CN114076701A - Dried blood spot quality control product for newborn screening and preparation method thereof - Google Patents
Dried blood spot quality control product for newborn screening and preparation method thereof Download PDFInfo
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- CN114076701A CN114076701A CN202110833836.XA CN202110833836A CN114076701A CN 114076701 A CN114076701 A CN 114076701A CN 202110833836 A CN202110833836 A CN 202110833836A CN 114076701 A CN114076701 A CN 114076701A
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- Investigating Or Analysing Biological Materials (AREA)
Abstract
The invention discloses a dry blood spot quality control product for newborn screening and a preparation method thereof, wherein the dry blood spot quality control product comprises a filter paper carrier, blood working solution is soaked on the filter paper carrier, the blood working solution takes Chinese race blood as matrix solution, the matrix solution and extracting solution are mixed according to a certain proportion to form the dry blood spot quality control product, and the extracting solution comprises amino acid, free acyl carnitine, lysolecithin phosphatidylcholine, orotic acid and succinylacetone. The dry blood spot quality control product has good uniformity and stability, and can be used as an indoor quality control product in a newborn screening project; the preparation process is simple and convenient to operate.
Description
Technical Field
The invention relates to a chemical reference substance and a preparation method thereof, in particular to a dried blood spot quality control substance for screening neonates and a preparation method thereof.
Background
The screening of neonatal diseases refers to screening of diseases such as paraphenylacetonuria, congenital hypothyroidism and the like before clinical symptoms do not appear through neonatal blood examination, so that an organism can be effectively treated before being damaged, and the children can be effectively prevented from being disabled. The newborn screening belongs to three-level prevention and is one of the main means for preventing birth defects, and a sample for screening the newborn diseases is a filter paper dry blood sheet. In the quality control scheme of a newborn disease screening laboratory, the adoption of stable and reliable quality control products is a necessary guarantee for indoor quality control work and an important basis for indoor quality evaluation, and the accurate newborn screening result can ensure that a child patient can obtain correct treatment in time.
However, most laboratories for screening genetic and metabolic disease tandem mass spectrometry in China have the current situations that the standardization (the use of self-prepared reagents is poor in stability, the indoor quality control is not realized, and the indoor quality evaluation is not involved), the quality control materials using western race blood as a substrate solution are poor, the quantity of the quality control materials is insufficient, and the types of compounds contained in the quality control materials are relatively few.
The existing patents have more detection methods for screening newborn, but the research on the quality control of the dry blood spots screened by the newborn is less. At present, a few manufacturers develop quality control products for screening newborn in China, for example, in the amino acid and acyl carnitine dry blood spot quality control product and the preparation method thereof disclosed in the Chinese patent document with publication number CN107144453A, the dry blood spot quality control product contains 8 amino acids and 16 acyl carnitines; in a certain enterprise standard of newborn screening of the quality control of the blood spots with the standard number of Q/HZBR001-2016, the dry blood spot quality control of the tandem mass spectrometry comprises 27 amino acids and carnitine; the quality control of the U.S. CDC comprises 31 standards; the quality control product of platinum elmer only contains 23 standards. The quality control range of the above patents or related products can only include three traditional diseases, namely amino acid metabolism disorder (including urea cycle disorder), organic acid metabolism disorder and fatty acid oxidation metabolism disorder. Therefore, there is a need for improvements to existing neonatal metabolite screening methods.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a dried blood spot quality control product for screening newborn and a preparation method thereof, the preparation process is simple, the operation is convenient, and the quality control product has good uniformity and stability.
The technical scheme adopted by the invention for solving the technical problems is to provide a dry blood spot quality control product for screening newborn infants, which comprises a filter paper carrier, wherein a blood working solution is soaked on the filter paper carrier, the blood working solution takes Chinese race blood as a matrix solution, the matrix solution is mixed with an extracting solution according to a certain proportion, and the extracting solution comprises amino acid, free acyl carnitine, lysolecithin phosphatidylcholine, orotic acid and succinylacetone.
Further, the amino acids include 14 kinds of amino acids, which are alanine, arginine, citrulline, glycine, leucine, isoleucine, glutamic acid, methionine, ornithine, phenylalanine, proline, tyrosine, valine, and aspartic acid, respectively.
Further, the free and acyl carnitines include 20 kinds of carnitine, which are free carnitine, acetyl carnitine hydrochloride, propionyl carnitine hydrochloride, malonyl carnitine/3-hydroxy-isovaleryl carnitine, butyryl carnitine hydrochloride, valeryl carnitine hydrochloride, glutaryl carnitine/3-hydroxy-caproyl carnitine hydrochloride, adipoyl carnitine, octanoyl carnitine hydrochloride, decanoyl carnitine hydrochloride, lauroyl carnitine hydrochloride, myristoyl carnitine hydrochloride, palmitoyl carnitine hydrochloride, hydroxypalmitoyl carnitine hydrochloride, octadecanoyl carnitine/octadecanoyl carnitine hydrochloride, 3-hydroxyoctadecanoyl carnitine hydrochloride, C26 carnitine hydrochloride, succinyl carnitine hydrochloride, and 4-hydroxybutyryl carnitine, respectively.
Further, the lysophosphatidylcholine is C26: 0-LPC.
Further, the matrix solution and the extracting solution are mixed according to a volume ratio of 9: 1, mixing.
Further, the matrix solution is blood type A, and the filter paper carrier is Whatman 903 filter paper dried blood slice.
