importance.
In 1985, recombinant human growth hormone (rhGH) received approval from the US Food and Drug Administration (FDA) for the treatment of children with severe GHD. Since then, over the past nearly forty years, the application of rhGH has been progressively expanded to enhance the height outcomes in children with a variety of growth disorders, including chronic renal insufficiency (CRI), ISS, SGA without catch-up growth, Prader-Willi Syndrome (PWS), Noonan syndrome (NS), Turner syndrome (TS) and SHOX haploinsufficiency [ 118 , 119 ]. The advent of high-throughput sequencing technology has ushered in a period of rapid advancement in the field of genetics and genomics, and this progress has significantly broadened our capacity for diagnosing and treating conditions associated with short stature. We are now entering a transformative era characterized by molecular diagnosis and the tailoring of therapeutic interventions to the specific genetic makeup of individuals, including their responsiveness to rhGH therapy [ 120 ]. It has been observed that pathogenic variants in the aggrecan ( ACAN ), natriuretic peptide receptor 2 ( NPR2 ), and Indian hedgehog ( IHH ) genes, which are integral to growth plate development, have been consistently associated with a positive response to rhGH therapy [ 121 , 122 , 123 , 124 , 125 ]. In this review, we delineated the growth response observed in patients harboring ANKRD11 variants who received rhGH therapy (Table 2 ). The ages at initiation of rhGH treatment ranged from 5.2 to 14 years, and the treatment duration extended from 0.58 to 3 years. Following rhGH treatment, all patients exhibited varying levels of catch-up growth, as reflected by a range in Δ height SDS from 0.14 to 1.87. Among the nine patients, five showed a significant height improvement, reaching values above − 2 SDS ( -0.75 SDS for patient 3, − 0.7 SDS for patient 4, -1.86 SDS for patient 5, -1.8 SDS for patient 8 and − 1.91 SDS for patient 9). Most patients displayed either a good or moderate response to rhGH therapy. However, there was an exception with patient 3, a 7.9-year-old girl, whose height SDS only increased by 0.14 following a continuous treatment period of 0.58 years. Practically, a four-year-old girl form Australia with ANKRD11 variant (c.6472G > T, p.Glu2158*), showed no response to rhGH therapy [ 49 ]. The girl was not included in Table 2 due to the lack of height data. The potential existence of additional factors that may be contributing to the suboptimal response to rhGH remains uncertain.
Given the evidence suggesting that the ANKRD11 gene acts as a potential tumor suppressor due to its interaction with the p53 protein, particular attention should be paid to the safety profile of rhGH therapy, particularly oncogenic risks [ 126 ]. However, observational studies have reported no increased risk of mortality or the development of primary cancers among pediatric patients receiving rhGH treatment [ 127 , 128 , 129 ]. The implementation of cancer surveillance in patients clinically diagnosed as having KBGS due to ANKRD11 variants has been previously contemplated, and few patients were reported to develop malignant tumors [ 130 , 131 ]. Short stature is one of all KBGS phenotypes that can be effectively treated with growth-promoting drugs, but there are few patients receiving rhGH treatment. The approval and accessibility of rhGH therapy for KBGS may be limited in certain countries, which highlights the imperative for further investigation and research within this specialized domain. In alignment with the recommendations proposed by Reynaert et al. [ 58 ], we advocate for a more favorable stance towards the implementation of short-term rhGH therapy for ANKRD11 variant-induced KBGS patients with severe short stature.
