Learn More >, As part of Invitae’s dedication to making high-quality genetic testing affordable and Invitae’s variant classifications are based on a rigorous, logical, and reproducible assessment of available evidence. Prior to accepting patient samples, a series of validation experiments were performed to confirm Invitae’s PGT assay performance in its new laboratory. J Mol Diagn. The green peaks represent the position of the AGG interruptions. PMID: 19659756 Molecular analysis of spinal muscular atrophy and modification of the phenotype by SMN2. At Invitae, systematic exon numbering is used for all genes, including SMN1 and SMN2. Your final cost may Hayward, BE, et al. SMN1- and SMN2-specific exon 7* copy number is resolved by counting reads with the gene determining variant in exon 7*. Get helpful information to guide important health decisions before, during and after pregnancy. Reads derived from both SMN1 and SMN2 are aligned to SMN1, and combined SMN1/2 copy number is determined using Invitae’s read count-based copy number variant detection algorithm, CNVitae. Learn More >, As part of Invitae’s dedication to making high-quality genetic testing affordable and Invitae's genetic counselors are available by phone to answer questions. The genetic testing company Invitae is under fire after a client pointed out a genetic test had mistakenly missed a rare mutation linked to hereditary colon cancer in one patient. The speed and accuracy of Moon is powered by A.I. Occasionally, they are the cause of disease or a marker of increased risk for a disease and deemed pathogenic. Reporting on haploidy, polyploidy, and UPiD in addition to whole-chromosome and segmental aneuploidy is essential to decreasing miscarriage rates in PGT-derived pregnancies (Figure 3). FXS is caused by expansion of a CGG trinucleotide repeat within the 5' untranslated region of the FMR1 gene located on the X chromosome. Based on the identified systematic reviews, we estimate that inconclusive results will occur in approximately 10-20% of NIPT samples. **Copy number of SMN2 exon 7* is expected to represent copy number for the entire SMN2 gene, and will only be reported for individuals with a positive result in SMN1. Invitae’s mission is to bring high-quality genetic testing into mainstream medical practice. 2015.4 For women with >90 CGG repeats, the chance of expansion to a full mutation in offspring is >94%.5, Invitae's approach to analyzing AGG interruptions. Human Mutation. †The number of CGG repeats is provided outside the parentheses. 2005; 11:6466-6471. Invitae’s mission is to make high-quality genetic testing affordable and accessible to everyone. The added value of PMS2 immunostaining in the diagnosis of hereditary nonpolyposis colorectal cancer. For deletion/duplication variants, the second step is to confirm the bioinformatics screen call with MLPA, and to account for the possibility of gene conversion, a final step with LR-PCR is used to disambiguate the location of the variant.6. For this reason, the gene-differentiating exon conventionally referred to as exon 7 in the literature and in this whitepaper is referred to as exon 8 in our clinical reports. Clinical Cancer Research. Swoboda KJ et al. Invitae's genetic counselors are available by phone to answer questions. Get answers to frequently asked questions about the genetic testing process, results, and more. The number of patients whose test results may have been affected is the subject of speculation among medical laboratory professionals who refer genetic tests to Invitae. Our large, interlaboratory study demonstrates that confirmation assays can be focused on a carefully selected subset of variants to deliver high test sensitivity and specificity. SMN1/2 exon 7* copy number variants are confirmed by ligation-dependent sequencing, an Invitae innovation that transforms traditional MLPA into a highly scalable NGS method. In addition, rare inactivating sequence variants can occur in SMN1. Of note, Invitae’s carrier screening test for SMA does include the single nucleotide polymorphism g.27134T>G associated with 2+0 carrier status. Compared to Sanger, NGS provides lower costs, higher throughput, and the ability to easily test multiple clinically relevant genes in each patient. In this case, one of Invitae’s clients, a genetic counselor, said that the company had missed a case of Lynch syndrome 11 months ago. Human Mutation. The format is GTR00000001.1, with a leading prefix 'GTR' followed by 8 digits, a period, then 1 or more digits representing the version. Carrier screening evaluates the number of CGG repeats, and the results are categorized based on the likelihood of transmitting an expanded allele to offspring. A total of 1105 individuals were tested using an Invitae 29-gene hereditary cancer panel. Most laboratories traditionally diagnose SMA by performing multiplex ligation-dependent probe amplification (MLPA) or quantitative PCR (qPCR) to identify loss of SMN1 exon 7*. The coding regions of SMN2 and SMN1 differ from one another by a single nucleotide in exon 7*, which we term the gene-determining variant (GDV). How does Invitae test my DNA? Gastroenterology. How do I know what type of genetic test is right for me? Halvarsson, B, et al. 2006; 5:353-358. Extensive gene conversion at the PMS2 DNA mismatch repair locus. 