The invention also provides a preparation method of the dried blood spot quality control product for screening newborn infants, which comprises the following steps: s1, preparing a standard product: preparing standard solutions of various target compounds, and then preparing mixed standards with corresponding concentrations in proportion; s2, preparation of a blank filter paper sheet: placing the blank filter paper sheet in an oven for drying; s3, preparation of dried blood spot quality control products: adding the mixed standard into the blood, and uniformly mixing to prepare blood working solution; transferring the blood working solution by using a liquid transfer gun, slowly adding the blood working solution to the filter paper printing ring, and transferring the blood to a clean room for natural air drying after the blood is primarily coagulated; s4, controlling qualified blood spots: controlling the blood specimen to naturally infiltrate into the blood spot ring line, and enabling the diameter of the formed blood spot to cover the diameter of the seal ring.
Further, in step S1, a standard solution with a low concentration is prepared by a weight-weight method, a standard solution with a high concentration is prepared by a mother liquor dilution method, and the target compounds and the concentrations are controlled as follows:
the low control concentration of the alanine is 800-900 mu mol/L, and the high control concentration is 1600-2000 mu mol/L;
the low control concentration of arginine is 150-200 mu mol/L, and the high control concentration is 380-450 mu mol/L;
the low control concentration of citrulline is 80-120 mu mol/L, and the high control concentration is 250-350 mu mol/L;
the low control concentration of glycine is 800-1200 mu mol/L, and the high control concentration is 2500-3000 mu mol/L;
the low control concentration of leucine/isoleucine is 300-400 mu mol/L, and the high control concentration is 900-1100 mu mol/L;
the low control concentration of methionine is 90-140 mu mol/L, and the high control concentration is 310-400 mu mol/L;
the low control concentration of ornithine is 240-340 mu mol/L, and the high control concentration is 700-1000 mu mol/L;
the low control concentration of phenylalanine is 200-280 mu mol/L, and the high control concentration is 600-750 mu mol/L;
the low control concentration of proline is 500-650 mu mol/L, and the high control concentration is 1500-1750 mu mol/L;
the low control concentration of the succinylacetone is 3-7 mu mol/L, and the high control concentration is 12-18 mu mol/L;
the low control concentration of tyrosine is 300-420 mu mol/L, and the high control concentration is 950-1250 mu mol/L;
the low control concentration of valine is 310-450 mu mol/L, and the high control concentration is 800-1100 mu mol/L;
the low control concentration of the free carnitine is 80-140 mu mol/L, and the high control concentration is 240-310 mu mol/L;
the low control concentration of the acetyl carnitine hydrochloride is 50-82 mu mol/L, and the high control concentration is 120-180 mu mol/L;
the low control concentration of propionyl carnitine hydrochloride is 8-13 mu mol/L, and the high control concentration is 22-32 mu mol/L;
the low control concentration of malonyl carnitine is 1-1.7 mu mol/L, and the high control concentration is 4-6 mu mol/L;
the low control concentration of butyrylcarnitine hydrochloride is 2.2-3.2 mu mol/L, and the high control concentration is 5.5-8.5 mu mol/L;
the low control concentration of the valeryl carnitine hydrochloride is 0.9-1.5 mu mol/L, and the high control concentration is 2.6-3.8 mu mol/L;
the low control concentration of the glutaryl carnitine hydrochloride is 0.55-0.85 mu mol/L, and the high control concentration is 1.5-2.1 mu mol/L;
the low control concentration of the caproyl carnitine hydrochloride is 0.48-0.72 mu mol/L, and the high control concentration is 1.5-2.1 mu mol/L;
the low control concentration of the adipyl carnitine is 0.9-1.5 mu mol/L, and the high control concentration is 3.2-4.8 mu mol/L;
the low control concentration of the octanoyl carnitine hydrochloride is 0.48-0.72 mu mol/L, and the high control concentration is 1.5-2.1 mu mol/L;
the low control concentration of the decanoyl carnitine hydrochloride is 0.8-1.2 mu mol/L, and the high control concentration is 2.3-3.3 mu mol/L;
the low control concentration of lauroyl carnitine hydrochloride is 1.28-1.92 mu mol/L, and the high control concentration is 4.2-6.2 mu mol/L;
the low control concentration of the myristoyl carnitine hydrochloride is 1.44-2.16 mu mol/L, and the high control concentration is 4.2-5.4 mu mol/L;
the low control concentration of the palmitoyl carnitine hydrochloride is 10-15 mu mol/L, and the high control concentration is 25-37 mu mol/L;
the low control concentration of the hydroxy palmitoyl carnitine hydrochloride is 0.32-0.48 mu mol/L, and the high control concentration is 2-3 mu mol/L;
the low control concentration of the octadecanoyl carnitine is 2-2.7 mu mol/L, and the high control concentration is 4-6 mu mol/L;
the low control concentration of the 3-hydroxyoctadecanoyl carnitine is 0.16-0.4 mu mol/L, and the high control concentration is 1.2-2.0 mu mol/L;
the low control concentration of the orotic acid is 0.24-0.36 mu mol/L, and the high control concentration is 8-12 mu mol/L;
the low control concentration of the glutamic acid is 220-340 mu mol/L, and the high control concentration is 700-800 mu mol/L;
the low control concentration of the aspartic acid is 200-300 mu mol/L, and the high control concentration is 680-760 mu mol/L;
the low control concentration of the C26 carnitine hydrochloride is 1-1.5 mu mol/L, and the high control concentration is 5-7 mu mol/L;
c26, wherein the low control concentration of 0-LPC is 1-1.5 mu mol/L, and the high control concentration is 5-7 mu mol/L;
the low control concentration of the succinyl carnitine hydrochloride is 1.85-2.65 mu mol/L, and the high control concentration is 5.4-7.4 mu mol/L;
the low control concentration of the 4-hydroxybutyryl carnitine is 1.2-1.8 mu mol/L, and the high control concentration is 5-6.6 mu mol/L.
Further, the step S2 includes baking the blank filter paper sheet in an oven at 65 ℃ for 1.5 h.
Further, the step S3 is to control the height of the pipette tip from the center of the filter paper sheet to be 1-2cm, a slow one-off blood dripping mode is adopted, and the step S4 is to control the diameter of the blood spot to be 10-12 mm.