Human longitudinal bone growth is persistently driven by the process of endochondral ossification within the epiphyseal growth plate that is characterized by three histologically distinct zones (resting, proliferative, and hypertrophic zones) throughout the stages of postnatal development [ 132 ]. As the slowly-cycling reserve cells, resting chondrocytes are maintained in a wingless-related integration site (Wnt)-inhibitory environment, and it contains a certain proportion of parathyroid hormone-related protein (PTHrP)-expressing skeletal stem-like cells producing rapidly proliferating columnar chondrocytes parallel to the direction of bone elongation [ 133 ]. Proliferative zone chondrocytes will differentiate into hypertrophic chondrocytes characterized by specific expression of type X collagen gene ( Col10a1 ), and further undergo apoptosis or osteoblasts trans-differentiation, thereby contributing to bone elongation [ 134 , 135 ]. The orchestrated differentiation of chondrocytes within the growth plate is governed by a complex interplay of numerous genes that are involved in a variety of signaling pathways, including hormonal signaling, paracrine signaling, intracellular pathways and extracellular matrix homeostasis (Fig. 5 ) [ 68 , 136 , 137 , 138 ]. Functional variants in any of these genes can disrupt the growth plate chondrogenesis and impair the subsequent bone elongation. It was hypothesized that ANKRD11 plays a direct role in the transcriptional regulation of certain critical genes via intracellular pathways in the process of growth plate development [ 68 ]. In a prior investigation, Yoda mice with an N-ethyl-N-nitrosourea (ENU)-induced mutation in the ANKRD11 gene, exhibited a markedly reduced body size and presented with a phenotype reminiscent of osteoporosis compared to littermate controls [ 3 ]. However, no alterations were observed in the histological structure of the tibial growth plate and plasma IGF-1 level between six-month-old Yoda mice and wild-type mice. Given that growth plate in rodents do not undergo fusion but are instead subject to an age-related decrease following sexual maturation [ 139 ], it can be inferred that adult mice with ANKRD11 deficiency may not well accurately reflect the aberrant differentiation process of growth plate chondrocytes during rapid bone elongation. Data obtained from the International Mouse Phenotyping Consortium (IMPC) indicate that C57BL/6 N mice carrying a heterozygous ANKRD11 tm1b(EUCOMM)Wtsi allele exhibited a reduction in body length when compared to their littermate controls ( https://www.mousephenotype.org/data/genes/MGI:1924337 ). Additionally, mice with a conditional deletion of the ANKRD11 gene in neural crest cells dispalyed ossification centers that were either incapable of expansion or failed to fuse, demonstrating the critical regulatory role of ANKRD11 gene in intramembranous ossification [ 22 ]. In vitro studies further revealed that ANKRD11 was capable of enhancing the transactivation of the p21 gene, a key factor in the chondrogenic differentiation of ATDC5 cells induced by insulin supplements [ 61 ]. The chondrogenic differentiation of ATDC5 cells induced by insulin-transferrin-selenium is a widely recognized in vitro model mimicking endochondral ossification [ 140 , 141 , 142 , 143 ]. The potential role of the ANKRD11-p21 signaling pathway in growth plate development as a plausible mechanism to elucidate the short stature observed in KBGS patients warrants further investigation. To elucidate the functional mechanisms of the ANKRD11 gene in the physiological process of growth plate development, it is essential to conduct further study employing a mouse model with chondrocyte-specific ANKRD11 ablation, utilizing the CRISPR/Cas9 and Cre/LoxP recombination system.
Disease-causing genes associated with short stature through affecting the endochondral ossification of epiphyseal growth plate. The ANKRD11 gene may be implicated in this process as a transcription regulator. RZ: resting zone, PZ: proliferative zone, PHZ: prehypertrophic zone, HZ: hypertrophic zone
Frameshift and nonsense were the most common types of ANKRD11 variants. Approximately half of the KBGS patients harboring ANKRD11 variants had short stature. However, the current study has not established a clear correlation between the genotype and this phenotypic manifestation. Some patients harboring ANKRD11 variants may initially be diagnosed as syndromic short stature due to limited recognition of KBGS. While patients with ANKRD11 variants exhibit a positive response to rhGH therapy, further investigation is warranted to substantiate its efficacy and safety. Functional variants in the ANKRD11 gene can potentially disrupt the longitudinal growth of bones by influencing the orderly differentiation process of growth plate chondrocytes, which needs deeper investigation through fundamental research to elucidate its underlying mechanisms.
The original contributions presented in the study are included in the article/Supplementary Materials, further inquiries can be directed to the corresponding authors.
American college of medical genetics and genomics
Activation domain
Alteration/deficiency in activation 3
Amplified in breast cancer 1
Association for molecular pathology
Ankyrin repeats-containing cofactor
Ankyrin repeat domain containing-protein 11
One-way analysis of variance
Brain-derived neurotrophic factor
[(CAMP-response-element binding protein)-binding protein]-associated factor
(CAMP-response-element binding protein)-binding protein
CAMP-response-element binding protein
Chronic renal insufficiency
Electroencephalogram
N-ethyl-N-nitrosourea
Estrogen receptor
Food and drug administration
Growth hormone
Growth hormone deficiency
Growth hormone insensitivity
Genome-wide association study
Histone acetylase
Histone deacetylase
Histone 3 lysine 9
Histone 4 lysine 5
Histone 4 lysine 8
Histone 4 lysine 16
Height standard deviation score
Hypertrophic zone
Insulin-like growth factor
Insulin-like growth factor binding protein 3
Isolated growth hormone deficiency
Indian hedgehog
International mouse phenotyping onsortium
Insertion or deletion
Intelligence quotient
Idiopathic short stature
Ligand-binding domain
Multiple pituitary hormone deficiency
Magnetic resonance imaging
Nuclear localization signal
Natriuretic peptide receptor 2
Nuclear receptors
Noonan syndrome
Online mendelian inheritance in man
Per-Arnt-Sim
Parathyroid hormone-related protein
Protein-truncating variant
Prader-Willi syndrome
Proliferative zone
Repression domain
Recombinant human growth hormone
Resting zone
Standard deviation
Standard deviation score
Small for gestational age
Single nucleotide polymorphism
Secondary ossification center
Transcriptional enhanced associate domain
Tyrosine receptor kinase B
Turner syndrome
Whole exome sequencing
Wingless-related integration site
Yes-associated protein
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This work was supported by Research Fund for Academician Lin He New Medicine (JYHL2019FZD01) and the PhD Research Foundation of Affiliated Hospital of Jining Medical University (2018-BS-007), and was partly supported by Shandong Traditional Chinese Medicine Science and Technology Development Plans Project (2019 − 0486).