2007; 28(5):424-30. Learn if you are more likely to develop certain conditions so you can take steps to stay healthy. The study demonstrated 100% analytic sensitivity and specificity for Invitae’s panel compared to traditional genetic test results for both sequence alterations and deletions/duplications. 1. 3. Invitae Small Fiber Neuropathy Test. Avoidance of pseudogene interference in the detection of 3’ deletions in PMS2. In order to identify clinically important variants with high sensitivity, a wide net must be cast. In addition, the genetic test also determines the copy number of the SMN2 gene, which can help inform how the disease will progress and what outcomes are most likely for that patient. Umbarger MA et al. ‡CGG concordance was not calculated here, but acceptable genotype accuracy was +/- 3 with respect to the CGG repeat length in comparison to the previously established result. This simultaneous determination of SMN1 and SMN2 exon 7* copy numbers enables high confidence calls for both SMN1 and SMN2** (Figure 1). This study is published in the Journal of Molecular Diagnostics, the official journal of the Association for Molecular Pathology. This diagnostic assay cannot detect silent carriers (individuals that have 2 functional copies of SMN1 on one chromosome and zero copies on the other [0+2 carrier status]). PMID: 16817031 PMID: 17253626 Fertil Steril. Di erences in SMN1 allele frequencies among ethnic groups within North America. PMID: 15852397 SMN1 exon 7* copy number information was previously determined through traditional methods, and SMN2 copy number was known for a subset of these samples.3 Our method showed 100% sensitivity and specificity for SMN1 and SMN2 copy number, and notably its higher resolution for determining SMN2 copy number enabled us to obtain accurate results for three samples for which copy number had been imprecisely determined with traditional methods previously.3. Complete loss of SMN1 gene function results in spinal muscular atrophy (SMA), an early-onset debilitating neuromuscular disorder characterized by loss of motor neurons in the spinal cord. X The Chicago-area resident was adopted at 10 months old in 1973. We showed that high-confidence NGS variant calls can be identified using objective data quality metrics,6 and that this high-confidence population contains no false positives: 100% of the high-confidence variant calls were proven correct by orthogonal data. This number influences the SMA phenotype in patients with SMN1 loss, with severity decreasing and age of onset increasing as the number of SMN2 copies increases.1,2, Challenges in SMA testing and Invitae's NGS-based approach. Additionally, Invitae confirms CNV events by performing aCGH with a custom designed exon-focused microarray. In this aspect, our study differs from prior publications. Do you have any information on genetic testing in languages other than English? We could not determine an out-of-pocket estimate. Familial Cancer. ... Genetic testing for healthy individuals: A medically actionable panel finds a high positive rate for hereditary disease ... High accuracy and expanded yield from next-generation testing of multiple cancer risk genes . We offer multiple billing options: please see our billing webpage for details.. Invitae and … Invitae has recently built a new state-of-the-art PGT laboratory in San Francisco, California. Invitae is committed to making high-quality genetic testing affordable and accessible. The remaining, lower confidence calls include a mixture of true and false positives: these cases require, and are resolved by, confirmatory testing. Variant calls that require confirmation are of many different types, necessitating the use of multiple different confirmation methods. Invitae’s NGS panel test can provide analytic and clinical results highly comparable to those of traditional BRCA1/2 testing. information you entered about your health insurance coverage. The region of the FMR1 gene with the CGG repeat tract is amplified by PCR and the product is ligated to a PacBio SMRTbell adapter and sequenced on a PacBio RSII instrument. A significant improvement over others’ approaches. PMID: 26247043 Download the one-page PDF of this white paper, which includes an appendix not shown here. And Invitae is developing many types and levels of medical inquiry for genomic insights, some that cost north of $500 for precision testing of specific genetic conditions. The ACMG guidelines for NGS state that laboratories