Compared with the prior art, the invention has the following beneficial effects: the quality control product for dry blood spots for screening newborns, provided by the invention, comprises 14 amino acids, 20 free acyl carnitines, 1 lysolecithin phosphatidylcholine, orotic acid and succinylacetone, and 37 quality control substances in total, and can cover the indoor quality control requirements of four major metabolic disorders of amino acid metabolism (including urea cycle disorder), organic acid metabolism disorder, fatty acid oxidative metabolism disorder and peroxisome; the preparation process is simple, the operation is convenient and fast, and the method has important significance for screening and controlling the quality of the hereditary metabolic diseases of Chinese population.
Drawings
FIG. 1 is a sample of a sheet of certified dry blood spot filter paper according to example 1 of the present invention;
FIG. 2 is a sample diagram of dried blood spot filter paper sheets having blood spot volumes of 10. mu.L, 25. mu.L, 50. mu.L and 75. mu.L according to example 2 of the present invention;
FIG. 3 is a sample diagram of a dried blood spot filter paper sheet having blood spot heights of 1-2cm, 3-4cm and 5-6cm according to example 3 of the present invention;
FIG. 4 is a sample graph of a dried blood spot filter paper sheet in which the blood spot velocity in example 3 of the present invention is a blood sample dropwise added and one-time added.
Detailed Description
The invention is further described below with reference to the figures and examples. These examples are intended to illustrate the invention and are not intended to limit the scope of the invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred experimental methods and materials described herein are exemplary only.
Instruments, materials and reagents:
electron analytical balance (mettler, XPR205), microplate constant temperature oscillator (Thermo, WZ80-2), electric hot blast dry box (shanghai-chemostat instruments ltd., BPG-9040A), liquid chromatography mass spectrometer (PerkinElmer, Qsight 220).
Standard substance: glycine and free carnitine are LGC products; orotic acid is a product of Bailingwei Beijing; propionyl carnitine is a ladder loving product; succinylacetone, octadecyl carnitine, C26:0-LPC, acetyl carnitine, malonyl carnitine, succinyl carnitine, glutaryl carnitine, adipoyl carnitine, palmitoyl carnitine, hydroxypalmitoyl carnitine, 3-hydroxypentadecanoyl carnitine are sigma products; caproyl carnitine, caprylyl carnitine, capric acyl carnitine, lauroyl carnitine and myristoyl carnitine are TRC products; alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, ornithine, proline, arginine, citrulline, glutamic acid, aspartic acid, methionine, 4-hydroxybutyryl carnitine, valeryl carnitine, C26-carnitine are products of Shanghai' an spectral laboratory science and technology GmbH. Reagents and drugs used: methanol, acetonitrile, formic acid and anhydrous oxalic acid are all LC-MS grades, water is ultrapure water, blank human whole blood is from Shanghai blood bank, and the filter paper model is Whatman 903 filter paper dry blood slice acquisition card. The method comprises the following specific steps:
s1, preparing a standard product
Preparing standard solutions of 37 target compounds, wherein the standard solutions are uniform and clear and have no insoluble substances; then preparing mixed standards with corresponding concentrations according to the proportion;
s2 preparation of blank filter paper sheet
Placing the blank filter paper sheet in a 65 ℃ oven, and drying for 1.5 h;
s3 preparation of dried blood spot quality control product
100 mu L of mixed standard containing 37 standard substances is added into 900 mu L of blood, and the blood working solution is prepared after uniform mixing. And (3) transferring 50 mu L of blood working solution by using a liquid transfer gun, slowly adding the blood working solution to the filter paper seal ring, and transferring the filter paper seal ring to a clean room for natural air drying for 6h after the blood is primarily coagulated. The dried blood slice filter paper is the dried blood spot quality control product and is stored in a refrigerator at the temperature of minus 20 ℃ (organic pollution is avoided).
S4, judging qualified blood spots: the blood specimen completely and naturally infiltrates into the blood spot ring line, and the diameter of the formed blood spot is 10-12 mm.
The high and low concentrations of the dry blood spot quality control substances are shown in Table 1.
TABLE 1 information table of high and low concentrations of each quality control material
The technical scheme of the invention is further explained by combining the embodiment.
Example 1 determination of Dry blood Spot Filter paper spotting
Mixing the blood with water according to the ratio of 9: 1, sucking a certain amount of blood mixture by a calibrated 100 mu L pipette, controlling the distance between a suction head and the center of a blood spot, slowly adding the blood to a Whatman 903 filter paper dry blood spot collecting card (with a print ring diameter of 10mm), checking the diffusion condition of the blood in the filter paper, and judging whether the blood spot is qualified or not by a visual inspection method.
Example 2 determination of blood volume
In example 1, 10. mu.L, 25. mu.L, 50. mu.L and 75. mu.L of blood samples were added to dry filter paper blood, and the spread of different amounts of added blood was observed. From the formation of blood spots, the spot formed with a spot blood volume of 50. mu.L covered just the diameter of the ring (10 mm).
Example 3 determination of blood Spot height
In example 1, blood samples were taken at heights of 1-2cm, 3-4cm and 5-6cm from the filter paper sheet, respectively, to observe the formation of blood spots. The result shows that the height of the pipette tip from the center of the filter paper piece has no obvious difference on the size and the diffusion speed of the blood spot, but the repeatability and the operability of the blood spot formed under the condition that the pipette tip is 1-2cm from the center of the filter paper blood piece are stronger in terms of the convenience of operation.
EXAMPLE 4 determination of Spot blood velocity
In example 1, spotting was performed in two different blood velocity-by-point spotting manners, one-time spotting and one-drop spotting, respectively. The result shows that different blood velocities have influence on blood spot formation, the blood spot formed by dropwise adding the blood is slightly smaller than the blood spot formed by dropwise adding the blood at one time, the diffusion speed is slightly slower, and in order to ensure that the blood spot is completely stained by the halo on the whole ring, the mode of slowly and once adding the blood is recommended.