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Dongye He, Mei Zhang, Yanying Li, Fupeng Liu & Bo Ban
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DYH performed the literature search and wrote the manuscript. MZ, YYL and FPL performed the literature search and collected ANKRD11 variants from ClinVar database. BB provided guidance on the data collection and critically revised the manuscript. All authors have reviewed and approved the final manuscript.
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He, D., Zhang, M., Li, Y. et al. Insights into the ANKRD11 variants and short-stature phenotype through literature review and ClinVar database search. Orphanet J Rare Dis 19 , 292 (2024). https://doi.org/10.1186/s13023-024-03301-y
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α | |||||||||||
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0.1 | 0.2 | 0.3 | 0.4 | 0.5 | 0.6 | 0.7 | 0.8 | 0.9 | |||
β | 0 | Z1 | 4.82 × 10 | 3.50 × 10 | 2.19 × 10 | 1.90 × 10 | 1.34 × 10 | 9.49 × 10 | 5.34 × 10 | 0.00 × 10 | 0.00 × 10 |
Z2 | 1 | 0.95 | 0.8368985 | 0.8 | 0.6857143 | 0.5714286 | 0.3811921 | 0 | 0 | ||
0.1 | Z1 | 4.82 × 10 | 3.64 × 10 | 3.19 × 10 | 2.27 × 10 | 1.98 × 10 | 1.64 × 10 | 1.18 × 10 | 1.10 × 10 | 9.38 × 10 | |
Z2 | 1 | 0.955 | 0.9228571 | 0.8264286 | 0.775 | 0.6464286 | 0.5371429 | 0.4857143 | 0.2649475 | ||
0.2 | Z1 | 4.82 × 10 | 3.78 × 10 | 3.37 × 10 | 2.59 × 10 | 2.33 × 10 | 1.87 × 10 | 1.62 × 10 | 1.55 × 10 | 1.43 × 10 | |
Z2 | 1 | 0.96 | 0.9314286 | 0.8457143 | 0.8 | 0.6857143 | 0.5885714 | 0.5428571 | 0.3942857 | ||
0.3 | Z1 | 4.82 × 10 | 4.11 × 10 | 3.55 × 10 | 2.90 × 10 | 2.68 × 10 | 2.28 × 10 | 2.06 × 10 | 2.00 × 10 | 1.90 × 10 | |
Z2 | 1 | 0.975 | 0.94 | 0.865 | 0.825 | 0.725 | 0.64 | 0.6 | 0.47 | ||
0.4 | Z1 | 4.82 × 10 | 4.21 × 10 | 3.73 × 10 | 3.31 × 10 | 3.07 × 10 | 2.69 × 10 | 2.50 × 10 | 2.44 × 10 | 2.36 × 10 | |
Z2 | 1 | 0.9785714 | 0.9485714 | 0.9014286 | 0.8585714 | 0.7642857 | 0.6914286 | 0.6571429 | 0.5457143 | ||
0.5 | Z1 | 4.82 × 10 | 4.31 × 10 | 3.92 × 10 | 3.56 × 10 | 3.36 × 10 | 3.09 × 10 | 2.94 × 10 | 2.88 × 10 | 2.81 × 10 | |
Z2 | 1 | 0.9821429 | 0.9571429 | 0.9178571 | 0.8821429 | 0.8142857 | 0.7607143 | 0.7214286 | 0.6214286 | ||
0.6 | Z1 | 4.82 × 10 | 4.41 × 10 | 4.10 × 10 | 3.82 × 10 | 3.65 × 10 | 3.43 × 10 | 3.32 × 10 | 3.27 × 10 | 3.21 × 10 | |
Z2 | 1 | 0.9857143 | 0.9657143 | 0.9342857 | 0.9057143 | 0.8514286 | 0.8085714 | 0.7771429 | 0.6971429 | ||
0.7 | Z1 | 4.82 × 10 | 4.51 × 10 | 4.28 × 10 | 4.07 × 10 | 3.94 × 10 | 3.78 × 10 | 3.69 × 10 | 3.66 × 10 | 3.61 × 10 | |
Z2 | 1 | 0.9892857 | 0.9742857 | 0.9507143 | 0.9292857 | 0.8885714 | 0.8564286 | 0.8328571 | 0.7728571 | ||
0.8 | Z1 | 4.82 × 10 | 4.62 × 10 | 4.46 × 10 | 4.32 × 10 | 4.24 × 10 | 4.13 × 10 | 4.07 × 10 | 4.05 × 10 | 4.01 × 10 | |
Z2 | 1 | 0.9928571 | 0.9828571 | 0.9671429 | 0.9528571 | 0.9257143 | 0.9042857 | 0.8885714 | 0.8485714 | ||
0.9 | Z1 | 4.82 × 10 | 4.72 × 10 | 4.64 × 10 | 4.57 × 10 | 4.53 × 10 | 4.47 × 10 | 4.44 × 10 | 4.43 × 10 | 4.42 × 10 | |