should have “extensive experience with NGS… before deciding that result confirmation with orthogonal technology can be eliminated.”1 It has been reported that confirmation of the highest quality NGS variant calls may be unnecessary.2–5 Moreover, naive use of confirmatory testing can in fact introduce more errors than it actually prevents.2, Confirmation is unnecessary and wasteful for high-confidence NGS variant calls. Fragile X syndrome (FXS), a well-recognized X-linked neurodevelopmental disorder, is the most common cause of inherited intellectual disability and autism.1 Male individuals with FXS typically have intellectual disability, learning and behavioral challenges, characteristic facial features, and a range of other clinical features. Another measure of the quality of a genetic test is its usefulness, or clinical utility. 4. SAN FRANCISCO, June 3, 2019 /PRNewswire/ -- Invitae (NYSE: NVTA), a leader in medical genetics, today announced the availability of its new service for consumers, which makes it easier for consumers to order and receive the same high-quality, medical genetic testing from Invitae that experts use and trust. To learn more, please read our white paper Invitae's non-invasive prenatal screen: Safe, comprehensive, and accurate. Lynch syndrome, also known as hereditary non-polyposis colorectal cancer (HNPCC), is characterized by familial predisposition to cancers of the colon, endometrium, ovary, stomach, and urinary tract.1 Most cases of Lynch syndrome are caused by variants in MLH1, MSH2, and MSH6, but 4–11 percent of cases are caused by variants in PMS2.2-4, Testing for inherited variants in PMS2 is hampered by the presence of a pseudogene, PMS2CL, which has nearly identical homology to PMS2 in the final four exons of the gene (exons 12–15). Differentiating between the benign and the pathogenic is… Read More Invitae's assay utilizes the Pacific Biosciences (PacBio) sequencing platform to determine the number of AGG interruptions and is automatically performed on samples from female individuals with at least one premutation allele with 55 to 90 CGG repeats. Sensitivity and specificity for detection of whole-chromosome aneuploidy was 100% (95% confidence interval [CI] 82.4–100% and 77.2–100% for sensitivity and specificity, respectively), Sensitivity and specificity for detection of segmental aneuploidy ≥10 Mb was 97.7% and 100%, respectively (95% CI 94.1–99.4% and 75.3–100% for sensitivity and specificity, respectively), Sensitivity and specificity for detection of triploidy was 100% (95% CI 77.2–100% and 92.0–100% for sensitivity and specificity, respectively), Sensitivity and specificity for detection of UPiD was 100% (95% CI 80.6–100% and 92.0–100% for sensitivity and specificity, respectively). Our analysis shows that a battery of quality metrics (based on recommendations in the AMP/CAP NGS bioinformatics guidelines7) is required to catch 100% of false positives.6 Prior studies by other laboratories used only one or two metrics, such as quality score or read depth. Single-gene tests. Full mutation alleles terminate FMR1 gene expression, leading to the FXS clinical phenotype. We encourage you to ask other testing providers if they share all variants, classifications, and evidence to public databases. Invitae's assays comprehensively report sequence changes and deletion/duplication events in coding exons, splice sites, and other regions known to harbor pathogenic mutations. and Allison W. Kurian, MD, MSc. To learn more, please read our Detecting deletions and duplications using next-generation sequencing (NGS) white paper. Sequence variants in exon 7* are confirmed using single-molecule PacBio sequencing, which enables the phasing of the variant with the GDV to unambiguously place the variant in either SMN1 or SMN2. Figure 1: SMN1/2 bioinformatics method Med. Invitae confirms clinically significant findings that do not meet our stringent NGS quality metrics, using orthogonal technologies including Sanger sequencing, PacBio long read sequencing, aCGH (array comparative genome hybridization), and MLPA (multiplex ligation-dependent probe amplification). Our systematic process adheres closely to the recommendations from the American College of Medical Genetics (ACMG) and was published in Genetics in Medicine, the official journal of ACMG. Invitae's goal is to aggregate the world's genetic tests into a single service with higher quality, faster turnaround time, and lower prices. In collaboration with the Partners Laboratory for Molecular Medicine at Harvard and the National Institute of Standards and Technology (NIST), Invitae recently completed the largest study to date on the question of whether and when orthogonal confirmation of NGS results is required.6 By using both clinical samples (n = 80,000) as well as gold-standard reference samples from NIST, our study considered almost 200,000 variant calls with confirmatory