The following experiments are combined to further illustrate the advantages of the amino acid, free acyl carnitine, lysolecithin, orotic acid and succinylacetone dried blood spot quality control product prepared by the method.
And (3) evaluating the uniformity of the dried blood spot quality control product:
in the experiment, citrulline (Cit), proline (Pro), acetyl carnitine (C2), decanoyl carnitine (C10) and 3-hydroxyoctadecanoyl carnitine (C18OH-3) are selected as target substances to prepare a dried blood spot quality control product, and a non-derivatization method LC-MS/MS is adopted for determination, so that A, B groups of diluents are adopted for extraction in the experiment due to the fact that the solubility of the 3-hydroxyoctadecanoyl carnitine in water is poor, and the result is shown in Table 1.
TABLE 1 test batch homogeneity test results with 5 standard substances
Note: samples A1, A2, A3 represent samples from the same spot (see below), and A1, B1, C1 represent samples from the same site of different spots (see below).
According to the test results in table 1, the RSD in 4 index batches tested by the group A is 8.20-11.40%, and the RSD in 5 index batches tested by the group B is 3.47-8.34%; the peak area difference of two groups of blood spot samples under the same test index is controlled within 10.23%, and the detection response is higher by using the group A samples, however, the group added with methanol has lower relative standard deviation (RSD%), and better reproducibility (the results are similar after 3 times of repeated tests of 5 target uniformity tests). The uniformity of the quality control product obtained by the invention is good.
Evaluating the short-term stability of the dried blood spot quality control product:
in the experiment, citrulline (Cit), proline (Pro), acetyl carnitine (C2), decanoyl carnitine (C10) and 3-hydroxyoctadecanoyl carnitine (C18OH-3) are selected as target substances to prepare the dried blood spot quality control product, and the 3-hydroxyoctadecanoyl carnitine is dissolved in methanol and diluted by LC-MS water due to the poor solubility of the 3-hydroxyoctadecanoyl carnitine in water. The results of the non-derivatization LC-MS/MS method measurements of group B samples stored at-20 and group C dried blood spot quality control products accelerated at 45 ℃ for 9 days are compared. The results are shown in Table 2.
TABLE 2 accelerated stability test results for test batches containing 5 standard substances
The results in Table 2 show that the RSD in 5 index batches tested by the group B is 5.35-11.50%, and the RSD in 5 index batches tested by the group C is 5.14-14.26%; the peak area difference of the two groups of blood spot samples under the same test index is controlled within-2.37% -1.19%, and the sample detection response is not obviously different, which shows that the difference between the sample accelerated at 45 ℃ by 9d and the sample preserved at-20 ℃ is not obvious, and the sample accelerated at 9d of the test batch of 5 standard substances can be basically judged to be stable (the batch is repeated for 3 times, and the conclusion is similar). From the accelerated results, it can be generally concluded that the dried blood spot quality control of the present invention is stable for at least 6 months when stored at-20 ℃.
Evaluation of uniformity among dry blood spot quality control material batches:
in the experiment, 8 standard substances such as citrulline (Cit), proline (Pro), acetyl carnitine (C2), decanoyl carnitine (C10), 3-hydroxyoctadecanoyl carnitine (C18OH-3), orotic acid (ORA), Succinylacetone (SA), C26:0-LPC and the like are selected to prepare 2 different batches of dried blood spot quality control products, a non-derivatization method LC-MS/MS is adopted for determination, methanol dissolution and formic acid dissolution assistance are adopted due to the fact that the solubility of the 3-hydroxyoctadecanoyl carnitine and the solubility of the C26:0-LPC in water are poor, and finally LC-MS water dilution is adopted for designing batch experiments to compare the uniformity and the reproducibility of blood spot samples among batches. The results are shown in Table 3.
TABLE 3 batch-to-batch uniformity test results
According to the test results in Table 3, the RSD in 5 indexes tested in batch 1 is 4.07-8.14%, and the RSD in 8 indexes tested in batch 2 is 2.32-10.94%; the peak area difference of the two groups of blood spot samples under the same test index is controlled within 7.05 percent, and the sample detection response does not distinguish obvious difference, which shows that the dried blood spot samples prepared in different batches have no obvious difference, and the uniformity and the repeatability between batches can be basically judged to be good.
Evaluating the long-term stability of the dried blood spot quality control product:
for quality control products of dry blood tablets, one of the key parameters of stability, especially long-term stability. The dried blood slices with the high and low concentration levels are kept at-20 ℃, taken out after a certain time, returned to room temperature, subjected to recovery rate measurement on samples, subjected to parallel measurement for 10 times, and the corresponding CV values are calculated, and the results are shown in the following table.