Z2 | 1 | 0.9964286 | 0.9914286 | 0.9832714 | 0.9764286 | 0.9628571 | 0.9521429 | 0.9442857 | 0.9242857 | ||
1 | Z1 | 4.82 × 10 | 4.82 × 10 | 4.82 × 10 | 4.82 × 10 | 4.82 × 10 | 4.82 × 10 | 4.82 × 10 | 4.82 × 10 | 4.82 × 10 | |
Z2 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 |
Variable Title | Value |
---|---|
Z | 3.32 × 10 |
Z | 80% |
V(1,2) | (1,1) |
U(1,2,3,4,5,6,7,8) | (0,0,0,0,0,1,0,1) |
α | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
0.1 | 0.2 | 0.3 | 0.4 | 0.5 | 0.6 | 0.7 | 0.8 | 0.9 | |||
β | 0 | Z1 | 4.84 × 10 | 4.70 × 10 | 4.52 × 10 | 4.20 × 10 | 3.68 × 10 | 3.54 × 10 | 3.41 × 10 | 3.15 × 10 | 2.65 × 10 |
Z2 | 1 | 0.9928571 | 0.9785714 | 0.9428571 | 0.8494217 | 0.8142857 | 0.7571429 | 0.5928571 | 0 | ||
0.1 | Z1 | 4.84 × 10 | 4.72 × 10 | 4.55 × 10 | 4.27 × 10 | 3.82 × 10 | 3.70 × 10 | 3.58 × 10 | 3.35 × 10 | 3.31 × 10 | |
Z2 | 1 | 0.9935714 | 0.9807143 | 0.9485714 | 0.8624167 | 0.8328571 | 0.7814286 | 0.6335714 | 0.5821429 | ||
0.2 | Z1 | 4.84 × 10 | 4.73 × 10 | 4.58 × 10 | 4.22 × 10 | 4.15 × 10 | 3.87 × 10 | 3.76 × 10 | 3.55 × 10 | 0.5821429 | |
Z2 | 1 | 0.9942857 | 0.9828571 | 0.9371429 | 0.9257143 | 0.8514286 | 0.8057143 | 0.6742857 | 0.6285714 | ||
0.3 | Z1 | 4.84 × 10 | 4.74 × 10 | 4.62 × 10 | 4.30 × 10 | 4.24 × 10 | 4.14 × 10 | 3.94 × 10 | 3.75 × 10 | 3.72 × 10 | |
Z2 | 1 | 0.995 | 0.985 | 0.945 | 0.935 | 0.91 | 0.83 | 0.715 | 0.675 | ||
0.4 | Z1 | 4.84 × 10 | 4.76 × 10 | 4.65 × 10 | 4.37 × 10 | 4.33 × 10 | 4.24 × 10 | 4.14 × 10 | 3.98 × 10 | 3.93 × 10 | |
Z2 | 1 | 0.9957143 | 0.9871429 | 0.9528571 | 0.9442857 | 0.9228571 | 0.88 | 0.7814286 | 0.7214286 | ||
0.5 | Z1 | 4.84 × 10 | 4.77 × 10 | 4.68 × 10 | 4.45 × 10 | 4.41 × 10 | 4.34 × 10 | 4.26 × 10 | 4.12 × 10 | 4.11 × 10 | |
Z2 | 1 | 0.9964286 | 0.9892857 | 0.9607143 | 0.9535714 | 0.9357143 | 0.9 | 0.8178571 | 0.7928571 | ||
0.6 | Z1 | 4.84 × 10 | 4.79 × 10 | 4.71 × 10 | 4.53 × 10 | 4.50 × 10 | 4.44 × 10 | 4.37 × 10 | 4.27 × 10 | 4.26 × 10 | |
Z2 | 1 | 0.9971429 | 0.9914286 | 0.9685714 | 0.9628571 | 0.9485714 | 0.92 | 0.8542857 | 0.8342857 | ||
0.7 | Z1 | 4.84 × 10 | 4.80 × 10 | 4.75 × 10 | 4.61 × 10 | 4.58 × 10 | 4.54 × 10 | 4.49 × 10 | 4.41 × 10 | 4.40 × 10 | |
Z2 | 1 | 0.9978571 | 0.9935714 | 0.9764286 | 0.9721429 | 0.9614286 | 0.94 | 0.8907143 | 0.8757143 | ||
0.8 | Z1 | 4.84 × 10 | 4.82 × 10 | 4.78 × 10 | 4.69 × 10 | 4.67 × 10 | 4.64 × 10 | 4.61 × 10 | 4.56 × 10 | 4.55 × 10 | |
Z2 | 1 | 0.9985714 | 0.9957143 | 0.9842857 | 0.981286 | 0.9742857 | 0.96 | 0.9271429 | 0.9171429 | ||
0.9 | Z1 | 4.84 × 10 | 4.83 × 10 | 4.81 × 10 | 4.77 × 10 | 4.76 × 10 | 4.74 × 10 | 4.73 × 10 | 4.70 × 10 | 4.70 × 10 | |
Z2 | 1 | 0.9992857 | 0.9978571 | 0.9921429 | 0.9907143 | 0.9871429 | 0.98 | 0.9635714 | 0.9585714 | ||
1 | Z1 | 4.84 × 10 | 4.84 × 10 | 4.84 × 10 | 4.84 × 10 | 4.84 × 10 | 4.84 × 10 | 4.84 × 10 | 4.84 × 10 | 4.84 × 10 | |
Z2 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 |
Variable Title | Value |
---|---|
Z | 3.37 × 10 |
Z | 92% |
V(1,2) | (1,1) |
U(1,2,3,4,5,6,7,8) | (0,0,0,0,0,1,0,1) |
α | ||||||||