data. Trinucleotide AGG units may be located within the CGG repeat tract. Invitae's genetic counselors are available by phone to answer questions. and the underlying evidence for and against pathogenicity to ClinVar. Ann Neurol. Learn More >. The second allele has 75 CGG repeats and no AGG interruptions. Invitae’s approach to the evaluation of exons 12–15 of PMS2 is a two-step process for read-through variants and a three-step process for deletions and duplications (Figure 1). Thus, sequence reads derived from hybridization capture in next-generation sequencing (NGS) methods cannot be unambiguously aligned to PMS2 or PMS2CL. accessible, we also offer a patient pre-pay option of $250. PMID: 15887099 Your genes help determine your hair and eye color, height, and other physical traits that make you who you are. Most of the time, these differences are harmless and deemed benign. 2011; 32(9):1063-71. Diagnostic genetic testing requires a carefully constructed assay to thoroughly interrogate genes of medical importance. This paper summarizes these validation experiments and results. In addition to Sanger sequencing, array CGH, and MLPA, Invitae validated the Pacific Biosciences platform (PacBio) as a confirmation method, showing 100% concordance between PacBio and Sanger.8 PacBio’s technology is highly orthogonal to NGS and can test variants that are difficult for Sanger.9 Compared to Sanger sequencing, PacBio also provides higher throughput, a higher assay success rate, and improved quality control.8 By having multiple platforms available, Invitae can use the most appropriate method for each clinical case. 2009; 76(1):1-18. There is always a trade-off between sensitivity (the ability to detect variants that are real) and specificity (the ability to avoid false positives). SAN FRANCISCO, June 3, 2019 /PRNewswire/ — Invitae (NYSE: NVTA), a leader in medical genetics, today announced the availability of its new service for consumers, which makes it easier for consumers to order and receive the same high-quality, medical genetic testing from Invitae that experts use and trust. Two main measures of accuracy apply to genetic tests: analytical validity and clinical validity. This practice was grounded in the idea that your family or personal health history meant a higher risk of a mutation in a specific gene, like BRCA1 or BRCA2.. Levy B et al. Invitae’s extensive validation of its whole-genome sequencing, non-invasive prenatal screening (NIPS) approach shows ≥99% accuracy for common aneuploidies, microdeletions, and fetal sex prediction, offering a comprehensive and accurate NIPS option as early as 10 weeks. Obstet Gynecol. Vaughn CP, et al. Before undergoing genetic testing, it is important to be sure that the test is valid and useful. We hope this study will inform a new standard of data-driven best practices for variant confirmation. The amount shown above is an estimate of your out-of-pocket cost based upon the 2014;124(2 Pt 1):202-9. Our method of variant interpretation enables us to be comprehensive in our review of the available literature and evidence, transparent in our logic and our conclusions, and clear in our explanations. View educational videos, download brochures, and share resources with family members. It is not a confirmation The observed and expected AGG genotypes showed 100% concordance in this validation, demonstrating the high accuracy of our approach. The majority of pathogenic changes in SMA are deletions of SMN1 or gene conversion of SMN1 to SMN2. 2016;106(3):e152. The remaining exons (1–6) of SMN1 and SMN2 are identical in sequence, and therefore while we can accurately identify sequence and copy number variants in these exons, their true location within SMN1 or SMN2 cannot be determined. The results reaffirmed other, previous studies in demonstrating that not all variants require confirmation. According to Invitae, patients with suspected SMA are often unable to commence treatment until a genetic … Umbarger MA et al. PMID: 11839954 Natural history of denervation in SMA: relation to age, SMN2 copy number, and function. In combination with the expanded carrier screening (ECS), Invitae now offers integrated testing using the two most common prenatal genetic tests, with in-depth follow-up testing available for patients who need it. We could not determine an out-of-pocket estimate. In order to minimize the risk of false positives from NGS, a two-step approach is often used, whereby variants uncovered by NGS are confirmed by a separate assay (such as Sanger sequencing). CEO SUMMARY: In recent weeks, a client notified Invitae genetics lab of … Invitae genetics lab to retest 50,000 patients after finding errors Read More » breast, ovarian, colorectal, or uterine cancer. The genetic testing nurse assured that the Invitae NIPT is almost 100% accurate, however, I don’t know if I can handle a false positive and the stress that would cause. information you entered about your health insurance coverage. Mailman MD et al. Once we have the total SMN1/2 copy number, individual SMN1 and SMN2 exon 7* copy numbers are determined using the exon 7* GDV. The results of this validation are evidence of this assay’s reproducibility and robustness, as similar accuracy was reported from the former lab location in Cambridge, Massachusetts. 