TABLE 4-20 deg.C storage of low concentration dried blood spot quality control recovery and CV value for 1 year
| Analyte | Configured concentration | LC35-1 | LC35-2 | LC35-3 | LC35-4 | LC35-5 | LC35-6 | LC35-7 | LC35-8 | LC35-9 | LC35-1.0 | Mean value | CN | Recovery rate |
| Ala | 850 | 1156 | 1000 | 1008 | 1025 | 1163 | 980 | 919 | 681 | 1398 | 833 | 1016 | 19％ | 120％ |
| Arg | 180 | 150 | 163 | 167 | 163 | 146 | 173 | 162 | 161 | 178 | 172 | 164 | 6％ | 91％ |
| Cit | 100 | 118 | 115 | 114 | 114 | 109 | 131 | 108 | 120 | 133 | 118 | 118 | 7％ | 118％ |
| Gly | 1050 | 958 | 1274 | 1095 | 1175 | 1199 | 1332 | 1050 | 989 | 1337 | 1304 | 1171 | 12％ | 112％ |
| Leu\lle | 700 | 655 | 727 | 627 | 649 | 733 | 584 | 698 | 586 | 764 | 674 | 670 | 9％ | 96％ |
| Met | 115 | 72 | 79 | 74 | 66 | 81 | 67 | 65 | 73 | 88 | 63 | 73 | 11％ | 63％ |
| Orn | 300 | 294 | 422 | 394 | 318 | 320 | 410 | 323 | 391 | 375 | 343 | 359 | 12％ | 120％ |
| Phe | 240 | 184 | 189 | 171 | 168 | 222 | 163 | 175 | 158 | 197 | 159 | 179 | 11％ | 74％ |
| Tyr | 360 | 365 | 370 | 352 | 374 | 345 | 338 | 367 | 365 | 426 | 364 | 367 | 6％ | 102％ |
| Val | 390 | 341 | 401 | 376 | 390 | 412 | 338 | 318 | 350 | 417 | 400 | 374 | 9％ | 96％ |
| Glu | 280 | 244 | 249 | 256 | 265 | 257 | 254 | 233 | 298 | 224 | 258 | 253.7 | 8％ | 91％ |
| SA | 5.0 | 4.1 | 5.5 | 3.2 | 4.8 | 5.9 | 6.0 | 4.6 | 5.8 | 4.0 | 4.6 | 4.8 | 19％ | 96％ |
| C0 | 110 | 119 | 121 | 92 | 103 | 116 | 105 | 107 | 100 | 113 | 124 | 110 | 9％ | 100％ |
| C2 | 68 | 72 | 74 | 71 | 68 | 59 | 67 | 70 | 66 | 71 | 67 | 69 | 6％ | 101％ |
| C3 | 10.5 | 12.6 | 12.7 | 11.6 | 12.2 | 11.6 | 12.4 | 11.7 | 11.8 | 12.5 | 12.2 | 12.1 | 4％ | 115％ |
| C4 | 2.8 | 1.5 | 1.6 | 1.5 | 1.5 | 1.4 | 1.5 | 1.4 | 1.4 | 1.6 | 1.5 | 1.5 | 5％ | 54％ |
| C3DC/C4OH | 1.40 | 1.04 | 1.07 | 1.07 | 1.02 | 1.04 | 1.03 | 1.03 | 1.04 | 1.09 | 1.05 | 1.05 | 20％ | 75％ |
| C5 | 1.20 | 0.70 | 0.75 | 0.64 | 0.74 | 0.72 | 0.73 | 0.66 | 0.70 | 0.82 | 0.68 | 0.71 | 7％ | 59％ |
| C4DC | 2.2 | 1.5 | 1.1 | 1.7 | 1.0 | 1.2 | 1.0 | 1.6 | 1.4 | 1.7 | 1.5 | 1.4 | 20％ | 64％ |
| C6 | 0.60 | 0.38 | 0.39 | 0.39 | 0.40 | 0.39 | 0.38 | 0.35 | 0.38 | 0.40 | 0.41 | 0.39 | 4％ | 64％ |
| C5DC/C6OH | 0.70 | 0.57 | 0.42 | 0.49 | 0.58 | 0.49 | 0.51 | 0.53 | 0.46 | 0.57 | 0.43 | 0.51 | 11％ | 72％ |
| C8 | 0.6 | 0.59 | 0.61 | 0.57 | 0.53 | 0.64 | 0.63 | 0.59 | 0.57 | 0.64 | 0.62 | 0.60 | 6％ | 100％ |
| C10 | 1 | 1.07 | 1.06 | 0.96 | 0.98 | 0.98 | 1.04 | 0.99 | 1.06 | 1.21 | 1.05 | 1.04 | 7％ | 104％ |
| C12 | 1.6 | 1.34 | 1.42 | 1.29 | 1.20 | 1.33 | 1.26 | 1.31 | 1.47 | 1.68 | 1.56 | 1.39 | 11％ | 87％ |
| C14 | 1.8 | 1.70 | 1.52 | 1.49 | 1.36 | 1.69 | 1.44 | 1.64 | 1.85 | 1.89 | 1.55 | 1.61 | 11％ | 90％ |
| C16 | 12.5 | 14.04 | 13.62 | 13.70 | 13.82 | 12.95 | 13.66 | 14.51 | 14.39 | 12.45 | 14.01 | 13.71 | 5％ | 110％ |
| C16OH | 0.4 | 0.23 | 0.23 | 0.21 | 0.21 | 0.27 | 0.20 | 0.25 | 0.29 | 0.48 | 0.23 | 0.26 | 32％ | 65％ |
| C18 | 2.3 | 1.20 | 1.24 | 1.10 | 0.97 | 1.12 | 1.14 | 1.35 | 1.60 | 1.47 | 1.35 | 1.25 | 15％ | 55％ |
| C18OH | 0.2 | 0.14 | 0.14 | 0.13 | 0.13 | 0.13 | 0.14 | 0.14 | 0.17 | 0.16 | 0.14 | 0.14 | 9％ | 70％ |
| C26：O-LPC | 1.2 | 1.00 | 1.08 | 0.80 | 1.24 | 1.35 | 1.65 | 1.23 | 1.39 | 0.90 | 1.42 | 1.21 | 21％ | 100％ |
| ORA | 0.5 | 0.33 | 0.67 | 0.45 | 0.58 | 0.72 | 0.51 | 0.54 | 0.45 | 0.63 | 0.49 | 0.55 | 21％ | 110％ |
TABLE 5-20 deg.C storage for 1 year high concentration dried blood spot quality control recovery rate and CV value
| Analyte | Configured concentration | HC35-1 | HC35-2 | HC35-3 | HC35-4 | HC35-5 | HC35-6 | HC35-7 | HC35-8 | HC35-9 | HC35-10 | Mean value | CV | Recovery rate |
| Ala | 1750 | 1479 | 1114 | 1450 | 2001 | 1710 | 1965 | 1845 | 1643 | 1777 | 1460 | 1637 | 18％ | 94％ |