---|---|---|---|---|---|---|---|---|
0.1 | 0.2 | 0.3 | 0.4 | 0.5 | 0.6 | 0.7 | 0.8 | 0.9 |
1.65 × 10 | 1.65 × 10 | 1.65 × 10 | 1.61 × 10 | 1.51 × 10 | 1.48 × 10 | 1.37 × 10 | 1.34 × 10 | 1.21 × 10 |
1 | 1 | 1 | 0.9228571 | 0.9714286 | 0.9642857 | 0.9150749 | 0.888311 | 0.7168279 |
1.65 × 10 | 1.65 × 10 | 1.65 × 10 | 1.61 × 10 | 1.52 × 10 | 1.50 × 10 | 1.40 × 10 | 1.37 × 10 | 1.26 × 10 |
1 | 1 | 1 | 0.9935714 | 0.9742857 | 0.9678571 | 0.9232892 | 0.8982267 | 0.7361599 |
1.65 × 10 | 1.65 × 10 | 1.65 × 10 | 1.61 × 10 | 1.54 × 10 | 1.52 × 10 | 1.43 × 10 | 1.40 × 10 | 1.33 × 10 |
1 | 1 | 1 | 0.9942857 | 0.9771429 | 09744286 | 0.9315568 | 0.9085202 | 0.8056308 |
1.65 × 10 | 1.65 × 10 | 1.65 × 10 | 0.62 × 10 | 1.55 × 10 | 1.53 × 10 | 1.46 × 10 | 1.43 × 10 | 1.37 × 10 |
1 | 1 | 1 | 0.995 | 0.98 | 0.975 | 0.939905 | 0.919635 | 0.8278087 |
1.65 × 10 | 1.65 × 10 | 1.65 × 10 | 0.62 × 10 | 1.57 × 10 | 1.55 × 10 | 1.49 × 10 | 1.47 × 10 | 1.41 × 10 |
1 | 1 | 1 | 0.9957143 | 0.9828571 | 0.9785714 | 0.9482679 | 0.9307498 | 0.8485393 |
1.65 × 10 | 1.65 × 10 | 1.65 × 10 | 1.63 × 10 | 1.58 × 10 | 1.57 × 10 | 1.52 × 10 | 1.50 × 10 | 1.45 × 10 |
1 | 1 | 1 | 0.9664286 | 0.9857143 | 0.9821429 | 0.9566604 | 0.9418646 | 0.8732143 |
1.65 × 10 | 1.65 × 10 | 1.65 × 10 | 1.63 × 10 | 1.57 × 10 | 1.48 × 10 | 1.43 × 10 | 1.41 × 10 | 1.39 × 10 |
1 | 1 | 1 | 0.9971429 | 0.9885714 | 0.9857143 | 0.9654133 | 0.9530132 | 0.8985714 |
1.65 × 10 | 1.65 × 10 | 1.65 × 10 | 1.64 × 10 | 1.61 × 10 | 1.60 × 10 | 1.57 × 10 | 1.56 × 10 | 1.53 × 10 |
1 | 1 | 1 | 0.9978571 | 0.9914286 | 0.9892857 | 0.9742857 | 0.964634 | 0.9238566 |
1.65 × 10 | 1.65 × 10 | 1.65 × 10 | 1.64 × 10 | 1.62 × 10 | 1.62 × 10 | 1.61 × 10 | 1.59 × 10 | 1.57 × 10 |
1 | 1 | 1 | 0.9985714 | 0.9942857 | 0.9928571 | 0.9885714 | 0.97625 | 0.9489286 |
1.65 × 10 | 0.2 | 0.3 | 0.4 | 1.64 × 10 | 1.64 × 10 | 1.63 × 10 | 1.63 × 10 | 1.62 × 10 |
1 | 1.65 × 10 | 1.65 × 10 | 1.61 × 10 | 0.9971429 | 0.9964286 | 0.9942857 | 0.9895536 | 0.9785714 |
1.65 × 10 | 1 | 1 | 0.9228571 | 1.65 × 10 | 1.65 × 10 | 1.65 × 10 | 1.65 × 10 | 1.65 × 10 |
1 | 1.65 × 10 | 1.65 × 10 | 1.61 × 10 | 1 | 1 | 1 | 1 | 1 |
Variable Title | Value |
---|---|
Z | 1.42 × 10 |
Z | 94% |
V(1,2) | (1,1) |
U(1,2,3,4,5,6,7,8) | (1,0,1,1,0,1,0,1) |
α | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
0.1 | 0.2 | 0.3 | 0.4 | 0.5 | 0.6 | 0.7 | 0.8 | 0.9 | |||
β | 0 | Z1 | 1.65 × 10 | 1.65 × 10 | 1.65 × 10 | 1.61 × 10 | 1.51 × 10 | 1.48 × 10 | 1.37 × 10 | 1.34 × 10 | 1.21 × 10 |
Z2 | 1 | 1 | 1 | 0.9228571 | 0.9714286 | 0.9642857 | 0.9150749 | 0.888311 | 0.7168279 | ||
0.1 | Z1 | 1.65 × 10 | 1.65 × 10 | 1.65 × 10 | 1.61 × 10 | 1.52 × 10 | 1.50 × 10 | 1.40 × 10 | 1.37 × 10 | 1.26 × 10 | |
Z2 | 1 | 1 | 1 | 0.9935714 | 0.9742857 | 0.9678571 | 0.9232892 | 0.8982267 | 0.7361599 | ||
0.2 | Z1 | 1.65 × 10 | 1.65 × 10 | 1.65 × 10 | 1.61 × 10 | 1.54 × 10 | 1.52 × 10 | 1.43 × 10 | 1.40 × 10 | 1.33 × 10 | |
Z2 | 1 | 1 | 1 | 0.9942857 | 0.9771429 | 0.9744286 | 0.9315568 | 0.9085202 | 0.8056308 | ||