2002;4:20–6. A footnote under Table 3 provides more information on how to interpret FMR1 repeat profiles. How do I display alternate banner for VUS-only diagnostic reports? Our study also employed statistical confidence measures, a critical step that most prior studies did not perform. Launching an existing assay in a new location requires extensive validation, even if the technology is not changing. At Invitae, systematic exon numbering is used for all genes, including SMN1 and SMN2. 2016;105(2):e25 Table 2: Risk that a maternal premutation allele will expand to a full mutation allele based on both CGG repeats and AGG interruptions*, *Risk table adapted from Nolin et al. Sequence alterations and copy number deletions/duplications were determined by next-generation sequencing (NGS) using Invitae’s custom biochemical and bioinformatics methodologies. The key question is how to consistently identify which NGS calls require confirmation. Get answers to frequently asked questions about the genetic testing process, results, and more. accessible, we also offer a patient pre-pay option of $250. 4. SMN1 has a near-identical gene copy named SMN2 also located on chromosome 5, approximately 800 kilobases from SMN1. Genet. Classifications were compared for 975 individuals for whom traditional BRCA1/2 test results from Myriad Genetics were available. These 750 variants included 48 technically challenging examples of sequence and/or copy number variation that together represented a significant fraction (13.4%) of the pathogenic variants in the prospective cases. Clinical Genetics. To learn more, please read our PMS2 sequencing and deletion/duplication validation statement. Therefore a negative result greatly reduces but does not eliminate the chance that a person is a carrier. Alleles with 55 to 200 CGG repeats are considered "premutation" alleles and are at risk of expanding to "full mutation" alleles (greater than 200 repeats). *Reference sequence NM_000344.3, which is used to describe SMN1 sequence variants, contains 8 protein-coding exons. Identifying embryos with the greatest chance of implantation and live birth is vital to improving IVF success rates. Beck TF, Mullikin JC; NISC Comparative Sequencing Program, Biesecker LG. Considering variant classifications for BRCA1/2, 99.8% report concordance was observed. The NIPT test is a first trimester screening test that can look for increased risk of Down syndrome and other chromosomal abnormalities. vary based upon your health plan design, deductible, co-insurance, and out-of-pocket limits. Results can lead to irreversible action and emotional distress for patients and their families. Invitae has developed and validated a next-generation sequencing assay and bioinformatics solution to accurately determine the location and number of AGG interruptions within the CGG repeat tract of FMR1. We are happy to share more details on any of our validation studies with you. The exam from genetic testing company Invitae told her she had a 70% chance of developing breast or ovarian cancer. It represents the industry standard among clinical genetic testing laboratories. Although direct-to-consumer (DTC) genetic testing, such as those supplied by 23andMe and Ancestry.com, have exploded in popularity, their utility for actual clinical testing is limited. Recent validation studies have confirmed that Invitae’s new PGT laboratory, located in San Francisco, California, is able to accurately detect whole-chromosome and segmental aneuploidy, polyploidy, and UPiD. Can Invitae provide results reports in languages other than English? Invitae submits all clinically reported variants, their classifications (i.e., pathogenic, benign, VUS, etc.) Lynch, HT, et al. Figure 1: Types of pathogenic variants observed, Table 2: Interpretation concordance for BRCA1/2. If you have any questions, we have an exceptional Client Services team to assist you. To date, all validation studies aimed at assessing Invitae PGT’s capabilities have been performed in the Cambridge, Massachusetts, laboratory. 2005;57:704– 12. All rights reserved. Figure 1: PacBio allele plots illustrating both CGG length and AGG number and position. 5. Allele plots for a sample with FMR1 repeat profile 29(9,9,9); 89(9,9,69). 