| Arg | 420 | 363 | 281 | 346 | 349 | 333 | 452 | 400 | 421 | 368 | 343 | 369 | 14％ | 88％ |
| Cit | 300 | 322 | 258 | 332 | 319 | 305 | 425 | 400 | 380 | 372 | 341 | 350 | 14％ | 117％ |
| Gly | 2700 | 2578 | 2127 | 2595 | 3341 | 2613 | 2976 | 2673 | 2821 | 2346 | 2109 | 2618 | 15％ | 97％ |
| Leu\lle | 2000 | 1705 | 1447 | 1726 | 1898 | 1777 | 2010 | 1787 | 1977 | 1804 | 1763 | 1791 | 9％ | 90％ |
| Met | 360 | 269 | 211 | 239 | 295 | 277 | 315 | 235 | 275 | 272 | 251 | 262 | 12％ | 73％ |
| Orn | 860 | 9/9 | /38 | 895 | 925 | 980 | 1165 | 1005 | 1088 | 9/8 | 902 | 964 | 13％ | 112％ |
| Phe | 670 | 453 | 417 | 498 | 549 | 554 | 674 | 530 | 505 | 570 | 519 | 524 | 14％ | 78％ |
| Tyr | 1140 | 1432 | 1048 | 1281 | 1319 | 1458 | 1819 | 1397 | 1402 | 1600 | 1324 | 1402 | 15％ | 123％ |
| Val | 920 | 1048 | 576 | 875 | 845 | 901 | 1187 | 855 | 890 | 769 | 846 | 888 | 17％ | 97％ |
| Glu | 760 | 789 | 823 | 756 | 801 | 788 | 736 | 779 | 728 | 745 | 756 | 770.1 | 5％ | 101％ |
| SA | 15.0 | 13.3 | 12.4 | 14.3 | 17.5 | 13.8 | 14.2 | 15.5 | 12.2 | 14.3 | 15.1 | 14.2 | 11％ | 97％ |
| C0 | 280 | 301 | 221 | 283 | 288 | 273 | 404 | 334 | 349 | 336 | 305 | 314 | 16％ | 112％ |
| C2 | 153 | 131 | 103 | 129 | 130 | 150 | 187 | 166 | 152 | 136 | 136 | 141 | 17％ | 92％ |
| C3 | 27 | 26.2 | 21.6 | 25.1 | 27.4 | 26.2 | 34.2 | 26.5 | 32.2 | 25.8 | 25.4 | 27.1 | 14％ | 101％ |
| C4 | 7 | 4.1 | 3.2 | 3.3 | 3.8 | 4 | 5.2 | 3.8 | 4.1 | 3.8 | 3.4 | 3.8 | 16％ | 55％ |
| C3DC/C4OH | 5.8 | 5.50 | 5.42 | 5.37 | 5.47 | 5.32 | 5.56 | 5.43 | 5.47 | 5.39 | 5.34 | 5.44 | 12％ | 94％ |
| C5 | 3.2 | 2.0 | 1.5 | 1.7 | 1.7 | 1.8 | 2.5 | 1.9 | 2.2 | 2.0 | 1.9 | 1.9 | 16％ | 60％ |
| C4DC | 2.2 | 1.4 | 1.0 | 1.2 | 1.3 | 1.3 | 1.7 | 1.2 | 1.4 | 1.2 | 1.4 | 1.3 | 15％ | 60％ |
| C6 | 4 | 2.6 | 3.1 | 2.3 | 2.2 | 2.6 | 2.7 | 2.5 | 2.6 | 2.5 | 2.7 | 2.6 | 9％ | 65％ |
| C5DC/C6OH | 1.8 | 1.4 | 1.3 | 1.4 | 1.3 | 1.2 | 1.2 | 1.3 | 1.7 | 1.3 | 1.3 | 1.3 | 11％ | 72％ |
| C8 | 1.8 | 1.8 | 1.5 | 1.5 | 1.8 | 1.9 | 2.3 | 2.0 | 2.3 | 2.1 | 1.8 | 1.9 | 15％ | 105％ |
| C10 | 2.8 | 3.7 | 3.4 | 3.6 | 3.2 | 3.1 | 2.9 | 3.4 | 3.1 | 3.0 | 3.8 | 3.3 | 8％ | 118％ |
| C12 | 5.2 | 6.2 | 5.2 | 6.0 | 5.3 | 5.7 | 4.9 | 5.8 | 6.5 | 5.8 | 6.0 | 5.7 | 8％ | 110％ |
| C14 | 4.8 | 5.0 | 4.1 | 1.4 | 4.2 | 4.0 | 4.2 | 5.5 | 4.6 | 4.9 | 4.0 | 4.5 | 11％ | 94％ |
| C16 | 31.2 | 39.9 | 41.1 | 42.3 | 33.6 | 39.3 | 35.5 | 27.6 | 33.1 | 40.8 | 29.0 | 36.2 | 14％ | 116％ |
| C16OH | 2.5 | 1.69 | 1.42 | 1.64 | 1.65 | 1.5 | 2.05 | 2.00 | 2.45 | 1.81 | 1.37 | 1.8 | 25％ | 72％ |
| C18 | 5 | 3.0 | 2.6 | 2.5 | 3.1 | 3.2 | 3.8 | 3.4 | 2.2 | 2.9 | 3.0 | 3.0 | 15％ | 60％ |
| C18OH | 1.6 | 1.50 | 1.36 | 1.64 | 1.43 | 1.0 | 1.08 | 1.10 | 1.92 | 1.07 | 1.16 | 1.3 | 23％ | 81％ |
| C26：O-LPC | 6 | 5.68 | 6.64 | 5.06 | 7.23 | 6.56 | 6.92 | 4.99 | 6.21 | 4.40 | 6.0 | 16％ | 100％ | |
| ORA | 10 | 9.16 | 6.67 | 7.93 | 8.31 | 10.84 | 11.97 | 9.00 | 8.34 | 8.34 | 8.28 | 8.9 | 17% | 89％ |
According to the test results in tables 4 and 5, under the condition of keeping at-20 ℃, after the dry blood spots are stored for one year, the recovery rate of each substance is 50-130%, the CV value is 35%, and the latest quality requirement of neonatal disease tandem mass spectrometry screening technical experts' consensus in 2019 at present is that the recovery rate is 40-140%, the CV value is less than 35%, and the long-term stability is more than 6 months. Therefore, the quality control product of the dried blood spots prepared by the invention meets the requirements of related indexes; the quality control product comprises 37 quality control indexes, and can meet indoor quality control requirements of four major metabolic disorders of amino acid metabolism (including urea cycle disturbance), organic acid metabolism, fatty acid oxidation metabolism and peroxisome.