0.3 | Z1 | 1.65 × 10 | 1.65 × 10 | 1.65 × 10 | 0.62 × 10 | 1.55 × 10 | 1.53 × 10 | 1.46 × 10 | 1.43 × 10 | 1.37 × 10 | |
Z2 | 1 | 1 | 1 | 0.995 | 0.98 | 0.975 | 0.939905 | 0.919635 | 0.8278087 | ||
0.4 | Z1 | 1.65 × 10 | 1.65 × 10 | 1.65 × 10 | 0.62 × 10 | 1.57 × 10 | 1.55 × 10 | 1.49 × 10 | 1.47 × 10 | 1.41 × 10 | |
Z2 | 1 | 1 | 1 | 0.9957143 | 0.9828571 | 0.9785714 | 0.9482679 | 0.9307498 | 0.8485393 | ||
0.5 | Z1 | 1.65 × 10 | 1.65 × 10 | 1.65 × 10 | 1.63 × 10 | 1.58 × 10 | 1.57 × 10 | 1.52 × 10 | 1.50 × 10 | 1.45 × 10 | |
Z2 | 1 | 1 | 1 | 0.9664286 | 0.9857143 | 0.9821429 | 0.9566604 | 0.9418646 | 0.8732143 | ||
0.6 | Z1 | 1.65 × 10 | 1.65 × 10 | 1.65 × 10 | 1.63 × 10 | 1.57 × 10 | 1.48 × 10 | 1.43 × 10 | 1.41 × 10 | 1.39 × 10 | |
Z2 | 1 | 1 | 1 | 0.9971429 | 0.9885714 | 0.9857143 | 0.9654133 | 0.9530132 | 0.8985714 | ||
0.7 | Z1 | 1.65 × 10 | 1.65 × 10 | 1.65 × 10 | 1.64 × 10 | 1.61 × 10 | 1.60 × 10 | 1.57 × 10 | 1.56 × 10 | 1.53 × 10 | |
Z2 | 1 | 1 | 1 | 0.9978571 | 0.9914286 | 0.9892857 | 0.9742857 | 0.964634 | 0.9238566 | ||
0.8 | Z1 | 1.65 × 10 | 1.65 × 10 | 1.65 × 10 | 1.64 × 10 | 1.62 × 10 | 1.62 × 10 | 1.61 × 10 | 1.59 × 10 | 1.57 × 10 | |
Z2 | 1 | 1 | 1 | 0.9985714 | 0.9942857 | 0.9928571 | 0.9885714 | 0.97625 | 0.9489286 | ||
0.9 | Z1 | 1.65 × 10 | 1.65 × 10 | 1.65 × 10 | 1.65 × 10 | 1.64 × 10 | 1.64 × 10 | 1.63 × 10 | 1.63 × 10 | 1.62 × 10 | |
Z2 | 1 | 1 | 1 | 1 | 0.9971429 | 0.9964286 | 0.9942857 | 0.9895536 | 0.9785714 | ||
1 | Z1 | 1.65 × 10 | 1.65 × 10 | 1.65 × 10 | 1.65 × 10 | 1.65 × 10 | 1.65 × 10 | 1.65 × 10 | 1.65 × 10 | 1.65 × 10 | |
Z2 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 |
Variable Title | Value |
---|---|
Z | 1.43 × 10 |
Z | 96% |
V(1,2) | (1,1) |
U(1,2,3,4,5,6,7,8) | (1,0,1,1,0,1,0,1) |
Criterion Illustration | Criterion Components | Basic Model | Basic Model with Inventory Management | Multi-Period Basic Model with Inventory Management | Multi-Period Basic Model with Inventory Management and Green Logistics |
---|---|---|---|---|---|
Overall Satisfaction of Customers | 85% | 92% | 94% | 96% | |
Total Costs | 3.32 × 10 | 4.37 × 10 | 1.42 × 10 | 1.43 × 10 |
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Khalilzadeh, M.; Antucheviciene, J.; Božanić, D. A Bi-Objective Model for the Multi-Period Inventory-Based Reverse Logistics Network: A Case Study from an Automobile Component Distribution Network. Systems 2024 , 12 , 299. https://doi.org/10.3390/systems12080299
Khalilzadeh M, Antucheviciene J, Božanić D. A Bi-Objective Model for the Multi-Period Inventory-Based Reverse Logistics Network: A Case Study from an Automobile Component Distribution Network. Systems . 2024; 12(8):299. https://doi.org/10.3390/systems12080299
Khalilzadeh, Mohammad, Jurgita Antucheviciene, and Darko Božanić. 2024. "A Bi-Objective Model for the Multi-Period Inventory-Based Reverse Logistics Network: A Case Study from an Automobile Component Distribution Network" Systems 12, no. 8: 299. https://doi.org/10.3390/systems12080299
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IMAGES