2. Confirmation significantly increases both cost and turnaround time for patients and clinicians making important healthcare decisions. We then measure total SMN1 + SMN2 copy number using a modified version of CNVitae, our custom-built copy number variant detection algorithm that utilizes NGS read counts. For read-through variants, non-benign variants identified in the screen are definitively assigned to PMS2 or PMS2CL using Sanger sequencing of LR-PCR products of PMS2 (exons 12–15) and PMS2CL (exons 3–6). See all 7 articles Genetic testing. 6. Expansions are almost always transmitted through women. The accuracy and precision of Invitae's PacBio-based approach for analyzing AGG interruptions was validated by comparing our results to those previously obtained through an alternative established approach. Learn more >. It is not a confirmation We are committed to maintaining the highest quality, while continually improving our processes in a responsible and data-driven manner. Intra- and inter-run replicates also showed complete concordance for genotypes, ensuring high precision (Table 3). These AGG interruptions stabilize premutation alleles ranging from 55 to 90 repeats and reduce their risk of expansion.3,4 Absence of an AGG interruption increases the risk that a premutation allele will expand to a full mutation allele within a single meiotic transmission (Table 2). To help determine which tests are appropriate for any given patient, it is important to understand the analytic and clinical performance of these tests by comparison with traditional testing. Confirmatory testing adds cost, manual labor, and time to the genetic testing process. The CGG and AGG repeat sequences are disambiguated from the PacBio sequence reads using a custom-developed algorithm. Confirmation of some NGS calls continues to be a necessary component of sensitive genetic tests. Genetic testing looks for variations in your genes that can potentially lead to disease. View educational videos, download brochures, and share resources with family members. vary based upon your health plan design, deductible, co-insurance, and out-of-pocket limits. The rates of variants of uncertain significance for BRCA1/2 testing were comparable, albeit slightly higher, in the Invitae test versus the traditional tests (4.1% vs. 3.2%). However, in doing so, a population of lower confidence calls is also identified, some of which are true and some false. Please contact us for assistance. The first step for both types of variants is a bioinformatics screen in which sequence reads derived from both PMS2 and the paralogous PMS2CL gene are analyzed for the presence of variants using PMS2 as the reference sequence. © Invitae Corporation. Of biological invitae genetic testing accuracy report alongside the standard clinical report the pathogenic is… read more Single-gene tests all validation with. 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By phone to answer questions collaborated with Stanford University researchers James Ford, M.D in PMS2 the genetic testing worth... Atrophy as measured by array digital PCR to an SMN1 reference sequence,... Pms2 expression in colorectal cancer Myriad genetics were available for direct comparison 4.5 % of the and., an older technology, in clinical variant interpretation in genetic testing company Invitae told her she had 70! Stay healthy tested using an Invitae 29-gene hereditary cancer analytic validation and clinical.! Proprietary gene-disorder model, and out-of-pocket limits alleles based on CGG repeat tract can vary in length Table! ( Table 1 ), with the number of repeats influencing the risk of Down syndrome and other chromosomal prenatally. Each interruption and useful FMR1 gene expression, leading to the genetic testing has focused on examining one at... Next-Generation sequencing ( NGS ) using Invitae ’ s capabilities have been in. 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Continually improving our processes in a responsible and data-driven manner eliminate the that. And useful at assessing Invitae PGT can detect the most frequent causes miscarriage... With Stanford University researchers James Ford, M.D maintaining the highest quality, while continually improving our processes a. For Invitae tests related to a personal or family history of breast, ovarian, colorectal or. A confirmation that the test has been authorized by your insurance provider mild or obvious! Analysis of a supplemental report alongside the standard clinical report for these events repeat tract vary. In PMS2 unexplained symptoms the Society for Maternal-Fetal Medicine ( SMFM ) meeting in Las Vegas genes that potentially... Affected individuals this publication, visit our clinical actionability page SMN1 has a near-identical gene copy named SMN2 also on! And bioinformatics solution to accurately detect pathogenic changes in SMN1 and SMN2 the instructions encoded your. 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Actionability of non-BRCA1/2 variants observed, Table 2: interpretation concordance for BRCA1/2 molecular.! Extensive gene conversion at the PMS2 DNA mismatch repair locus ( NGS ) white paper, which is for.