And (3) integrating the test results: the uniformity and stability test of the blood spot quality control product meets the requirements of related indexes, the reproducibility of the blood spot preparation process is good, and the indoor quality control requirement of newborn screening can be met.
Although the present invention has been described with respect to the preferred embodiments, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (10)
1. The dry blood spot quality control product for newborn screening comprises a filter paper carrier and is characterized in that a blood working solution is soaked on the filter paper carrier, the blood working solution takes Chinese race blood as a matrix solution, the matrix solution and an extracting solution are mixed according to a certain proportion, and the extracting solution contains amino acid, free acyl carnitine, lysolecithin phosphatidylcholine, orotic acid and succinylacetone.
2. The dried plaque quality control material of claim 1 wherein said amino acids comprise 14 amino acids, each of alanine, arginine, citrulline, glycine, leucine, isoleucine, glutamic acid, methionine, ornithine, phenylalanine, proline, tyrosine, valine, and aspartic acid.
3. The dried plaque quality control material for neonatal screening of claim 1 wherein, the free and acyl carnitines include 20 kinds of carnitine, which are respectively free carnitine, acetyl carnitine hydrochloride, propionyl carnitine hydrochloride, malonyl carnitine/3-hydroxy-isovaleryl carnitine, butyryl carnitine hydrochloride, valeryl carnitine hydrochloride, glutaryl carnitine hydrochloride/3-hydroxy-caproyl carnitine, caproyl carnitine hydrochloride, adipoyl carnitine, caprylyl carnitine hydrochloride, lauroyl carnitine hydrochloride, myristoyl carnitine hydrochloride, palmitoyl carnitine hydrochloride, hydroxypalmitoyl carnitine hydrochloride, capryloyl carnitine/capryloyl carnitine hydrochloride, 3-hydroxyoctadecanoyl carnitine hydrochloride, C26 carnitine hydrochloride, succinoyl carnitine hydrochloride, and 4-hydroxybutyryl carnitine.
4. The dried blood spot quality control product for screening newborn infants according to claim 1, wherein the lysophosphatidylcholine is C26: 0-LPC.
5. The dried blood spot quality control for neonatal screening of claim 1, wherein the matrix fluid and the extract are mixed in a volume ratio of 9: 1, mixing.
6. The dried blood spot quality control for neonatal screening of claim 5, wherein said matrix fluid is blood type A and said filter paper carrier is Whatman 903 filter paper dried blood sheet.
7. A method of preparing a dried blood spot quality control for neonatal screening as claimed in any one of claims 1 to 6, comprising the steps of:
s1, preparing a standard product: preparing standard solutions of various target compounds, and then preparing mixed standards with corresponding concentrations in proportion;
s2, preparation of a blank filter paper sheet: placing the blank filter paper sheet in an oven for drying;
s3, preparation of dried blood spot quality control products: adding the mixed standard into the blood, and uniformly mixing to prepare blood working solution; transferring the blood working solution by using a liquid transfer gun, slowly adding the blood working solution to the filter paper printing ring, and transferring the blood to a clean room for natural air drying after the blood is primarily coagulated;
s4, controlling qualified blood spots: controlling the blood specimen to naturally infiltrate into the blood spot ring line, and enabling the diameter of the formed blood spot to cover the diameter of the seal ring.