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This is why the literature review as a research method is more relevant than ever. Traditional literature reviews often lack thoroughness and rigor and are conducted ad hoc, rather than following a specific methodology. Therefore, questions can be raised about the quality and trustworthiness of these types of reviews.
9.3. Types of Review Articles and Brief Illustrations. EHealth researchers have at their disposal a number of approaches and methods for making sense out of existing literature, all with the purpose of casting current research findings into historical contexts or explaining contradictions that might exist among a set of primary research studies conducted on a particular topic.
A literature review can be a part of a research paper or scholarly article, usually falling after the introduction and before the research methods sections. In these cases, the lit review just needs to cover scholarship that is important to the issue you are writing about; sometimes it will also cover key sources that informed your research ...
Examples of literature reviews. Step 1 - Search for relevant literature. Step 2 - Evaluate and select sources. Step 3 - Identify themes, debates, and gaps. Step 4 - Outline your literature review's structure. Step 5 - Write your literature review.
A literature review is defined as "a critical analysis of a segment of a published body of knowledge through summary, classification, and comparison of prior research studies, reviews of literature, and theoretical articles." (The Writing Center University of Winconsin-Madison 2022) A literature review is an integrated analysis, not just a summary of scholarly work on a specific topic.
The literature review represents a method because the literature reviewer chooses from an array of strategies and procedures for identifying, recording, understanding, meaning-making, and transmitting information pertinent to a topic of interest. Moreover,
This book includes steps for students and experienced scholars, with discussion of a variety of literature review types. Conducting research literature reviews:From the Internet to Paper (Fink, 2019). Available resources include Chapters 1 and 2. This edition includes recommendations for organizing literature reviews using online resources.
Literature Review is a comprehensive survey of the works published in a particular field of study or line of research, usually over a specific period of time, in the form of an in-depth, critical bibliographic essay or annotated list in which attention is drawn to the most significant works. Also, we can define a literature review as the ...
Literature reviews establish the foundation of academic inquires. However, in the planning field, we lack rigorous systematic reviews. In this article, through a systematic search on the methodology of literature review, we categorize a typology of literature reviews, discuss steps in conducting a systematic literature review, and provide suggestions on how to enhance rigor in literature ...
A literature review is a review and synthesis of existing research on a topic or research question. A literature review is meant to analyze the scholarly literature, make connections across writings and identify strengths, weaknesses, trends, and missing conversations. ... SAGE Research Methods is the ultimate methods library with more than ...
A literature review involves researching, reading, analyzing, evaluating, and summarizing scholarly literature (typically journals and articles) about a specific topic. The results of a literature review may be an entire report or article OR may be part of a article, thesis, dissertation, or grant proposal.
Literature Review. A literature review is a discussion of the literature (aka. the "research" or "scholarship") surrounding a certain topic. A good literature review doesn't simply summarize the existing material, but provides thoughtful synthesis and analysis. The purpose of a literature review is to orient your own work within an existing ...
Literature Review and Research Design by Dave Harris This book looks at literature review in the process of research design, and how to develop a research practice that will build skills in reading and writing about research literature--skills that remain valuable in both academic and professional careers. Literature review is approached as a process of engaging with the discourse of scholarly ...
A literature review is an integrated analysis-- not just a summary-- of scholarly writings and other relevant evidence related directly to your research question.That is, it represents a synthesis of the evidence that provides background information on your topic and shows a association between the evidence and your research question.
A Rapid Literature Review (RLR) is the fastest type of literature review which makes use of a streamlined approach for synthesizing literature summaries, offering a quicker and more focused alternative to traditional systematic reviews. Despite employing identical research methods, it often simplifies or omits specific steps to expedite the ...
Method details Overview. A Systematic Literature Review (SLR) is a research methodology to collect, identify, and critically analyze the available research studies (e.g., articles, conference proceedings, books, dissertations) through a systematic procedure [12].An SLR updates the reader with current literature about a subject [6].The goal is to review critical points of current knowledge on a ...
Types of Literature Review are as follows: Narrative literature review: This type of review involves a comprehensive summary and critical analysis of the available literature on a particular topic or research question. It is often used as an introductory section of a research paper. Systematic literature review: This is a rigorous and ...
Rapid review. Assessment of what is already known about a policy or practice issue, by using systematic review methods to search and critically appraise existing research. Completeness of searching determined by time constraints. Time-limited formal quality assessment. Typically narrative and tabular.
Keep it brief. The methods section should be succinct but include all the noteworthy information. This can be a difficult balance to achieve. A useful strategy is to aim for a brief description that signposts the reader to a separate section or sections of supporting information. This could include datasets, a flowchart to show what happened to ...
This paper draws input from a study that employed a systematic literature review as its main source of data. A systematic review can be explained as a research method and process for identifying ...
The Literature Review will place your research in context. It will help you and your readers: Locate patterns, relationships, connections, agreements, disagreements, & gaps in understanding. Identify methodological and theoretical foundations. Identify landmark and exemplary works. Situate your voice in a broader conversation with other writers ...
Sometimes in your literature review, you might need to discuss and evaluate relevant research methodologies in order to justify your own choice of research methodology. When searching for literature on research methodologies it is important to search across a range of sources. No single information source will supply all that you need.
In a literature review, using a single study or fact to "prove" an argument right or wrong is often a signal to the person reading your literature review (usually your professor) that you may not have appreciated the limitations of that study or its place in the broader literature on the topic. ... Advances in Methods and Practices in ...
Purpose: This article aims to critically analyse current literature that explores nurses' perspectives concerning the use of chemical restraints amongst people with dementia. It also aims to consolidate existing knowledge and generate a foundation for further research. Methods: This literature review followed the 12-step approach by Kable et al. A total of 17 articles were included following ...
The systematic literature review employed statistical methods to measure effect sizes and employed traditional univariate systematic literature review to synthesize the results. A table summarizing the literature that met the inclusion criteria was created to ensure transparency and clarity in the data coding process.
Methods. A targeted literature review was conducted. Literature databases (MEDLINE, Embase, and Cochrane reviews) were searched for studies describing clinical practice and treatment outcomes for oral treprostinil and selexipag globally, published in English (2012 to 2022). Electronic searches were supplemented by manual-searches of targeted ...
We investigated publicly available online resources including published literature in Web of Science, PubMed, Google Scholar, and Wanfang database by searching keywords "KBGS", "ANKRD11", "Short stature" and "Intellectual disability" as well as genetic testing records in ClinVar database between July 2011 and March 2024.
This literature review discusses specific challenges associated with drought risk assessments (DRA) within agricultural systems, particularly concerning the justification for indicator selection, aggregation methods, and DRA-informed adaptation strategies. ... DRA-related validation methods being conducted in the literature can be presented in ...
A Review of the Literature on Green Logistics in Supply Chain Management Eydi et al. [ 13 ] investigated a multiple-period multi-echelon closed-loop supply chain network problem for product collection and shipment to determine an optimum number of facilities and their locations as well as the transportation modes.