8. The method for preparing a dried blood spot quality control product for neonatal screening of claim 7, wherein the step S1 is to prepare a standard solution with a low concentration by weight-weight method and a standard solution with a high concentration by mother liquor dilution method, and the target compounds and concentrations are controlled as follows:
the low control concentration of the alanine is 800-900 mu mol/L, and the high control concentration is 1600-2000 mu mol/L;
the low control concentration of arginine is 150-200 mu mol/L, and the high control concentration is 380-450 mu mol/L;
the low control concentration of citrulline is 80-120 mu mol/L, and the high control concentration is 250-350 mu mol/L;
the low control concentration of glycine is 800-1200 mu mol/L, and the high control concentration is 2500-3000 mu mol/L;
the low control concentration of leucine/isoleucine is 300-400 mu mol/L, and the high control concentration is 900-1100 mu mol/L;
the low control concentration of methionine is 90-140 mu mol/L, and the high control concentration is 310-400 mu mol/L;
the low control concentration of ornithine is 240-340 mu mol/L, and the high control concentration is 700-1000 mu mol/L;
the low control concentration of phenylalanine is 200-280 mu mol/L, and the high control concentration is 600-750 mu mol/L;
the low control concentration of proline is 500-650 mu mol/L, and the high control concentration is 1500-1750 mu mol/L;
the low control concentration of the succinylacetone is 3-7 mu mol/L, and the high control concentration is 12-18 mu mol/L;
the low control concentration of tyrosine is 300-420 mu mol/L, and the high control concentration is 950-1250 mu mol/L;
the low control concentration of valine is 310-450 mu mol/L, and the high control concentration is 800-1100 mu mol/L;
the low control concentration of the free carnitine is 80-140 mu mol/L, and the high control concentration is 240-310 mu mol/L;
the low control concentration of the acetyl carnitine hydrochloride is 50-82 mu mol/L, and the high control concentration is 120-180 mu mol/L;
the low control concentration of propionyl carnitine hydrochloride is 8-13 mu mol/L, and the high control concentration is 22-32 mu mol/L;
the low control concentration of malonyl carnitine is 1-1.7 mu mol/L, and the high control concentration is 4-6 mu mol/L;
the low control concentration of butyrylcarnitine hydrochloride is 2.2-3.2 mu mol/L, and the high control concentration is 5.5-8.5 mu mol/L;
the low control concentration of the valeryl carnitine hydrochloride is 0.9-1.5 mu mol/L, and the high control concentration is 2.6-3.8 mu mol/L;
the low control concentration of the glutaryl carnitine hydrochloride is 0.55-0.85 mu mol/L, and the high control concentration is 1.5-2.1 mu mol/L;
the low control concentration of the caproyl carnitine hydrochloride is 0.48-0.72 mu mol/L, and the high control concentration is 1.5-2.1 mu mol/L;
the low control concentration of the adipyl carnitine is 0.9-1.5 mu mol/L, and the high control concentration is 3.2-4.8 mu mol/L;
the low control concentration of the octanoyl carnitine hydrochloride is 0.48-0.72 mu mol/L, and the high control concentration is 1.5-2.1 mu mol/L;
the low control concentration of the decanoyl carnitine hydrochloride is 0.8-1.2 mu mol/L, and the high control concentration is 2.3-3.3 mu mol/L;
the low control concentration of lauroyl carnitine hydrochloride is 1.28-1.92 mu mol/L, and the high control concentration is 4.2-6.2 mu mol/L;
the low control concentration of the myristoyl carnitine hydrochloride is 1.44-2.16 mu mol/L, and the high control concentration is 4.2-5.4 mu mol/L;
the low control concentration of the palmitoyl carnitine hydrochloride is 10-15 mu mol/L, and the high control concentration is 25-37 mu mol/L;
the low control concentration of the hydroxy palmitoyl carnitine hydrochloride is 0.32-0.48 mu mol/L, and the high control concentration is 2-3 mu mol/L;
the low control concentration of the octadecanoyl carnitine is 2-2.7 mu mol/L, and the high control concentration is 4-6 mu mol/L;
the low control concentration of the 3-hydroxyoctadecanoyl carnitine is 0.16-0.4 mu mol/L, and the high control concentration is 1.2-2.0 mu mol/L;
the low control concentration of the orotic acid is 0.24-0.36 mu mol/L, and the high control concentration is 8-12 mu mol/L;
the low control concentration of the glutamic acid is 220-340 mu mol/L, and the high control concentration is 700-800 mu mol/L;
the low control concentration of the aspartic acid is 200-300 mu mol/L, and the high control concentration is 680-760 mu mol/L;
the low control concentration of the C26 carnitine hydrochloride is 1-1.5 mu mol/L, and the high control concentration is 5-7 mu mol/L;
c26, wherein the low control concentration of 0-LPC is 1-1.5 mu mol/L, and the high control concentration is 5-7 mu mol/L;
the low control concentration of the succinyl carnitine hydrochloride is 1.85-2.65 mu mol/L, and the high control concentration is 5.4-7.4 mu mol/L;
the low control concentration of the 4-hydroxybutyryl carnitine is 1.2-1.8 mu mol/L, and the high control concentration is 5-6.6 mu mol/L.
9. The method for preparing a dried blood spot quality control product for neonatal screening of claim 7, wherein said step S2 comprises baking the blank filter paper sheet in an oven at 65 ℃ for 1.5 h.
10. The method for preparing a dried blood spot quality control product for neonatal screening as set forth in claim 7, wherein said step S3 is to control the height of the pipette tip from the center of the filter paper sheet to be 1-2cm, and said step S4 is to control the diameter of the blood spot to be 10-12mm by slowly dropping blood at one time.
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| CN117074589A (en) * | 2023-08-23 | 2023-11-17 | 山东英盛生物技术有限公司 | Method for detecting succinylacetone, amino acid and carnitine in maternal amniotic fluid |
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| CN106483208A (en) * | 2015-09-02 | 2017-03-08 | 实验室***诊断有限公司 | For detecting new method and the test kit of urea cycle disorder using mass spectrography |
| CN107144453A (en) * | 2017-05-24 | 2017-09-08 | 广州金域医学检验中心有限公司 | Amino acid and the dry blood cake quality-control product of fatty acyl carnitine and preparation method thereof |
| CN112379017A (en) * | 2020-11-02 | 2021-02-19 | 苏州新波生物技术有限公司 | Screening kit for non-derivatization multiple neonatal hereditary metabolic diseases |
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| CN106483208A (en) * | 2015-09-02 | 2017-03-08 | 实验室***诊断有限公司 | For detecting new method and the test kit of urea cycle disorder using mass spectrography |
| CN107144453A (en) * | 2017-05-24 | 2017-09-08 | 广州金域医学检验中心有限公司 | Amino acid and the dry blood cake quality-control product of fatty acyl carnitine and preparation method thereof |
| CN112379017A (en) * | 2020-11-02 | 2021-02-19 | 苏州新波生物技术有限公司 | Screening kit for non-derivatization multiple neonatal hereditary metabolic diseases |
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| CN117074589A (en) * | 2023-08-23 | 2023-11-17 | 山东英盛生物技术有限公司 | Method for detecting succinylacetone, amino acid and carnitine in maternal amniotic fluid |
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